2nd Annual ACE - 0 PDF

Preparing for and Handling an
FDA Inspection at Your Facility

Dawn Tavalsky
Sanofi Pasteur, Inc.
Objectives
FDAs Authority to Inspect
FDAs Authority to Inspect
Inspection Process
Centers and Offices
Office of the Commissioner Organization

g
g
Center for Biologics
Evaluation and Research Organization
Center for Devices and Radiological Health Organization.
Center for Drug Evaluation and Research Organization
Center for Food Safety and Applied Nutrition Organization.
Center for Tobacco Products Organization
Center for Veterinary Medicine Organization
National Center for Toxicological Research Organization
Office of Regulatory Affairs Organization
Organization.
Office of Regulatory Affairs (ORA)

http://www.fda.gov/ora/
Headquarters:
Rockville, MD
Regional Office:
Philadelphia, PA
District Office:
D
Detroit,
i MI
FDA Field Investigators
Conduct inspections to enforce the Food, Drug

and Cosmetic Act
Train themselves in evidence collection
If its not documented, it didnt happen.
10
FDA Inspection Process

FDA Office
Site Location
1. Select Site
4. Arrive (482)
2. Contact Site
5. Review Records
3. Schedule Site
6. Interview Staff
9. Write Report (EIR)
7. Present Findings
10. Classify Inspection
8. Depart (483)
11
Overview of FDA Enforcement Actions
12
FDA Forms
13
14
15
16
Selection Criteria
17
Preparing for the Audit
18
While there are several types of audits with several

different types of focus:
Annuall Flu
A
Fl Vaccine
V
i
Bi-annual audit
Pre Approval Inspection (PAI)
For Cause Audit
Etc
We will now discuss preparing for a PAI inspection

however many of the points apply to any type of FDA
audit.
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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
Quality Management System

Aseptic Processing
Presented by: Karen S Ginsbury
PCI Pharmaceutical Consulting Israel Ltd
For IVT ACE Conference
A t d
Amsterdam,
October
O t b 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
and develop a robust QMS for

y Aseptic Processing
3
Part I: Regulations, Revisions and

Guidance
y 21 CFR: US GMPs on aseptic
processing and latest revisions

y Annex 1: EU GMPs on aseptic
processing: February 2008
version
y FDA Aseptic Processing Guide
(2004)
4
10/3/2011
II. Aseptic Product and Process

Lifecycle
y ICH Q8: Product Development:
y Target
T
t Product
P d t Profile
P fil
y Critical Quality Attributes (CQA)
y Linking Parameters to CQAs
y Risk Assessment
y Control Strategy
y Lifecycle Management
y ICH Q9: Risk Management
5
III ICH Q10 Developing a Robust

Quality System for Aseptic Processing
y Investigational Product
Sterility Assurance Issues

y Personnel Training
y Validation, Operation and
Environmental Controls
y CAPA and Control Strategy
y Deviation
y Change Control
6
10/3/2011
Interactive Bit! (to be all along)

Develop a CAPA system
y develop a reporting and
assessment system for

monitoring the quality metrics of
an aseptic operation
y KPIs and feed items
7
Create Your Own Map (KPIs)

What items need to be controlled
10/3/2011
g
regulations
Aseptic Processing - Sterilization
y Section 211.67(a) Equipment cleaning and
maintenance is being revised to add the

phrase and/or sterilized after the word
sanitized in the current regulation
y This change updates the terminology to
reflect the fact that, in the context of sterile
drug products
products, the appropriate form of
sanitization would be sterilization
y This is consistent with our interpretation of this
regulation for more than 20 years and reflects
the
currently accepted industry practice
KPIs for depyrogenation

tunnel
y Temperature
y Time
y Air quality (post cycle: particles
10
well now / depends Karen

says YES!)
y Line speed
y Direction of air flowing into the
tunnel
10/3/2011
2008 / 9 Changes to GMP

regulations
Aseptic Processing Microbial Controls
y Section 211.84(d)(6) Testing and approval
or rejection of components drug product

containers, and closures, is being revised
to change the phrase that is liable to
microbiological contamination, to with
potential for microbiological contamination
y We believe this revision provides additional
clarity without changing the meaning or
intent of the regulation
11
KPIs on microbial specs

y Look at trends on incoming
materials
t i l / components
t
12
10/3/2011
Changes to GMP regulations

Aseptic Processing - Depyrogenation
y Section 211.94(c) Drug product containers and closures
13
is being revised to clarify that validation is required for

the depyrogenation processes
y To assure that certain drug products are suitable for
their intended use, drug product containers and
closures are required to be sterilized and
depyrogenated to remove microbial contamination and
pyrogens or endotoxin
y It has been longstanding industry practice to validate
the sterilization and depyrogenation processes to
assure consistent removal of microbial contamination
and pyrogens or endotoxin
y Lack of evidence of such validation and inadequacies in
the validation studies have been cited in FDA actions
throughout the years based on this regulation.
PCI Pharmaceutical Consulting
Israelsimply
Ltd
Accordingly,
this rule
clarifies 211.94(c) by
adding a new sentence at the end which states:Such

14
y Industry Objections Risk Management

y Where containers and closures are actively
y
rendered non-pyrogenic by a designated
depyrogenation process, the depyrogenation
process shall be validated
y Not ALL containers and closures require active
depyrogenation
y Some containers and closures are non-pyrogenic
by nature and/or design of their manufacturing
process(es) or have been qualified not to require
active depyrogenation
y Handling procedures are also designed and
controlled (e.g., bulk packaging, incoming parts
control, storage, personnel control) to minimize the
risk of pyrogen contamination during finished
10/3/2011

Aseptic Processing - Bioburden
y Paragraph
g p ((a)) of 211.110 Sampling
p g and
testing of in-process materials and drug

products is being revised to include
bioburden process control procedures and
tests, where appropriate
y The re
revised
ised reg
regulation
lation will
ill add biob
bioburden
rden
testing as the sixth example of process
control procedures (five others are already
listed)
15

Aseptic Processing Microbial
Control
y Paragraph (b) of 211.113
211 113 Control of
microbiological contamination is being

revised to include validation of aseptic
processes for drug products that are
purported to be sterile
y The current regulation mentions only
validation of sterilization processes, not
aseptic processes
16
10/3/2011

Control
y Even before 1987, when the Guideline for
17
18
Sterile Drug Products Produced by Aseptic

Processing was issued, industry routinely
conducted validation studies that substituted
microbiological media for the actual product to
demonstrate that its aseptic processes were
parts of validation studies are
validated. These p
often referred to as media fills. We believe that
this revision clarifies existing practices and
serves to harmonize the CGMP requirements
with Annex 1 of the EU GMPs, which requires
such
validation
10/3/2011
KPIs for microbial control

y Trending of EM data
y Trending of personnel monitoring
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
Main Changes
y Particulate Classification
(Airborne particles 5 micron)

y Media Simulations
y Bioburden monitoring
y Capping of (Freeze-Dried)
(Freeze Dried) Vials
20
10
10/3/2011
Previous
Now
21
Cleanroom and clean air device monitoring:

RISK ANALYSIS REQUIRED!
y Cleanrooms and clean air devices
should be routinely monitored in

operation and the monitoring
locations based on a formal risk
analysis study and the results
obtained during the classification
of rooms and / or clean air devices
22
11
10/3/2011
Duration of Monitoring
y 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)
y 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
y 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
23
Sample Size
24
12
10/3/2011
Media Simulations: Previous Acceptance Criteria
y The target should be zero
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
Media Simulations: Acceptance Criteria
26
13
10/3/2011
Bioburden: Added Text

y Bioburden assay should be performed on
each batch for both aseptically

p
y filled and
terminally sterilised products
y For overkill sterilisation products, bioburden
might be monitored only at suitable scheduled
intervals
y For p
parametric release systems,
y
, bioburden
assays should be performed on each batch
and considered as an in-process test
27
Capping of Freeze Dried Vials Added

Text
y Partially stoppered freeze drying
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
FDA Aseptic Processing

Guide
29

Guide
30
15
10/3/2011
(K)PIs for ISO 5 areas

y Airflows: patterns operational and compare to
previous
y Velocity
y Number of air changes in surrounding room:
31
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

Guide
32
16
10/3/2011
(KPIs) for Time limitations in

production
y Look at unit operations and gather
data to support maximum time

periods
y Visual inspection of any sterilized
item immediately prior to use for
g y of p
package
g
integrity
y KPI media fills and lack of sterility
test failures (which is a lousy KPI)
y KPI: environmental monitoring
33
KPIs for personnel

y Monitoring
y Supervision
p
y Media fills
y Gowning qualification
y GMP refreshers / micro / aseptic: frontal
training and demonstrations / tests of

some kinds
y On-the-job
O th j b evaluations
l ti
with
ith respectt tto
specific procedures / SOPs / written
instructions (aseptic review/ process
confirmation documented reviews)
34
17
10/3/2011

Guide
35

Guide
36
18
10/3/2011
KPIs on validation / qualification/ calibration

/ PM / malfunction maintenance
y Number and frequency of machine
37
malfunctions and review of PM

records
y Ensure that we capture data
relating to maintenance operations
in useable and trend-able formats
develop documentation that
supports this
y Any failures are captured and
placed in our trending systems

Guide
38
19
10/3/2011
(K)PIs for the aseptic process

itself
y Data pertaining to: the Sterilization process
y Steam (autoclave)
y Dry heat (depyrog)
y Ethylene oxide
Have a validated stencil for the chart record

INVESTIGATE ALL deviations from that stencil as representing a
shift
y Filtration
y
y
y
y
y
y
y
Sterilization process for filter

Wetting out of filter before start of filtration
Integrity
g y before and after
Pressure differential during
Time of filtration
Volume of filtrate
bioburden
y gamma
39
Part II Product Development

Target Product Profile
Critical Quality Attributes (CQAs)
Linking CQA to Production Parameters
Risk Assessment
Control Strategy
Lifecycle Product Management
40
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 A measured variable that
y physical, chemical,
has a known effect upon a biological, or

product quality attribute
microbiological property
or characteristic
y A process parameter that
mustt be
b controlled
t ll d within
ithi a y that
th t should
h ld be
b within
ithi an
specified range to assure
appropriate limit, range,
product quality
or distribution
y to ensure product quality
42
21
10/3/2011
Product and Process and

Variation
Sterility (Y): CQA affected by Variable Inputs (X)
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
Inputs to the process

control variability
of the Output
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
Adapted from slide by Moheb Naser, FDA
44
22
10/3/2011
Control Strategy
y Control Strategy
45
A planned set of controls, derived from

currentt product
d t and
d process
understanding, that assures process
performance and product quality.
y The controls can include parameters and
attributes related to drug substance and
drug
gp
product materials and components,
p
facility and equipment operating
conditions, in-process controls, finished
product specifications, and the associated
methods and frequency of monitoring and
PCIcontrol
Pharmaceutical Consulting Israel Ltd
TPP continued
y Considerations for the target product
profile should include:

p
y Dosage form and route of administration

y Dosage form strength(s)
y Therapeutic moiety release or delivery
and pharmacokinetic characteristics

(e.g., dissolution; aerodynamic
performance) appropriate to the drug
product dosage form being developed
y Drug product quality criteria (e.g.,
sterility, purity) appropriate for the
intended marketed product
46
23
10/3/2011
Risk Assessment, CQAs, Process

Parameters
y Risk assessment early in development identifies:
y Material attributes
y Process parameters
that have an effect on CQAs
y Repeat the risk assessment as development
progresses / knowledge is gained
y Identify and rank parameters (e.g., operational,
equipment, input material) with potential to have an

impact on product quality based on prior knowledge
and initial experimental data
y Initially long list, narrowed down as process
understanding increases and through DOE
(understand interaction of variables)
47
Risk Ranking Table

Risk Category
Ranking /
Definition
Severity
SEV
Likelihood of
Occurrence
OCC
Low
Medium
High
If the event occurs

and is not
detected it is NOT
likely to harm the
patient
If the event occurs

and is not detected it
may cause
moderate harm to
the patient
Direct and severe

impact to the
patient; life
threatening
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
If the event occurs

If the event occurs If the event occurs
there is a HIGH
it might be
it probably will
likelihood of
detected
NOT be detected
DET
PCI Pharmaceuticaldetection
Consulting Israel Ltd
48
Likelihood of
Detection
24
10/3/2011
Risk Priority Number

Scale 1 - 5
RPN
< 10 ?
SEV x
OCC X
DET
11 29 ?
30 ?
49
Sterility Control Strategy
50
25
10/3/2011
Lifecycle Product
Management
Developmen
t
CAPA
Annua
l
Produ
ct
Revie
w
51
Process
validation
Commerci
al
ICH Q10 Robust Quality System

for Aseptic Processing
Investigational Product
Sterility Assurance Issues
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
Personnel Training - KPIs

y Deviation operator error: recurrence
y Sterile Product
y (Capacity data)
y Testing of employee training
y On the Job evaluation
y Compliance to curriculum
y Certification
y Gowning results / EM data
y Media fill participation
y Health Reporting
54
27
10/3/2011
Validation - KPIs
55
EM - KPIs
56
28
10/3/2011
Deviations, Complaints, Rejected Batches KPIs
57
29
Points to Consider When

Investigating Environmental
Monitoring Failures
Dawn Tavalsky
Environmental Monitoring Components

Airborne nonviable particulate monitoring
Airborne viable contaminant monitoring
Viable
Vi bl contaminant
t i
t monitoring
it i off surfaces
f
Viable contaminant monitoring of personnel
Temperature and humidity monitoring
Pressure differential monitoring
Environmental Monitoring Components

Water monitoring:
Total organic carbon
C d ti it
Conductivity
Microbial Contaminants
Endotoxin
General Environmental Monitoring

Considerations
Monitoring frequencies and strategies
Establishment of a meaningful and manageable program
Sampling and testing procedures

Establishment of effective alert and action limits
Trending of results
General Environmental Monitoring

Considerations
Investigation and evaluation of trends as well as
excursions from alert and action limits
C
Corrective
ti actions
ti
to
t be
b implemented
i
l
t d in
i response to
t
environmental monitoring excursions
Personnel training - sampling, testing, investigating
excursions, aseptic technique
Scope of Environmental Monitoring Program

Should include monitoring of all environments where
products and their components are manufactured
All areas where
there
is
contamination
h
h
i a risk
i k off product
d
i
i
Should include monitoring of all water used for product

manufacturing as well as feed water to the final water
purification system (WFI System)
Regulatory Basis for Environmental Monitoring

Program
CFR GMP regulations
FDA Guidance Documents
USP IInformational
f
ti
l Chapter
Ch t
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.
Guideline on Sterile Drug Products Produced by

Aseptic Processing
Defines critical and controlled manufacturing areas
Recommends airborne nonviable and viable
contaminant
t i
t limits
li it
Provides some guidance on monitoring frequencies for
critical areas
10
Guideline on Sterile Drug Products Produced by

Aseptic Processing
Recommendations for air pressure differentials
Includes guidance on aseptic media fills
N t Thi
Note:
This guidance
id
document
d
t was written
itt iin 1987 and
d
is in need of revision
11
Microbial Evaluation and Classification of Clean Rooms and

Clean Zones
USP General Information Chapter <1116>

Establishment of clean room classifications
Federal
F d
l Standard
S
d d 209E
Importance of EM program
Personnel training in aseptic processing
Establishment of sampling plans and sites
suggested sampling frequencies
12
Microbial Evaluation and Classification of Clean Rooms and

Clean Zones
Establishment of alert and action limits

Suggests limits for airborne, surface and personnel
contaminant
t i
t levels.
l
l
Methods and equipment for sampling
Identification of isolates
Aseptic media fills
Emerging technologies - barrier; isolator
13
Federal Standard 209E

Airborne Particulate Cleanliness Classes in Clean
Rooms and Clean Zones
Approved
A
d by
b the
th GSA for
f use by
b all
ll Federal
F d l Agencies
A
i
Frequently referenced for controlled environment
particulate requirements: Classes 100, 10,000 and
100,000 (based on particles > 0.5)
14
Guidance for Industry for Sterile Validation Process Validation in

Applications for Human and Veterinary Drug Products
Scope limited to final drug product manufacturing and data

required for application submission (NDA, BLA)
Requests
q
information on:
Buildings and facilities
Manufacturing operations for drug product
Filter validation
Validation of hold times
15
Guidance for Industry for Sterile Validation Process Validation in

Applications for Human and Veterinary Drug Products
Requests information on:

Sterilization and depyrogenation
Media fills and actions taken when they fail
Microbiological monitoring of the environment
Airborne microorganisms, personnel, surfaces, water system,
product component bioburden
Yeasts, molds, anaerobes

Exceeded EM limits
16
Viable and Nonviable Contaminant Limits
Classifi- Nonviable (>0.5)

cation ft3
m3
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
Nonviable Particulate Monitoring

Airborne cleanliness classifications should be met
during operations
Nonviable
N
i bl monitoring
it i should
h ld occur routinely
ti l during
d i
operations
Monitoring during static conditions is done as part of
HVAC qualification and may be done periodically after
that to insure area meets acceptable conditions before
use or following cleaning
22
11

Locations for monitoring should be established during
performance qualification; probes placed close to work
surface
f
Monitoring frequencies vary:
For aseptic processing areas, during each use
For other, controlled areas, varies from each use to weekly
or less depending on use of area
23

HVAC Validation and Maintenance Considerations:
Air velocity, airflow patterns and turbulence should be
validated; smoke studies to determine flow patterns during
static and dynamic conditions
HEPA filter integrity testing
HEPA filter efficiency testing
Air pressure differentials
24
12
Microbial Monitoring
Airborne viable contaminants
Surface contaminants
walls
ll
equipment surfaces
countertops
floors
Personnel contaminants
25
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)
All lots of media for EM sampling should be growth

promotion tested
26
13
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
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
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
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
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
Should also establish common flora - will aid in

investigations
31
Setting Alert and Action Limits

Action limits (for the most part) have been established
in a variety of guidance documents
Alert
Al t limits
li it
Lower than action limits
Reflect actual historical results under normal processing
conditions
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
In response to excursions outside the

action limits and out-of-trend results
the following will be reviewed:
Videntification of the isolates & a
determination of their possible origin
Van investigation of the status of the
environmental control systems
V the occurrence of atypical activity in
the processing area
36
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
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
Investigations and Corrective Actions

The investigation procedures to be followed should be
pre-established and included in SOPs
Depending
off the
D
di on the
th outcome
t
th investigation,
i
ti ti
corrective actions should be pre-established to the
extent possible
40
20
Investigations and Corrective Actions

Imperative that EM results be linked to product release
so that affected products are not released until
i
investigation
ti ti completed
l t d
Material Review Board or equivalent should be
consulted prior to releasing product that was
potentially affected by adverse environmental
conditions
41
Corrective Actions
V Additional environmental controls

p g
V more intense sampling
V revision to aseptic practices
V review of cleaning & sanitization
practices
V determine sensitivity of the isolate to
disinfectant
V enhanced supervision
V retraining of clean room personnel
V additional product testing
42
21
Corrective Actions
Development off a check list

i is
i strongly
recommended to document the
corrective actions
V Laboratory and manufacturing
investigation reports needed to justify
continued production and release of
product
V
43
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
Temperature and Humidity

Control of temperature and humidity required for
aseptic processing areas
21 CFR 211
211.42(c)(10)(ii)
42( )(10)(ii)
Generally 65 F and 35-50% humidity are average

Too high - Increases personnel shedding
Too low - Increase static electricity
45
Temperature and Humidity

Temperature should be controlled throughout all
manufacturing areas
Temperature
and
T
t
d humidity
h idit should
h ld be
b monitored
it
d and
d
controlled in warehouse areas where
temperature/humidity sensitive raw materials are
stored
If not able to control humidity, need procedure to follow if
humidity exceeds limit
46
23
Water Requirements
Test
TOC
Conductivity
Micro
Micro.
Purity
EndoToxin
Potable Purified WFI

Water Water
none
500 ppb 500 ppb
none
See USP Table
500
CFU/ml
100
CFU/ml
none
none
10 CFU/
100 ml
0.25
EU/ml
47
Water For Injection

Defined by USP
Water purified by distillation or reverse osmosis
Prepared
water
with
the U
U.S.
P
d from
f
t complying
l i
ith th
S EPA
National Primary Drinking Water Regulations
Contains no added substance
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
Water System Monitoring

WFI Systems
Microbial quality and endotoxin
Daily system monitoring
Each use point at least weekly
TOC and Conductivity

Weekly system monitoring
can be taken from worst case point (end of loop, return to tank)
51
Water System Monitoring

Purified Water Systems
Weekly monitoring of system for:
microbial
i bi l quality
lit
TOC
conductivity
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
Microbial Monitoring Devices

Slit-to-Agar (STA) - Powered by vacuum, air taken in
through a slit below which is a slowly revolving plate.
Sieve
draws
in
Si
iimpactor
t - Vacuum
V
d
i air
i through
th
h
perforated cover which is impacted onto petri dish
containing nutrient agar
56
28

Centrifugal Sampler - consists of a propeller that pulls a
known volume of air into the unit and then propels the
air
i outward
t
d to
t impact
i
t on a nutrient
t i t agar strip
ti
Sterilizable Microbiological Atrium (SMA)- similar to sieve
impactor; cover contains uniformly spaced orifices;
vacuum draws in air which is impacted on agar plate
57

Surface Air System Sampler - An integrated unit
containing an entry section with an agar contact plate;
behind
b hi d is
i a motor
t and
d turbine
t bi that
th t pulls
ll air
i in
i through
th
h
the perforated cover and exhausts it beyond the motor.
Settle plates - qualitative; may be useful in worst case
locations
58
29

Surface contaminant monitoring devices:
Contact Plates - plates filled with nutrient agar; for regular
surfaces
Swabs - useful for hard to reach or irregular surfaces; swab
placed in suitable diluent and inoculated onto
microbiological plate
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
Must validate growth promotion after exposure of settle

plates (or other plates) for prolonged time periods.
60
30
Fluid flow and Cleaning

Validation A Turbulent
Relationship
Jeffrey Felker
Dawn Tavalsky
Fluids in Motion
Fluids can move or flow in many ways.

ways
Water may flow smoothly and slowly in a quiet stream
or violently over a waterfall.
The air may form a gentle breeze or a raging tornado.
To deal with such diversity, it helps to identify some of
the basic types of fluid flow.
flow
Steady or Unsteady Fluid Flow
In steady flow the velocity of the fluid particles at

any point is constant as time passes.
passes
Unsteady flow exists whenever the velocity at a
point in the fluid changes as time passes.
3
Turbulent Flow
Turbulent fflow is an extreme kind of

unsteady flow and occurs when there
are sharp obstacles or bends in the path
of a fast-moving fluid.
In turbulent flow, the velocity at a point
changes erratically from moment to
moment both in magnitude and
moment,
direction.
Compressible or Incompressible Fluid Flow
Most liquids are nearly incompressible; that is, the density of a

liquid remains almost constant as the pressure changes.
To a good approximation, then, liquids flow in an
incompressible manner.
In contrast, gases are highly compressible. However, there are
situations in which the density of a flowing gas remains
constant
t t enoughh that
th t the
th flow
fl can be
b considered
id d
incompressible.
Viscous or Nonviscous Fluid Flow

A viscous fluid, such as honey, does not flow readily and is
said to have a large
g viscosity.
y
In contrast, water is less viscous and flows more readily;
water has a smaller viscosity than honey.
The flow of a viscous fluid is an energy-dissipating process.
A fluid with zero viscosity flows in an unhindered manner
with no dissipation of energy.
energy
Although no real fluid has zero viscosity at normal
temperatures, some fluids have negligibly small viscosities.
An incompressible, nonviscous fluid is called an ideal fluid.
6
Streamline Flow
When the flow is steady, streamlines are often used to represent

the trajectories of the fluid particles.
A streamline is a line drawn in the fluid such that a tangent to the
streamline at any point is parallel to the fluid velocity at that point.
Steady flow is often called streamline flow.
7
(a) In the steady flow of a liquid, a colored dye reveals the

streamlines (b) A smoke streamer reveals a streamline
streamlines.
pattern for the air flowing around this pursuit cyclist, as he
tests his bike for wind resistance in a wind tunnel.
The Equation of Continuity
Q: Have you ever used your thumb to control the water flowing
f
from
th
the endd off a hose?
h ?
The Equation of Continuity
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
For steady flow, the speed, pressure, and elevation of an

incompressible and nonviscous fluid are related by an equation
discovered by Daniel Bernoulli (17001782).
13
Bernoullis Equation
In the steadyy flow of a nonviscous,, incompressible

p
fluid of
density , the pressure P, the fluid speed v, and the elevation
y at any two points (1 and 2) are related by
14
Applications of Bernoulli's Equation
The tarpaulin that covers the cargo is flat when the truck is
stationary but bulges outward when the truck is moving.
15
Household Plumbing
In a household plumbing system, a vent is necessary to equalize the

pressures at points A and B, thus preventing the trap from being
emptied. An empty trap allows sewer
gas to enter the house.
16
Curveball Pitch
17
Airplane
18
Images - Laminar/Turbulent Flows
Laser - induced florescence image of an

incompressible turbulent boundary layer
Laminar flow (Blood Flow)
Simulation of turbulent flow coming out of a

tailpipe
Turbulent flow
Laminar flow
19
http://www.engineering.uiowa.edu/~cfd/gallery/lim-turb.html
Lets Discuss Turbulent Flow
20
10
21
22
11
23
Criterion for Turbulent vs. Laminar Flow in a Pipe

The behavior of flow in pipes is determined by the Reynolds
number Re.
Flow tends to become turbulent when Re > 3000.

Flow is always laminar when Re < 2000.
For 2000 < Re < 3000, the behavior is unpredictable and
often switches back and forth between laminar and
t b l t
turbulent.
When conditions are carefully controlled so that the flow
is perfectly motionless at the inlet of the pipe and the pipe
is free of vibrations, then it is possible to maintain laminar
flow even at Re > 3000. 24
12
Shear stress distribution across a pipe section
For steady, uniform flow, the momentum balance in s for

the fluid cylinder yields
25
Turbulent flow is less efficient than laminar flow:
Velocity profile
for turbulent flow
Velocity profile
if flow were laminar
everywhere
Thin, laminar boundary layer

If flflow could
ld remain
i llaminar,
i
th
the pipe
i could
ld ttransportt more
fluid for a given pressure gradient.
The swirls and eddies associated with turbulence make
the fluid appear as though it had a much higher viscosity
26
where flow is turbulent.
13
Energy Loss in Valves

Function of valve type and valve position
The complex flow path through valves can
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
Flow at pipe inlets and losses from fittings
Rounded inlet
Sharp-edged inlet
Head loss for inlets, outlets, and fittings:
where K is a parameter that depends on the geometry.

For a well-rounded inlet, K = 0.1, for abrupt inlet K = 0.5
(much less resistance for rounded
inlet).
28
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
Energy Loss due to Gradual Expansion
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 )
Reynolds number based on

orifice diameter Red
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
Boundary layer buildup in a pipe

Because of the shear force near the pipe wall, a boundary layer
forms on the inside surface and occupies a large portion of the
flow area as the distance downstream from the pipe entrance
i
increase.
At
A some value
l off this
hi distance
di
the
h boundary
b
d
layer
l
fills
fill the
h
flow area. The velocity profile becomes independent of the axis in
the direction of flow, and the flow is said to be fully developed.
Pipe
Entrance
34
17
Pipe Flow Head Loss

(constant density fluid flows)
Pipe flow head loss is

proportional to the length of the pipe
proportional to the square of the velocity
(high Reynolds number)
Proportional inversely with the diameter of

the pipe
increasing with surface roughness

independent of pressure
Total losses in the pipe system is obtained by
summing individual head losses of
roughness, fittings,
f
valves ..itc
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
Reynolds Number Calculation

Diameter D
Viscosity
D
Density
it
Velocity V
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 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
Circuit Volume (L)
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
Adequate turbulence (Flow rate) for CIP
ft/sec
5 ft/sec
5 ft/sec
70
35
10/5/2011
Writing SOPs and Batch Records

WritingSOPsandBatchRecords
Writing SOPs and Batch

Records--Robert Pallo
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
y Doit

y Doit
y Writeit

10/5/2011
y Doit
y Writeit
y Testit

y SOPWritingEssentials

10/5/2011
y Be Brief

y AskemployeesusingtheSOPfortheirinput

10/5/2011
y Prepareafirstdraft

y Runawalkthrough

10/5/2011
y Runawalkthrough
y Solicitfeedbackandmakecorrections

y Runawalkthrough
y Solicitfeedbackandmakecorrections
y Makeitofficial!

10/5/2011
y BenefitsofsolidSOPs

y Decreasetrainingtime

10/5/2011
y Increaseconsistency

y FulfillCompliancerequirements

10/5/2011
y Communicateeffectivenessmeasures

y Retainandtransferknowledge

10/5/2011
y Documentimprovementandchange

y Documentimprovementandchange
y Decreaseerrorrate

10
10/5/2011
y UnderstandingtheProcess
y BallisticProcess
y
y
y
Characteristicofthemotionofobjectsmovingundertheir
ownmomentum
Ifthereisnowaytoprovidefeedbacktochangeoradjusta
process,thisisaballisticprocess
TheBallisticProcessismostcommon
E.g.Anautoclavecycle;amanufacturingprocedure

y BallisticProcess
y Controlledprocess
y
Monitortheinputsandoutputsandmakecorrectivechanges
totheprocessinordertoachievethedesiredoutput
E.g.afillingmachinewherethefillweightisconstantly
adjusted.

11
10/5/2011
y BallisticProcess
y Controlledprocess
y AdaptiveProcess
y
y
y
Aprocessthatlearns
Canchangeovertimetoimproveeffectiveness
E.g.allowsausertoidentifyiftheprocessneedsmodification
andtheycanhavetheoptiontoupdatetheprocedure
NotagoodGMPidea

y WritingaProcedure
y Discovery
y Design
y Development
y Deployment

12
10/5/2011
y WritingaProcedure
y Discovery
y
y
Understandtheproblemorprocess
Aprocedureisneededtodescribethestepsofabusiness
process.Sobeforewecanwritethat,weneedtodiscoverwhat
isexpected.
Needtounderstand
y Whoarethesources/resources
y Whataretheinputsandoutputs
y Whoarethecustomers
y Whataretheeffectivenesscriteria
y Whatisthecorrectiveactioniftheprocessdoesntwork

y WritingaProcedure
y Discovery
y Design
y
y
y
y
Thisiswhereyouspendyourtime
Aprocessmapwillhelpcommunicatetheproceduraldesign
andcollectfeedbackbeforewewriteoutthewrittensteps
Performawalkthroughwiththedesign
RememberPDCA(PLAN DO CHECK ACT)

13
10/5/2011
y WritingaProcedure
y Discovery
y Design
y Development
y
Importantquestion:Whoistheaudience?Novices,
occasionalusersorfrequentusers?

y WritingaProcedureforfrequentusers
y Donotrequirealotofexplanation
y Mightonlyneedachecklist
y Priorityisnavigationratherthanexplanation

14
10/5/2011
y WritingaProcedureforoccasionalusers
y Maynotnecessarilybeexperienced
y Mayfillinforsomeonefromtimetotime
y Mayrequiremoreexplanationorsomehowandwhy
y Priorityisexplanation,notnavigation

y WritingaProcedureforthenovice
y Leaveoutthedetail
y Makeitastepbystepprocedure
y Providethedetailsinanaccompanyingtraining
document
y and

15
10/5/2011
y WritingaProcedureforthenovice
y Leaveoutthedetail
y Makeitastepbystepprocedure
y Providethedetailsinanaccompanyingtraining
document
y and
y NoticethattheBESTSOPsarewritteninthisstyle!

y Reviewofthewrittenprocedure
y ThesevenCs
y
y
y
y
y
y
y
Context
Consistency
Completeness
Control
Compliance
Correctness
Clarity

16
10/5/2011
y WritingaProcedure
y Discovery
y Design
y Development
y Deployment

y Deployment
p y
y Training
y Auditing
y Continuousimprovement

17
10/5/2011

SOP
Writing
g Essentials
Be Brief
Be Clear and Concise


SOP
Writing Essentials
Be Brief
Clear and Concise
The shorter, the better

18
10/5/2011

SOP
Writing Essentials
Be Brief
Clear and Concise
SOPs should say what to do, not how to
do it


SOP
Writing Essentials
Be Brief
Clear and Concise
SOPs should say what to do, not how to
do it
Pictures are worth a thousand words

19
10/5/2011

Why
Do I Need SOPs?
Consistency
SOPs Reduce Variation
SOPs facilitate training
People can support SOPs (particularly if
they
y help
p write them))


Types
of SOPs?
Simple Steps or checklist

Easy to write and easy to follow.
Works well for well understood tasks

20
10/5/2011

Types
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

Types
of SOPs?
Annotated Pictures.
Works well when there are language
barriers.
Shortens complex and detailed SOPs

21
10/5/2011

Types
of SOPs?
Annotated Pictures.


When
to Write an SOP
If there are key areas of concern

Identify one or two top priority areas
for attention.
Apply the Pareto Rule

22
10/5/2011

LANGIAPPE (a little something extra!)
PARETOS LAW
Vilfredo Pareto ((1848-1923))
(a) 80 percent of the results are achieved by 20 percent of
the group.
(b) 20 percent of your effort will generate 80 percent of your
results.
(c) In any process, few elements (20 percent) are vital and
many elements
l
(80 percent)) are trivial.
i i l
(d) If you have to do ten things, two of those are usually worth
as much as the other eight put together.
(e) 20 percent of the tasks account for 80 percent of the value.
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

SOP
Format
Purpose and Scope

Definitions
Materials and equipment needed
Assignment of responsibility
Step
St
by
b step
t
procedure
d
References
Approval signatures

The
Standard Operating
g Form
Form
Gateway to Excellent SOP Compliance

24
10/5/2011

The
Standard Operating
g Form
Form
Gateway to Excellent SOP
Compliance
Includes the critical parts of a procedure
in a batch record format


The
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

SOF
Format
Step by step procedure

Indication of target parameters
Place to indicate actual data
Place to sign and date
Master Record approval signatures
Final Batch approval signatures

SOF
Tips
Do not make the form too busy

26
10/5/2011

SOF
Tips

Provide plenty of room to record data


SOF
Tips

Provide plenty of room to record data
Try to reduce the requirement for
signatures to an acceptable minimum

27
10/5/2011
STEP
OPERATION
Check cleaning log.
Perform a pre-production line clearance per

SOP 07007.
Sanitize stationary equipment as per SOP

07712 prior to set up.
All Operators / Personnel sign in / out

sheet.
C/B
Total number of technicians

present at one time:
_________________
TIME IN
CHECK OPERATIONS
MS
DATE
Room No.:
_____________
Note: Only the validated number of personnel

(SEVEN) are allowed inside the fill room at one
time. Additional signatures may be placed on
the back of this page.
NAME
P/B
DATA/RESULTS
CT
C
L
AC
MO
EM
OTHER
TIME
OUT

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
y ExampleSOF
MANUFACTURING REVIEWED BY/DATE
QUALITY ASSURANCE REVIEWED BY/DATE

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.
29
10/5/2011
y FINALCOMMENTS
Phone: 714-246-4413
Email: Pallo_robert@allergan.com
_
g

30
Cleaning Validation
Coverage Studies
Jeff Felker
Dawn T
D
Tavalsky
l k
Background Information
Cleaning Methods
Cleaning Parameters
TACT Cleaning Parameters
TACT Cleaning Parameters
Cleaning Equipment
Required Flow Rate for Static Spray Ball
10
Required Flow Rate Compared to Static
11
Required Flow Rate Compared to Static
12
13
14
15
16
Cleaning Technology
17
What is a Riboflavin Coverage Test?

Riboflavin
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
Riboflavin under UV Light
Other Components Used for Coverage

Studies or Added to Riboflavin
Vitamin K
Hydroxyethyl cellulose (HEC)
Corn
Starch
C
St
h
Sucrose
NaCl
Dried Detergent
Vitamin K Fluorescence
Detecting Riboflavin
Uses for The Riboflavin Test
* A coverage test also qualifies that a final rinse sample taken during
cleaning validation or cleaning monitoring, is a composite sample from
all surfaces
Objective of the Coverage Test

Objective:
The objective of this test is to verify that the
sprayballs/wands/bars
b ll /
d /b
associated
i t d with
ith the
th system
t
are
capable of delivering cleaning solutions to all exposed
product contact surface areas. Often spray ball
coverage testing is performed as part of the final
vessel factory acceptance test. Coverage testing may
be performed on-site using the actual equipment that
will be used to clean the vessel.
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)
Flowrate and Pressure

More Pressure and More Flow are Good Right??
Wrong
10
Too Little OR Too Much Pressure is Bad!
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
Use an Atomizing Sprayer to Apply

Riboflavin
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
2. For vessels with sprayballs/wands/bars that are tested directly

as part of this test, there will be 100% coverage as indicated by the
observance of no fluorescence.
Note: If fluorescence is observed and can not be corrected by
modification of the spray ball or cleaning cycle, the system will
most likely have to have a manual cleaning step performed in
order to effectively clean the area that is not covered by the
sprayball/wand/bar.
Acceptance Criteria Met?
Yes ____ No ____ Initials/Date:____
Initials/Date:
//____
If No, explain in comments:
Reviewed By:_______________________ Date: __________
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
Rotary Spray Head in Action
18
Rotary Jet Head In Action
19
Stationary Spray Ball Technology
20
10
Installation in Process Tanks
Rotary Jet Head Technology
10
Cleaning Case
Rotary Jet Head
Cleaning Behind the Agitator Shaft
Cleaning of Shadow Areas
10
11
Effective Strategies to Design a Aseptic

Facility
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
1. Architectural Design and Construction

Aseptic Design Criteria
Aseptic
must be an integrated
design
p facilityy layout
y
g
g that satisfies
process and equipment layout requirements while catering for
good levels of access for operability, maintenance, personnel,
product, component and raw material movements
movements..
Architectural design should provide a contained environment,
with selected room finishes to enhance hygiene, environment
and safety level and the design must comply with relevant fire
codes and building regulations
regulations..
Structural framework and building fabric
fabric must also be
considered for any impact on the finished room environment
environment..
Fundamental aspects of building location and block layout
should be considered
considered.. Careful attention should be given to the
location of air intakes and exhausts in relation to the prevailing
wind direction, neighboring facilities exhausts and the risk of
cross--contamination.
cross
contamination.
Amjad

Facility

Aseptic Facility Layout Considerations:
Considerations:
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
Conceptual Layout is developed by combining all necessary building blocks in an

arrangement that meets facility layout requirements that should integrate equipment needs
and access and movement requirements for people, components, etc..
etc.. to permit
development of an efficient layout
layout..
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

Material/Personnel Flow, in order to produce an acceptable
sterile product, the design
g of personnel and material flows
should minimize or prevent the introduction of contamination to
04.. Aseptic Processing Area
Area..pdf
the clean area
area.. 04
One-way personnel flow is preferred, providing physically separate entry and
Oneexit routes or the separation can be achieved by ? ISO 14644
14644--4
Process or operation waste should be removed from the aseptic area
without contaminating the product either by direct contact or passing through
areas.. How used machine p
areas
parts and canisters can be removed from the
area if there is no physical separation available between entry/exit ?
Due to the problems in maintaining the Differential pressure , the airlock to
be used between rooms or areas of different air quality classification.
classification.
Amjad

Facility

Integrated Facility Design:
Integrated facility design includes everything from the weighing
of components through the storing, packaging and labeling of the
finished product. Steps includes, mixing, formulating, filtering,
lyophilizing, filling, encapsulating and sterilizing.
The design of each element of the aseptic manufacturing facility
should contribute minimizing the contamination risk.
Important that integrated facility technology can be supported by
local personnel
personnel, such that maintenance and repair costs can be
minimized and facility up time be optimized.
Amjad

Room Function:
Function: Facility areas/rooms are divided into five general
functional categories
categories::
1.
Areas for aseptic processing of product or components
2.
Areas immediately adjacent to aseptic to the above, creating

material/personnel airlocks
airlocks..
3.
Preparation areas closely related to the aseptic processing area

area..
4.
Areas immediately adjacent to the above, comprising material

airlocks, personnel clean change, secondary packaging and other
associated areas (Pharmaceutical Areas)
Areas)..
5.
General ancillary/support functions, including warehousing, offices,

amenities plant room and circulation areas with no protection
requirements other than, perhaps a factory change/uniform for
unclassified areas
areas..
Amjad

Facility

GMP Critical Environmental Parameters
Parameters::
The production of sterile products requires a cleanroom environment
environment.. Process
vary which require specified conditions of following parameters
and products will vary,
[GMP Critical Parameters]
Parameters]:: 10
10.. ISO_Controlled Environment Design
Design..pdf
Temperature
Percent relative humidity (or moisture content)
content):: Temperature and relative humidity
requirements will vary by product type and proposed manufacturing
manufacturing..
Differential pressure
Clean up/recovery time
Particle Count
Airborne
Microbiological
Ai b
Mi bi l i l Levels
L
l
Filter integrity
Air Velocity for Class 100 areas
Differential pressure and particle count requirements will be determined by the

required product process cleanroom classification as per established systems.
systems.
Amjad

Commissioning:: The requirements for testing, commissioning
Commissioning
and qualification for sterile manufacturing facilities should assess
and include
include::
Good Engineering Practice
Direct Impact System
Indirect Impact System
GMP Critical Parameters
Critical Devices
Critical Instrument
HVAC System serving the aseptic area
Environmental monitoring / documenting system
Qualification of HVAC Systems

Amjad

Facility

Disturbance of Unidirectional Air Flow
Flow:: The
design
physical
obstacles such as the equipment
and operating
g of p
y
q p
p
g
procedure, personnel movement, should consider basic aerodynamic to
prevent serious turbulence. 03
03.. Disturbance in Unidirectional Air Flow.
Flow.pdf
Concept to achieve segregation of cleanrooms:
cleanrooms:
Displacement Concept [Low differential pressure, High Airflow]:
Displacement airflow should be more than 0.2m/s.
Differential pressure concept [High differential pressure, low airflow]:
Range
5 pa to 20
20pa to allow
doors to b
be opened
R
ll
d
d and
d to avoid
id
unintended cross
cross--flows due to turbulence.
Physical Barrier Concept: Use of impervious barrier to prevent
contamination.
Amjad

The FDA recommends that all cleanroom be designed and constructed to meet
the following expectations:
expectations:
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..
A positive pressure differential of at least 10

10--15 Pascals (Pa) (Equal to 0.04 0.06 inches of
water gauge) should be maintained between adjacent room of differing classifications (with
doors closed).
closed).
Amjad

Facility

Construction Features of Room Finishes
Have a smooth cleanable finish that is impervious to water, cleaning
d sanitizing
iti i solutions.
l ti
Th
h ld b
l
bl recesses
and
There should
be no unun-cleanable
and minimum of projecting ledges, shelves, cupboards, and equipment.
Be constructed of materials that resist chipping, flaking, oxidizing or
other deterioration.
All wall and floor junctions should be curved to facilitate appropriate
cleaning (i.e. coved base and flush as possible).
There must be no horizontal pipes or conduits located over exposed
components, in
in--process material, products, and drug
drug--product contact
surfaces, including drug product containers and closures after final
rinse.
All joints between disparate materials should be caulked with silicon
rubber or equivalent.
Amjad

Air Supply
HEPA filter integrity should be maintained to ensure aseptic conditions.
conditions. Leak
testing should be performed at installation to detect integrity breaches around the
sealing gaskets, through the frames or through various points on the filter media
media..
Among the filters that should be leak tested are those installed in dry heat
depyrogenation tunnels and ovens commonly used to depyrogenate glass vials.
vials.
(Where justified, alternate methods can be used to test HEPA filters in the hot
zones of these tunnels and ovens.
ovens.
Air volume requirements must be designed to maintain air pressure differential
between clean and less clean areas
areas..
Design should be such that higher pressures are maintained in critical areas and
decreased in less critical areas.
Pressure differentials between cleanrooms be monitored continuously throughout
each shift and frequently recorded.
Amjad

Facility

Study Design:
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
2. Current Goods Manufacturing Practice

What Does the FDA look for?
ildi and
dF
iliti
B
Building
Facilities
Is the facility suitable for the operations being carried out?
Is the facility readily cleanable.
Are there proper controls against cross-contamination?
Is there adequate ventilation while still keeping out sources of
contamination?
Are there adequate sanitary facilities?
Are the operational areas separate to prevent mix-ups and crosscontamination?
What is the source of the water supply?
Are there adequate systems for the handling and disposal of water?
Amjad

Facility

Materials Handling and Storage
factors such as temperature and
Can all physical factors,
humidity by monitored and controlled properly?
Is there properly segregation for incoming and
released materials?
Is there adequate storage space under the
required environmental conditions?
Are in-process materials properly stored?
Are containers suitable for raw materials and
intermediate product? fiber generation caused by
boxes contains glass vials\ampoules
Amjad

Equipment
Is the facility equipment suitable for the intended
use?
Is equipment designed to facilitate cleaning?
Are there proper filtration systems adequately
designed and properly functioning?
Does equipment design prevent contamination
from external sources?
Is Equipment Clearly and uniquely identified?
Amjad

Facility

Engineering Design: First step to define systems and
attributes that require GMP review on discipline basis.
Few GMP equipment listed:
Buffer Preparation material handling equipment

Media preparation materials handling equipment
Fermentation preparation material handling equipment.
Hygienic Vessels, tanks, pumps, filters, strainers and heat
exchangers.
Autoclaves and sterilizers
Depyrogenation ovens
Glass washing machinery
Centrifuges
Clean steam generators. Etc
Amjad

Cleanliness:
End product of any parenterial manufacturing effort are produced
in a stringently controlled, clean environment that must be
monitored and maintained in accordance with very strict
standards. Two viewpoints of cleanliness issues are:
The design of the facility in order to maintain an acceptable
GMP manufacturing environment (Clean/sterile)
The physical construction work during the execution of field
activies.
i i
The design related to cleanliness must be well defined in terms
of equipment, facility design, gowning and access control, HVAC
system design and cleaning protocols.
Amjad

Facility

Documentation:
Qualification and Validation: Equipment and system qualification
and validation are expressly required by the authority.
To provide a evidence, every project will need a comprehensive
documentation that should consist of:
Validation Master Plan
Design Qualification [DQ]
Installation Qualification [IQ]
Operational Qualification [OQ]
Performance Qualification [PQ]
Process Validation
Amjad

Equipment Controls and Instrument Calibration
Temperature and pressure monitoring devices for heat sterilization should be
calibrated at suitable intervals.
The sensing devices used for validation studies should be calibrated before and after
validation runs.
Devices used to monitor dwell time in the sterilizer should be periodically calibrated.
The microbial count of a biological indicator should be confirmed. Biological indicators
should be stored under appropriate conditions.
Where applicable, instruments used to determine the purity of steam should be
calibrated.
A conveyor belt should not pass through a partition between grade A or B and
processing area of lower air cleanliness , unless the belt is continuously sterilized like
sterilizing tunnel
For dry heat depyrogenation tunnels, devices (e.g. sensors and transmitters) used to
measure belt speed should be routinely calibrated. Bacterial endotoxin challenges
should be appropriately prepared and measured by the laboratory.
Amjad
10

Facility

Contamination Rates:
When filling
g fewer than 5,000 units, no contaminated units should be detected.
One (1) contaminated unit is should result in an investigation considered cause for
revalidation
When filling from 5,000 to 10,000 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, following
investigation.
When filling more than 10,000 units

One (1) contaminated unit should result in an investigation.
Two (2) contaminated units are considered cause for revalidation, following
investigation.
Amjad

Contact sterile materials only with sterile instruments:
Sterile instruments should always be used in handling of sterilized
materials Between uses
materials.
uses, sterile instruments should be held under class
100 (ISO 5) conditions and maintained in a manner that prevents
contamination. Instruments should be replaced as necessary throughout
an operation.
Move slowly and deliberately:

Rapid movements can create unacceptable turbulence in a critical area.
Such movements disrupt the unidirectional airflow, presenting a
challenge beyond intended cleanroom design and control parameters.
The principle of slow, careful movement should be followed throughout
the cleanroom
cleanroom..
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.
Multiple filling rooms:

Aseptic filling validation should be performed on all filling lines within a
facility on a rotating basis. Also, the differences in air flow and
turbulence can have a direct impact on the performance of the room.
Amjad
11

Facility
3. Quality Management to Meet Regul. Req.

Engineering Quality and Compliance
Quality Overkill: More quality is better quality or more money spent
to design in quality the better can cause as many problems as the lack
of quality in a facility design
design..
Organization attempt to ensure quality by selecting or specifying the
highest grade of materials, statestate-of
of--the
the--art equipment, complex
automation or the most stringent operating classification criteria are
missing the point
point..
Reasonable approach to examine specific requirements individual
operations and areas within the facility,
facility establish realistic and
achievable criteria and design the facility to meet specific needs
needs..
Spending money for unnecessary technology or more stringent
criteria will not impress the authority, nor will it guarantee the
elimination of errors.
Amjad
3. Quality Management to Meet Regul. Req.

Construction Quality
Quality in construction anticipates the need
for high quality workmanship and installation,
sound inspection and testing particles and
documented results.
The goal of a construction quality program is
to
t preventt errors and
d
Errors that cause project costs to increase.
Amjad
12

Facility
4. HVAC Considerations for Aseptic Facility

Sources of Particulate Contamination
Internal Sources: Contamination sources that arise within a sterile manufacturing
facility
generally
are
ac y ge
ea ya
e from:
o
The HVAC system
Process or Operations
Number of particles generated. 09. Number of Particles Generated Per Second Per Person.pdf
Human Particle Generation 08. Human Particle Generation.pdf
The Operations (normally the highest source of contamination), capping and crimping
process generate large number of particles, so room pressure reversals is critical and
need to be avoided, and should be located at separate station equipped with air
extraction
The introduction of components and equipments.
The introduction for raw materials
Adjacent, less controlled areas.
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

Environmental Standards and GMP
Layout
of Cleanroom:
Cleanroom:
y
Workstation Site and Organization
Organization:: Critical workstation or areas of risk should be sited
away from the entries and exits, major traffic pathways which would cause disruption of
the airflow pattern and high levels of contamination.
contamination.
Ancillary areas and adjacent cleanrooms
cleanrooms:: Consideration should be given to the location
and integration of ancillary areas such as service utility, cleaning, preparation, toilet and
refreshment facilities
facilities..
Vacuum cleaning equipment
equipment:: Either portable or built in should be provided to ensure
that particulate contamination can be removed during periodic cleaning
cleaning.. when
permanent vacuum cleaning system is provided, exhaust and the fan should be sited
outside the cleanroom.
cleanroom. When portable vacuum is used, it should be fitted with an
exhaust filter of at least the same efficiency as that filtering the environment air supply
Sprinkler systems
systems:: Consider potential contamination cleanrooms [supply piping
containing fire suppressant medium, whether water, chemical or gas], when sprinklers
piping is to run above ceiling, careful consideration should be given.
Amjad
13

Facility

Control and Segregation Concept
The zones with the highest cleanliness demands to be reduced to the
minimum size.
size.
Movement of material and personnel between adjacent clean zones give rise
to the risk of contamination transfer
transfer.. Special attention should be paid to the
detailed layout and the management
management.. 01
01.. Sterile Movement.
Movement.pdf
Air Flow Patterns are categorized into two:

two:
Unidirectional Flow ISO class 5 and cleaner need to be used.
used. 02
02.. Unidirectional Air
Flow..pdf
Flow
Non--Unidirectional Flow ISO class 6 or less 02

Non
02.. Unidirectional Air Flow.
Flow.pdf
Special attention should be taken in consideration for the location of filter
outlet which will have significant impact on the clean room performance.
performance.
Amjad

Disturbance of Unidirectional Air Flow:
Flow: The design of physical obstacles
such as the equipment and operating procedure, personnel movement,
h ld consider
id basic
b i aerodynamic
d
i to
t preventt serious
i
t b l
should
turbulence
03..
03
Disturbance in Unidirectional Air Flow
Flow..pdf
Concept to achieve segregation of cleanrooms:

cleanrooms:
Displacement Concept [Low differential pressure, High Airflow]:
Displacement airflow should be more than 0.2m/s.
Differential pressure concept [High differential pressure, low airflow]:
Range 5 pa to 20pa to allow doors to be opened and to avoid
unintended cross
cross--flows due to turbulence.
Physical Barrier Concept: Use of impervious barrier to prevent
contamination.
Amjad
14

Facility

HVAC System Design: Design of HVAC system to serve an
aseptic area and addressed to ensure successful operation.
Operational issues: Personnel represent the greatest risk to
environmental conditions.
Limiting the number of operations in the class 100 and class 10,000
areas.
Avoid personnel walking past critical areas unless essential.
Understand where operators will be stationed during normal
operation.
If regular
l iintervention
i iis needed
d d iinto a critical
i i l area consider
id glove
l
ports to prevent contamination.
Understand personnel traffic routes and perhaps increase air
changes to the busiest area i.e. change rooms.
Separate gowning and dede-gowning routes into aseptic process area.
Amjad

Physical issues:
Holes through walls [conveyor belts, sprinkler head covers]
Door clearance and tolerances
How air locks maintain pressure cascades and how long doors will be open
(consideration of time delays on loss of pressure alarms)
Door swings (will they close against the pressure, can they be opened)
Equipment locations
Physical locations of critical areas in relation to process operations and other
areas.
Provision of active pressure control or a static system to maintain pressure
between rooms.
How rooms will be sanitized (e.g. sanitization contact time duration, how
quickly odors must be diluted)
Amjad
15

Facility

HVAC Design Principles:
Dilution versus displacement
designs
p
g
In a displacement design dirty air is displaced by cleaner air, i.e.
unidirectional air flow.
In a dilution design dirty room air is mixed continuously with clean air, to
reduce the particulate load in the room air by turbulent air mixing.
Dilution System Design: Three fundamental requirements of turbulent

flow dilution cleanroom are:
Air supplied to the space should be significantly cleaner than the condition to
be
b maintained.
i t i d
Volume of clean air supplied should be sufficient to offset particulate gains in
the space and hence maintain the in operation condition.
Complete mixing of the clean supply and room air is required to achieve the
dilution effect.
Amjad

Qualification of HVAC System:
HVAC
System
serving
an
aseptic
manufacturing suite must be a direct impact
system i.e. its a failure to perform may
directly affect final product quality
quality.. Therefore,
qualification, testing, commissioning in line
with Good Engineering Practice need to be
considered carefully
carefully.. 11
11.. HVAC Validation Plan
Plan..pdf
Amjad
16

Facility

Integration of HVAC and Process Equipment:
Process and Product Knowledge:
Knowledge: Knowledge of the particular
products to be processed within the facility is fundamental to
HVAC design.
design. Having an early awareness of particular
requirements ensures that they can be accommodated within the
design..
design
Sterilizer types:
types: Key equipment selection that interacts with
HVAC and therefore will affect system design is the inin-feed
sterilizer.. There are two types
sterilizer
types::
Static Equipment:
Equipment: Such as Autoclaves, dry heat ovens
ovens..
Dynamic Equipment
Equipment:: Such as integrated sterilizing tunnels
tunnels..
Amjad

Air Handling Unit (AHU) Design Considerations:
AHU should operate under positive pressure to minimize the ingress of
dirty air from the plant or elsewhere.
Humidifiers present a risk of microbiological growth in the HVAC
system, so should be designed properly to drain away condensate.
If chemical dehumidification is necessary, the desiccant should not
support microbiological growth and be nonnon-shedding
Steam injection type humidifiers are preferable
preferable, as they sterilize the
water as it is added to the air stream.
Clean steam can be used to overcome some potential difficulties of
variable feed water conditions. Steam from main plant boilers must be
avoided as control of quality and boiler additives can be difficult.
Amjad
17

Facility

Air Handling Unit (AHU) Design Considerations:
S
d cooling
li coils
il should
h ld nott b
d D
i ttrays under
d coils
il
Sprayed
be used.
Drain
should be drained adequately to prevent standing water.
The arrangement of the AHU should include adequate access to
all sections. The internal finish should be nonnon-shedding and have
a minimum number of ledges to prevent dust accumulation.
The unit must be cleanable and able to withstand fumigation /
y
disinfection if necessary.
Location of fresh air intakes and exhaust outlets to minimize
effects of the systems performance due to external wind
pressures should be considered.
Amjad
5. Aseptic Process Overview

Critical Process Steps
Products
aseptic
oducts manufactured
a u actu ed by asept
c methods,
et ods, tthe
e
critical process steps are normally the activities during
which the sterilized product and container/closure are
exposed either to atmosphere or to surface, which
includes
Dispensing of materials
materials..
Formulation and sterile filtration
Filling and primary sealing
sealing..
Critical steps will include the preparation and

depyrogenation of components coming into contact
with the product, sterilization of process vessels and
contact equipment and cleaning processes.
processes.
Amjad
18

Facility
5. Aseptic Process Overview

Protection of the Product: To minimize
the risk of product contamination
Nested zone of protection around critical
processing areas.
Strict control of movement in and out of critical
areas.
Control of related activities.
activities
The point of fill is at least a class 100
environment, protected under unidirectional
air flow
Amjad
6. Important Consideration for Aseptic Facility
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

Facility

Health and Safety:
Potent and Toxic Products

Cleaning and Disinfectant Materials
Materials Handling
Surface and Safe Access
Fire prevention
Means of Escape
Protection
P t ti off Machinery
M hi
Electrical Safety
Safety of Pressurized Systems
Dust Explosion and Static Hazards
Amjad
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

Facility
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
Sinks and drains avoided, and excluded in Grade A and B

areas
Where installed, design, location, maintenance
Effective cleanable traps
Air breaks preventing backflow
Floor channels open and easily cleanable
Amjad
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
Warning system to indicate failure in air supply

Pressure indicators results regularly recorded
Water for Injection (WFI)
Produced, stored, distributed prevention of growth of microorganisms
Constant circulation at temperature above 70, or not more than 4
degrees Celsius
Amjad
21

Facility
Examples of contaminants
Amjad
Used in clean areas, passed through doubledouble-ended sterilizers &

use triple wrapping
Filling //stoppering
stoppering process:
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 accuracyaccuracy-Sampling technique

technique--fill inhibited if no container detected
detected--Online and offline checking
Fill reproducibility rejection( with lock) for no fill and no stopperstopper- fill container &stopper container counter
Pre and post gassing rate
Moving part above the filling table should be minimize
Change parts design for fitting and removing with minimum use of tooling
Capping /labelling process:

-
Crimping force checking and reproducibility
Rejection if there no container/stopper missing
Design of ease of cleaning and removing of metallic fragments generated by the crimping process
Unit counter & label reconciliation
Amjad
22

Facility
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
Recognize your sense of discovery

Take responsibility of your learning
Accept the risks inherent in learning with confidence, competency and
autonomy.
Amjad
23

Facility
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
Examples of observations during GMP audits
Critical deficiencies on Day 1, Major on Day 2 and Other on Day 3.
I d
t environmental
i
t l monitoring
it i programmes.
Inadequate
Inadequate control over equipment autoclave sterilisation cycles.
Inappropriate behaviour in clean rooms.
Changing rooms being too small with inadequate segregation.
Inappropriate process and personnel flow.
Single door autoclaves instead of double door.
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)
Expiry date of media not validated.
Growth promotion capability decreases rapidly in first week after preparation.
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

Facility
False zero in clean rooms:
Position plates directly under HEPA filters

Position plates well away from human activity
Use old plates that are dehydrated
Do not monitor filling machine setset-up
Do not use Sabouraud Dextrose media when fungal spores are likely to be
present
False zero in water testing:

Run water at the test point for 5 min. (Production wont do that)
Store the water sample as long as possible before testing (cells attach to
container walls)
Use the pour plate method
Use
the iincorrectt medium
U th
di
False zero in the sterility test:

Allow the membrane filter to dry out under vacuum
Place filter in the oxidised layer of Thioglycollate medium
Use old Thioglycollate that is fully oxidised
Amjad
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

Facility
The End
Amjad
Amjad Ganma, M.Sc (London)

Quality Unit Manager
Tabuk Pharmaceutical Manufacturing Co.,
Tabuk, Saudi Arabia
Per. Email: amjad_ganma@yahoo.com
Off. Email : amjad@tpmc.com.sa
Mobile num: 00966509522269
26
10/10/2011
Establishing Criteria for Cleaning

Validation
IVTs
ACE
C (EU)
( )
3 October 2011
Presented by:
Michael Gietl
Technical Service
Specialist
STERIS Corporation
michael_gietl@steris.com
Agenda
What is Cleaning Validation? Why Clean?

g Validation Regulatory
g
y Background
g
Cleaning
Cleaning Chemistry
Choosing Process Soils
Establishing Residue Limits
Microbial Considerations
Sampling & Analytical Methods
Group Activity: Grouping Strategies
Q&A
10/10/2011
Cleaning Validation Master Plan

Equipment
Characterization
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
Protocol Definition, Execution, and Summary

3
Report
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)
European Requirements EC Guide to GMP

Section 3: Premises and Equipment
((3.34 3.44 equipment
q p
design
g for cleanability)
y)
Section 5: Production
(5.19 cross-contamination, 5.21 5.24 Validation and
change control)
Annex 2: Manufacture of Biologicals
(15, 17 Design to promote cleanability)
Annex 15: Qualification and Validation
(36 42 Cleaning
Cl
i Validation;
V lid i
45 Revalidation)
R
lid i )
GMP Part II: GMP for APIs (aligned with ICH Q7A)
(5.2 Equipment Maintenance and cleaning; 6.2 Equipment
cleaning and use record; 12.7 Cleaning validation)
6
10/10/2011
EU Annex 15 36 42: Cleaning Validation

(contd)
Historically three consecutive trials should be performed
successfully
Test until clean not an appropriate substitute to
cleaning validation
Products which simulate the physicochemical properties
of substances to be removed may be used where those
materials are toxic or hazardous
EU Annex 15 36 42: Cleaning Validation

CV used to confirm the effectiveness of cleaning
procedure
Rationale for selecting carry over limits of product
residues, detergents and microbial contamination
based on materials involved
For similar products and processes, use a worst case
approach taking account of critical issues such as:
toxicity MOC,
toxicity,
MOC soil classification,
classification allergenicity,
allergenicity etc.
etc
10/10/2011
What Affects Cleaning?
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
Choosing the Right Soils

Which materials represent the greatest risk to the next
process
Is there justification to look for one residue as a worst
case when compared to other selected residues?
Establish limits for the chosen material based on:
Pharmacologic / toxicological data
Percent carryover
Permissible baseline (micro)
13
Risk Ranking Specific Soils

Parameter
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
> 2500 mg/kg

and 1250
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
The Three Types of Limits

Limits associated with the nature of the substance being
cleaned (pharmacological properties)
Limits associated with the percentage of contamination
(10 ppm, for example)
Limits associated with the process by which the material
is manufactured, cleaned, or analyzed (e.g. visibly clean)
21
Putting the Terms Together
Nature (Completed) Batch (Next Product)

1
Size x Dose (Next Product)

Safety Factor
Where:
Nature = Pharmacology of the active ingredient from the product
just completed
Batch = Batch size or volume or number of units of the next
product
Size = Surface area of shared or maximum equipment train
Dose = Amount (total dose weight) to be given per patient (daily or
per regime of the next product)
Safety Factor = Optional or variable term depending on other
considerations in the limit
22
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
Safety Factor Term

We want the amount of residual soil to be safe,
therefore may add a safety factor
Safety factor is any convenient number, usually a
factor of 10 (e.g. 100, 1000, 10000)
Safety factor is optional in some cases (not optional
when using terms such as LD50)
The greater the safety factor, the larger the reduction
in the limit
27
Safety Factor Term (Continued)

Common practice is to apply safety factors uniformly
within a plant
Topical Products: 10 to 100*
Oral Dosage Products: 100 to 1000*
Parenteral/Opthalmic Products: 1,000 to 10,000
Research/Investigational Products: 10,000 to 100,000
*Note: Significant rationale must be given if safety
factor is less than the industry-standard 1,000
28
14
10/10/2011
Limits for Cleaning Agents

No therapeutic index for cleaning agents
Commonly,
Commonly only information available is LD50
LD50 specific to animal model (e.g. rat) and route of
administration (e.g. oral, IV)
First calculate either Acceptable Daily Intake (ADI) or No
Observed Effect Level (NOEL):
ADI = LD50 (mg/kg) body weight (kg)
NOEL = LD50 (mg/kg)(5.610-4) x 70 kg1
The ADI or NOEL would take the nature place in equation
1
Doursman and Stara, J. Regulatory Toxicology and Pharmacology, 3, 224-238, 1983
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
Things to Avoid in Setting Limits

Limits based on analytical assay
LOQ (maybe?)
LOD (never!)
Limits based on compendial water specs
Limit unrelated to target residue
Limits selected arbitrarily
No documentation of rationale or risk ranking for how
selected
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
Identify and Define Sampling Methods
Swabs area to be used

Rinse define and qualify method
Microbial recovery?
Blanks and controls handling & methodology
Sample locations
ID
Justification
Risk rationale
34
17
10/10/2011
Sampling Methods
Swab
Rinse
Placebo
Physical Removal
Good
Poor
Moderate
Technique Dependent
Yes
No
No
Hard to reach locations
Poor
Good
Good
Adaptable to irregular surfaces
Moderate
Good
Moderate
Controlled Area
Yes
No
No
Non-Invasive
No
Yes
Yes
Adaptable to on-line monitoring
No
Yes
No
Can use solvents
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
Grouping for a Contract Manufacturing

Facility
Facility may not know next product
Want to avoid frequent re-validation of cleaning processes
How?
Develop cleaning matrix for products currently

produced in facility
Identify worst case soil, and validate the cleaning process

When new products are introduced into facility, add it
to matrix and determine if re-validation is required
Or
During original cleaning validation, adjust limits to

be low enough that the potential for re-validation
is reduced (based on historical manufacturing
trends)
37
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
Streamlining Cleaning Procedures

Through Grouping Strategies
Group Activity (Minerals)
Copyright by the STERIS Corporation 2010
39
Summary
Know your soils

Know your cleaning process
Be conservative
Use grouping to gain efficiency
Questions?
Thank You for Your Time!
40
20
10/4/2011
Improved Cleaning Efficiency in

Life Science Facilities
Presented By:
Clay Foutch
Vice President of Sales
www.foamtecintlwcc.com
Agenda
Introduction
Wiping
Wiping--Past, Present & Future
Wiping Challenges in the Life Science
Industry
Corrosion/Staining & Facility Appearance
Questions and Answers
10/4/2011
Foamtec International Company Overview
Foamtec International is ISO 9001:2000 and ISO 13485:2003

certified.
Vertically integrated manufacturing enables robust control of
quality, costs, and scheduling.
Advanced foaming and fabricating technologies enable the
development of cleaning products that improve SOP Compliance.
Micro fiber wipers and mops improve cleaning efficiency and are
suitable for cleaning disinfectant residues and nonnon-viable
contamination.
Products can be provided sterile or nonnon-sterile.
Data is available via the web proving lot traceability.
Kaizen Question (Challenge Assumptions)
Why do we use our current cleaning

practice?
Why do we use our existing cleaning

tools?
10/4/2011
Kaizen-1st Question (Why Wipe?)

Operation
Workstation
Cleanliness/Bioburdens
Component
Cleanliness/Bioburdens,
Silicone & Epoxy removal
Process Equipment
Cleaning
Equipment/Room
Maintenance/Disinfection
Risks
Non Value Steps, Wiping
Uniformity, Fibers & Soils
As Above + Productivity
As above + Lot Rejects
Fibers, Cost and

Downtime
Kaizen-2nd Questions
Question
Is Wiping Process Well
Defined & Understood?
What is the ReRe-Wiping

Rate?
How Would We Validate

Any Changes?
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
10/4/2011
Poly vs. Microfiber Characteristics

Woven Microfiber Wiper
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
Woven Microfiber Bundle
Wipers Used in Clean Rooms

Wiper Type
Non
Non--Wovens (Sontara)
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
10/4/2011
Wipers Used in Clean Rooms

Wiper Type
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
SS Work Station With 20 RA Surface

At 10x Mag.
PolyFoam Wiper /10
Strokes
Sontara/3 strokes
10/4/2011
Sontara- 10X Mag/LFW

Sontara, Out of Bag
Sontara, 3 Strokes
Polyester-10X Mag/LFW
Polyester, OutOut-OfOf-Bag
Polyester, 3 Strokes
10/4/2011
Foam Wiper-10X Mag/LFW

Foam, OutOut-of
of--Bag
Foam, 3 Strokes
HD Foam Wiper-10X Mag/LFW

HD Foam, OutOut-of
of--Bag
HD Foam, 3 Strokes
10/4/2011
Wiper Condition w/70% IPA

After Work Station Cleaning
Standard Polyester
wiper after wiping
stainless steel surface
Woven micro fiber

after wiping stainless
steel surface
Fiber Black Light Inspection
COATER POST POLYWIPE
COATER POST MICROFIBER
POLYESTER WIPER
MICROFIBER WIPER
* Using black light technology
10/4/2011
Non Viable Particle Data

Using Q3 Surface Particle Counter
MiraWIPE removes 98.8% non-viable particles at 0.5um
Polyester wipe removes 85.6% non-viable particles at 0.5um
Coater 1 Z PM ww 34
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
BASELINE AVG TOTAL
11.54
0.008
BASELINE AVG TOTAL
38.281
0.0533
POST POLYWIPE
NON-VIABLE PARTICLE READINGS
.5 um
5 um
POST MIRAWIPE POST

NON-VIABLE PARTICLE READINGS
.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
POST POLYWIPE AVG TOTAL
1.66
POST MIRAWIPE AVG TOTAL
.470
% NON-VIABLE
PARTICLE REDUCTION
85.6%
100.00%
% NON-VIABLE
PARTICLE REDUCTION
98.8%
100.00%
Fiber Contamination in Coating

Station
Polyester
Microfiber
wip
USING BLACKLIGHT TECHNOLOGY
Visible non-viable particles on the

surface after wiping stainless steel
with polyester wipes
No visible non-viable particles on

surface after wiping stainless steel
with MiraWIPE
10/4/2011
Contact Time = SOP Compliance
Wiping Sanitization
Sanitization with a
wipe should be
done with
Operators in mind
A minimum
contact time needs
to be achieved
Contact =
Cleaning
10
10/4/2011
Antimicrobial Effectiveness
First assess dry times in all areas!!

C
Contact
Kill
ill Time
i
Studies
S di (suspension--AOAC)
(
i
O C)
3-10 minutes
Organisms in suspension are easier to inactivate
Contact Kill Time Studies (surface)
3-10 minutes
Organisms dried on a surface are more difficult to
inactivate (as often found in clean rooms)
Residues
Sodium Hypochlorite
Phenol
Quaternary Ammonium
11
10/4/2011
Corrosion Remediation
Understand the Tradeoffs
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
12
10/4/2011
Cleaning versus Disinfection

Cleaning
(remove viable and non

viable particles from surfaces)
Disinfection
(kill viable
organisms on a surfaces)
Removal of particulates
and microbes from the
surface
Saturate and penetrate

the cell wall to kill the
organism
Removal of residues and

buildup that can
complicate
li t di
disinfection
i f ti
Disinfectants need a
specified Contact Time to
work
k
Particulates, residues &
irregular surfaces must
be factored
13
10/4/2011
Cleaning versus Disinfection
Surfaces complicate cleaning and

disinfection.
Flat surfaces are easier to clean, but dry
faster.
Intricate surfaces are harder to clean and
dry slower.
The remaining residue after rinse is the
question.
Why Cleaning?
Cleaning returns the surface to its original state, which

is good starting point for disinfection.
Cleaning addresses residues from earlier sanitization
Required by regulatory: 21CFR 211.67, Equipment
and utensils shall be cleaned, maintained and
sanitized
Good Cleaning means fewer viable organisms to be
killed. Good cleaning
g increases disinfection robustness
and reduces risk.
Good cleaning eliminates dead organisms and reduces
overall bioburdens.
14
10/4/2011
Corrosion is a serious issue:
Expensive:
-
Throwing parts away

3rdd Party remediation
d
Continuous cycle of remediating
Viewed as a serious issue by EHS, QA/QC,

Micro, Manufacturing, and Facilities
Today we will review a new procedure to
address these concerns.
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?
15
10/4/2011
Residue And Its Effective Removal
Steris Vesphene Se
disinfectant
residue cleaned
with MiraWIPE
& 70% alcohol
Residues that lead to

corrosion remaining
after the surfaces was
cleaned with
standard clean room
grade polyester
wipers & 70%
alcohol
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
Living with poor facility appearance due to

stains is a thing of the past
16
10/4/2011
Curing Oven Door

with Stains
Stains that were
observed throughout the
facility on SS equipment
that resisted cleaning
with polyester wipers
and alcohol. We were
invited to clean the SS
once the engineer saw
the results of our
corrosion cleaning kit.
Not all stains need

to be removed with
ScrubPADS!
The door was returned to like new
condition in about 10 minutes using
HT5790S MiraWIPE with 70% IPA.
3-4 wipers were wetted with 70%
IPA to remove the bulk of the
stains. Roughly 30
30--50 mls of 70%
IPA were consumed in this
operation.
The remaining stains were cleaned
off with 99% alcohol and another 4
wipers. A similar quantity of 99%
IPA was used.
10--15 cases/month of new
10
MiraWIPE business was developed
off of the purchase of 1 SS starter
kit.
17
10/4/2011
Rust Remediation 316 SS

7/9/10 vs. 3/31/11
Rust Remediation 304 SS 7/9/10

vs. 3/31/11
18
10/4/2011
A Clean Surface Is More Easily Disinfected!
The micro fiber 1-2um

star-shape characteristic
is able to reach into the
micro scratches on all
surfaces.
Fiber of Woven
Microfiber
Giving the microfiber the

ability to remove the sub
.2um particles gathered
within micro scratches.
Contaminants, soil and
Contaminants
even Bleach residue can
be lifted by the micro fiber
wipe.
Woven
Microfiber
Woven Microfiber
316L Stainless Steel Surface
19
10/4/2011
Epoxy Surface
Vinyl Surface
20
10/4/2011
Plastic Curtains
Poly vs. Microfiber Characteristics

Woven Microfiber Wiper
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.
Woven Microfiber Bundle
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
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
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!
Cleaning/Disinfection Challenges
Too Much Dead Space
Heavy Residues
Contact Time
New Light Weight

M
Mops
available
il bl
ISO Class 4 Micro
Fiber Mops and
Wipers
Poly/Foam
Laminated Mops and
wipers designed to
achieve wet time
23
10/4/2011
Corrosion Remediation Overview:

This procedure reduces costs:
1. Capital Equipment
2. Operating and Maintenance
3. Chemical
This procedure improves your customers facility:

1.
2.
3.
4
4.
Aesthetics
Sustainable solution
Green solution
Q lit control
Quality
t l improvement
i
t
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
24
IVT ACE Philadelphia, PA
The Next Generation

Advanced QC Microbiology
Rapid Testing Solutions / Lonza / 22 Jun 2011
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
Current state of QC Micro processes
Concepts for Automation
Introduction to Lonza and MODA Solution
Paperless EM case study at Auxilium
slide 3
Current State of QC Microbiology Processes
M Goetter/ Lonza / 22 Jun 2011
Todays QC Process Challenges

Disparate Data Points
Air, Surface, Water
Personnel
Media
Equipment
Islands of Information
Sample Records
Laboratory
Spreadsheets
Management
slide 5
Example: QC Sampling and Lab Processing
Current State: The Paper-based QC Process

Plan
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
Paper-based, redundant data recording & reconciliation

=
Increased labor and time costs & delays in data
analysis/reporting
=
Ineffective data analysis and trending
Impacts overall effectiveness of QC program
slide 7
Automation Concepts
B Toal / Lonza / 22 Jun 2011
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.
Source: Environmental Monitoring A Comprehensive Handbook, Volume 1

slide 9
Automated Field Data Capture
Featured: MODA-FDC platform, used for

field data capture in clean room areas
Stainless steel cart

Ergonomic tablet PC
Docking station
Thermal label printer
Barcode scanner gun
Proximity reader for RF badges
Space for equipment
Space for growth media
slide 10
Point of Sample Automation

Challenges
Solution Mobile Technology
Computers in aseptic environment,

must be sanitized
Small, mobile, durable, sanitizable

computing devices
Heat, radiation and chemical

disinfectants cannot be used on
standard business computer
Must not introduce air particulates

or facilitate microbial growth
Rugged computers that can be

sanitized exist, but are typically
deployed as a fixed workstation
(kiosk) used to control or monitor a
specific operation
Network access and equipment
interference provide inadequate
access to online resources
Leverages wireless or radiofrequency (RF) technology

Reads and prints barcodes and
RFID tags
Offline mode allows technician to
work when the network is not available
Eliminates need for paper schedules
and handwritten notes
slide 11
Todays QC Micro Lab

analysis and trending of environmental data is essential to
aid in the interpretation of process stability and assess overall
control performance.
EM Reports must be accurate, traceable, timely, and welldocumented.
Source: Environmental Monitoring A Comprehensive Handbook, Volume 1

slide 12
Automated Lab Processing
slide 13
Purpose-built QC Micro System

LIMS/Excel Challenges
Schedule management lacks flexibility

for non-routine events
Media and device information is
disconnected
Human intervention to move
information through sample
lifecycle (Sample > Test > Analyze
> Close)
Customized batch/chemistry- centric
LIMS dont capture critical Micro.
data (ex.- personnel, organisms)
Inadequate tools for data analysis and
trending
Solution Purpose-built System

Flexible schedule management allows,
routine and on-demand sampling with
frequent updates during the shift
System leverages pre-barcoded media
and device integration
Comprehensive workflow manages
and tracks samples from production
through the lab to management closeout
in accordance with SOPs
Purpose-built QC system stores, tracks
and trends all critical QC information for
quick reporting and analysis of highquality sample information
slide 14
Top 10 Best-Practice Requirements

1.
Workflow driven per SOPs
2.
Entirely paperless operation
3.
21 CFR Part 11 compliant
4.
Support full spectrum of test

methods (EM, Utility, Product)
5.
Support disconnected sample

collection anywhere in facility
6.
Device integration in clean

room and laboratory
7.
Comprehensive reporting with

trend analysis
8.
Visualization view activity

overlaid on facility maps
9.
Automatic notification for outof-spec events (alerts,

actions, missed samples)
10.
Ability to gracefully handle

process exceptions (dropped
plate, etc.)
slide 15
Introduction to Lonza and MODA Solution
B. Toal / Lonza / 22 Jun 2011
Lonzas Life-Science Platform
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
MODA Solution Value Proposition

More science. Less paper.

Quickly move from paper-intensive

QC Monitoring & Analysis
Increase operational efficiency,

improve quality, reduce costs
MODA-EM platform offers mobile

computing technology & advanced
visualization tools
slide 18
Current State: The Paper-based QC Process

Plan
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
The Paperless QC Process11 Steps Removed

Plan
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
Paperless Efficiency Example
Paper
8 hours
Paperless 4 Hours
Savings
4 Hours
slide 21
Example: Non-Viable Air Testing
The Paper-based QC Process
slide 22
Example: Non-Viable Air Testing
The Paperless Process
slide 23
Automated Reporting and Analytics
slide 24
slide 25
slide 26
MODA Solution Concept

Paperless, Automated Laboratory
MODA Solution Components
Mobile Data Acquisition
Systems
(ERP, LIMS, CAPA)
Flexible Workflow
Devices
Integration
On-Demand Analytics
Improved Compliance
Increased Productivity
Media
Expedited Decision Making
slide 27
Applied Best Practices - Case Study

at Auxilium
Nicole Quinlan
Senior Manager, Laboratory Systems
Auxilium Pharmaceuticals
Scope of the Auxilium QC Micro Program
Previous Processes & Need for Automation
Key Requirements for New Solution &

Selection Process
Implementation & Validation
Current State & Plans for Future

Auxilium was founded in 1999 (NASDAQ: AUXL)

Specialty Biopharmaceutical Company
Headquarters in Malvern, PA
Xiaflex Manufacturing and QC Laboratories
in Horsham, PA
Our Products:
TESTIM is used to treat adult males who have low
or no testosterone
Xiaflex is the only FDA-approved nonsurgical
treatment for adults with Dupuytren's Contracture
with a palpable cord
2011 Xiapex is approved and marketed in the EU
EM & Utility Monitoring

Microbial and Particulate

Monitoring for
Manufacturing Facility &
Personnel
Microbial, Endotoxin, and
Chemistry testing of all
critical utilities: WFI, RO
water, Clean Steam,
Nitrogen, Compressed
Gases
In Process Product Testing

Microbial and Endotoxin

testing of all in process
product
Working and Master Cell
Bank testing
Final Product Release
testing
8 Analysts working across 1.5 Shifts in 2 Micro Labs

Scheduling and work assignment performed

manually by shift supervisor
Controlled Paper Forms used to record results
All reports compiled manually, requiring data
verification
All trending performed manually
Large volume of paperwork increases

probability of data handling and paperwork
errors
Data entry and data review for reporting &
trending was 100% manual
Manual paperwork review process resulted in
a measureable lag time between test
completion and final reporting
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
Regulations and Guidance's

21CFR Part 11 Electronic Records ; Electronic
Signatures Scope and Application

Annex 11 Computerised Systems
ISPE GAMP 5 A Risk Based Approach to Compliant
GXP Computerized Systems
PIC/S Good Practices for Computerised Systems in
Regulated GXP Environments
PDA Technical Report No. 31 Validation and
Qualification of Computerized Laboratory Data
Acquisition Systems
Ensure the accuracy, integrity, and security of

the data
Ensure data is retrievable in an agency
inspection compatible format
Validation Model
Based on a scientific, documented, risk assessment
Based on an understanding of the supported
process and products
Verifies the system is fit for use based on the user
requirements
Paperless EM lifecycle
All sample and testing information is entered

directly into computerized system at time of
occurrence (real time). No reconciliation of
transcription process required.
Immediate access to EM results
Process owners will have access to test

results immediately after final readings due
to results being entered directly into system.
Greater flexibility in trending and reporting results

User Friendly
Designed for use by lab technicians

actually performing EM work.
Automatic notification of excursions through

the use of system generated emails
38
Mobile work stations for technicians to

access system from manufacturing cleanrooms in the plant.
Custom and ad hoc reporting for real-time
and historical data analysis.
Automatic tracking of
sample and EM process.
Scheduling of tasks; barcode label

printing; sample collection; incubation;
and testing.
Notify lab supervisors if scheduled samples are not collected.

Automatic rescheduling of samples based on limits.
Permit lab supervisors to easily schedule ad hoc & repeat samples.
39
Future Benefits and

Sustainable Compliance
Featured: MODA-FDC Cart

Stainless steel cart
Ergonomic tablet PC
Docking station
Direct thermal label printer
Barcode scanner gun
Space for equipment
Space for growth media
42
Paperless sampling in critical areas
44
Incubation
Plate Reads
Results Entry
Visualization
Trending

Workflow driven per SOPs

and Test Methods
Eliminated data entry and
transcription errors
Real time data entry with or
without network connectivity
MetOne Nonviable
integration
EM results available to
process owners faster
Eliminated scheduling errors
Part 11 / Annex 11
compliance
Reduced personnel related
deviations
Advanced support for
investigation activities

No wasted time locating

paperwork
Fewer corrections and
documentation errors
Quicker reviews
Notifications and automatic
rescheduling for deviations
Preventive notifications
before samples are missed
System generated final
results reports for LIMS
submission
Enhanced reporting and
analytics capabilities
Visualization results
overlaid on facility maps
Paper-Based System
MODA Solution
Significant number of
documentation errors
Eliminates documentation
errors
Long turn around time for

processing data
ShortShort-turn around time for

processing data
Paper presents particulate

and microbial contamination
risk
Clean room compatible

equipment reduces
contamination risk
GMP Compliance Risk
Sustainable GMP compliance
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
Substantial QC and QA hours

per month after data entry
Quick and efficient trending in

real time
Limited Scope of Trending

Reports
Wide array of trend report

formats
No Formal way of tracking

growth
Growth can be trended by

person, site, room, facility
Difficult to extract lotspecific data
lotlot-specific reporting for

Contract Manufacturing
All trending performed by QC

for QA and Manufacturing
Ease of trending allows others

(QA, Manufacturing) to
perform their own trending
Implementation & Validation
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Install MODA in Development Environment

Configure MODA with Test Methods & Master Data
(incl. Sites, Alerts/Actions, Sampling Plans, etc.)
Test Method walkthrough reviews with Micro SMEs
Micro SMEs perform hands on evaluation &
configuration review
Prepare full SDLC documentation for a configured
system (GAMP5 Category 4)
Fully validate in the QA environment (IQ, OPQ)
Conduct End User Training
Perform Installation Qualification in Production
Conduct Parallel Testing in Production Environment
Execute Cutover Plan & Go Live

6.
7.
8.
9.
10.
Install MODA in Development Environment

Configure MODA with Test Methods & Master Data
(incl. Sites, Alerts/Actions, Sampling Plans, etc.)
Test Method walkthrough reviews with Micro SMEs
Micro SMEs perform hands on evaluation &
configuration review
Prepare full SDLC documentation for a configured
system (GAMP5 Category 4)
Fully validate in the QA environment (IQ, OPQ)
Conduct End User training
Perform IQ in Production
Conduct Parallel Testing in Production environment
Execute Cutover Plan & Go Live [Target 3Q2011]
Auxilium & Lonza
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
NOTE: All images contained herein have been provided by

Lonza and do not depict actual Auxilium facilities,
equipment, or personnel.
10/5/2011
Enhanced Aseptic Processing

Using Risk Identification and
Control for Improving Your
Operations
p
Anne M Garstka
1
Goal
Share
with you seeds of knowledge
Provide
tools to help you think about risk

identification and control in a different
way
To
make you think
Inside
To
and outside of the box
learn from YOU!
10/5/2011
Food for Thought

In
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
the hazards associated

with
h the
h product
d
from
f
the
h conception
and design phase throughout the
production and distribution chain and
the end of the product life
WHAT
DOES THIS SOUND LIKE?
HACCP Basics
Validation Master Plan
Tools to assess hazards
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
R&D, Raw Material Management, manufacturing,

packaging, testing, and distribution
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
Conduct hazard analysis and consider any

measure to control identified hazard
10/5/2011
12 STAGES of HACCP
Determine
critical control points

Establish critical limits for each CCP
Establish a monitoring system for
each CCP
Establish corrective actions
Establish verification procedures
Establish documentation and record
keeping
9
PROCESS / DESIGN
OVERVIEW
10
10/5/2011
PROCESS / DESIGN OVERVIEW

FACTS
Every
organization has their own

process
There are similarities but then again
there are differences
Goal
For
you to swim lane your own process!

11
Swim Lanes..
Type
of process flow diagram that

allows
ll s one
n to
t ttrack
k activities
ti iti s with
ith th
the
players
Identifies
what is performed by whom

What is needed to perform the assigned
task
What is needed to pass the task
task on to
the next person
Identifies areas of concern along with
potential fixes
12
10/5/2011
GENERALs
What does your process look like? More

i
importantly
t tl --- where
h
d
do I start?
t t?
Starting materials
In-process
Fill / Finish
Packaging
Distribution
MORE?????
13
Group Activity!
14
10/5/2011
In the Beginning
What
does one need to understand

when product is manufactured by
aseptic means?
15
Media Fills
Global standards in combination with

applicable FDA regulations, guidances and
other relevant references to ensure a
pharmaceutical facility in under the
appropriate state of control. Appropriate
measures augmenting recommendation
with
ith supporting
ti EM and
d micro
i
d
date,
t will
ill
help to meet or exceed cGMP in a
pharmaceutical facility.
16
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
awareness, role of staff,

training, holistic approach
Emulate routine production process as
closely as possible
Simulations
FDA
performed
minimum 2x/year
Canada 4x/year
Know who you need to satisfy
(regulatory requirements)
18
10/5/2011
Rigorous Design: Quality Overview Summary

What parameters are evaluated during
the
h media
d fill
f ll to ensure the
h efficacy
ff
and
d
consistency of the process?
What filling line was used?
What types of sterile equipment was
used?
What is the number of units filled versus
number incubated?
How many media fills were performed and
when were they conducted?
What was the incubation conditions used
19
for the units?

How does the media fill simulate the
production parameters?
What are the hold times validated by the
media fill?
Is a matrix or bracketing approach
proposed?
p
p
What method is used to perform growth
promotion testing?
Were there any positive units during the
media fill?
20
10
10/5/2011

What
is the room requalification

q
f
schedule for media fills in the filling
room?
Is any reprocessing of components
or product proposed?
Is lyophilization of the finished drug
product or sterile API proposed?
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
firm has failed to conduct a

media fill representative of the
different packaging configurations
of your drug products for the past 2
years. Your firm has been using a
volume of x for media fills; however
commercial
i l products
d t are available
il bl iin
y and Z. In addition, you have not
established a maximum aseptic fill
duration
25
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
Beyond the Media Fill

Daily
y
sterility
y assurance
Personnel
Facility
(design, control, maintenance)

Aseptic processing line (design, control,
maintenance)
Process (personnel / material flow,
flow
layout)
HVAC / utilities (design, control,
maintenance)
27

Daily
y
sterility
y assurance
Response
to deviations and
environmental control trends
Disinfection regime and actual practices
Media fills
QA/QC
28
14
10/5/2011

Continued
Process Verification
f
Parameters to be monitored
Personnel
/ interventions
Sterility of product / product contact
surfaces
f
Conditions of non-product contact
surfaces
Production yields / quality of output
29
Personnel / interventions
Process observations, personnel monitoring,

sterility results
EM results, pressure differential monitoring,
periodic clean room certification
Ster l ty of product / product contact

Sterility
surfaces
Sterility test results, bioburden monitoring,

periodic requalification of utilities and
equipment
30
15
10/5/2011

Conditions
surfaces
EM
of
f non-product
p
contact
results
Production
yields / quality of output
Production
yields, analysis of product

d f t and
defects
d rejection
j ti rates,
t
production
d ti
downtime, customer complaints (AEs)
31
Got Contamination?
Now
what?
How do you investigate?
What do you focus on?
Processing
Procedures
Personnel
When
do you notify regulatory

agencies?
32
16
10/5/2011
Contamination Contributors
Sources
of
f Contamination
Raw
material suppliers
Inadequate cleaning
People
Inadequate procedures
Inadequate
d
processes
Can
you think of any others?

33
Contamination: Product Impact

Contamination
Recalls
Thin
glass flakes
Stainless steel particulates
Small white particles (polyethylene
terephthalate polyester)
Cracked glass
34
17
10/5/2011
Real World Real Solutions

Sub-visible
p
particles
Less
than 10 microns
Current standard 0.2 micron filter
Aggregates and potential impact
Stresses during production )freezing,

thawing agitation and foaming)
thawing,
Currently
--- gathering data
Patient safety
35

Isolators
Used
to separate external clean room

environment from the aseptic
processing line
Minimize exposure to personnel
Challenges
Glove integrity, Design, Maintenance,

Cleaning, Material transfer, Personnel, EM,
36
18
10/5/2011

Closed
Vial Technology
gy
Based
upon a closed container that can

be filled through a heat resealable
stopper
Container is provided stopper and ready to
fill vial
Vial: molded in class 100 followed by
sterilization
37

Closed
Key
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
10/3/2011
Environmental Controls
Diff. pressure cascade Cleaning

Ai filtration
Air
filt ti
Sanitization
S iti ti / Di
Disinfection
i f ti
Design of equipment Gowning
Design of facility
Computerized building
(ease of cleaning and system
maintenance materials
Sterilization of
off construction)
t ti )
components
Maintenance and PM Depyrogenization
SOPs
Utility and auxiliary
AIRLOCKs
systems
Microbial Control Strategy
KEEP THEM
OUT!
10/3/2011
To be discussed
Regulatory Considerations in Qualification
Environmental Monitoring (EM) Program
US and EU GMPs and EM

FDA aseptic processing guide
EU Annex 1
R
Regulatory
l t
requirements
i
t vs expectations
t ti
sterile vs non-sterile products
Recent Inspection findings
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
Application of Risk management tools

The people factor: qualification of gowning
10/3/2011
PCI
Pharm
ti
Previous
Current
PCI
Pharm
ti
10/3/2011

Cleanrooms and clean air devices should
be routinely monitored in operation and
the monitoring locations based on a formal
risk analysis study and the results
obtained during the classification of rooms
and / or clean air devices
PCI
Pharm
ti
Grade A: full duration of critical processing, including
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
1
0
PCI
Pharm
ti
10/3/2011
Sample Size
1
1
PCI
Pharm
ti
FDA Aseptic Processing Guide
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
ICH Q9 Risk Management
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
If YES; structured Risk Assessment may not

add value
If NO; structured Risk Assessment probably
will add value
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
Sterility Control Strategy
Informal Risk Assessment

1.
Analysis of facts
Defined cleaning procedure covers all equipment surfaces by

distillation/reflux or by manual procedure;
equipment is easily dismountable & most is transparent glassware;
(more)
2. Risk Assessment
2.1 Risk identification: Absence of analytical evaluation of equipment

cleanliness could allow carry over of unacceptable amounts of
residues from one batch to the next.
2.2 Risk analysis
Equipment is dedicated by manufacturing step.

Cleaning procedure includes disassembling of equipment, followed
by distillation/reflux and manual cleaning ....
(more)
2.3 Risk evaluation
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
Generally part of IND / NDA

and is a SPECIFICATION
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
FMEA Numbering for RPN

Have to pre-define a scale
Use numbers
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

Rather, the RPN
Allows
Allo s risks to be ranked
Allows action to be prioritised
Provides justifiable basis for decision making
including doing nothing!
Can be documented so history is available
14
10/3/2011
EM Sample Site Selection

Based on risk associated with product
contamination.
contamination
Sites that would represent the most inaccessible
or difficult area to clean.
Major contamination sources
Personnel
High traffic areas
Direct or potential product contact
Atmospheric
EM Sample Site Selection

Documented rationale for each selected site.
Each
E h selected
l t d sampling
li llocation
ti d
detailed
t il d on
area maps for each room.
Assures homogeneous sampling and
meaningful trending
15
10/3/2011
List of References (partial)

USP and Ph. Eur: Microbial Limits monographs and general
chapters on Microbiological Attributes of pharmaceutical
p
products
ICH Q6A: Setting specifications for APIs, excipients and products
FDA Inspection Guide: Microbiological Pharmaceutical Quality
Control Laboratories
Pharmacopeial Forum: Chapter <1117> Microbiological Good
Laboratory Practices
PDA TR#35 Proposed Training Model for Microbiological
Function in the Pharmaceutical Industry
PDA TR#13 : Fundamentals of an Environmental Monitoring
Program
Bacterial adhesion: Considerations Within A Risk-Based
Approach to Cleaning Validation, Tidswell E.C.
J. Pharm. Sci. and Tech. Vol. 59; No.1
And now to HACCP workshop
16
10/3/2011
Thank You for Your Attention

Did you enjoy the workshop?
What did you learn?
How will you implement what you learned
back in your company?
Contact Details
KAREN GINSBURY
pcikaren@netvision.net.il
17
Preventing
Contamination:
Taking the Mystery out
of Media Fills
Dawn Tavalsky
S
Sanofi
fi Pasteur
P t
TOPICS
Aseptic Processing a Quick Review

The Media Fill
Using a Risk Based Approach
Media Fill Guidance Documents
Media Fill Case Study
Revisions to TR22
Aseptic Processing
Aseptic Processing - Overview
Certain pharmaceutical products must be sterile

injections, ophthalmic preparations, irrigations solutions,
haemodialysis
y
solutions
Two categories of sterile products

those that can be sterilized in final container (terminally
sterilized)
those that cannot be terminally sterilized and must be

aseptically prepared
Objective is to maintain the sterility of a product,

assembled from sterile components
Operating conditions designed so as to prevent

microbial contamination

Objective
To review specific issues relating to the manufacture of

aseptically prepared products:
Manufacturing environment
Clean areas
Personnel
Preparation and filtration of solutions
Pre-filtration bioburden
Filter integrity/validation
Equipment/container
E i
t/
t i
preparation
ti and
d sterilization
t ili ti
Filling Process
Validation of aseptic processes
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
Classification of Clean Areas
Classified in terms of airborne particles

Grade
At rest
In operation
maximum permitted number of particles/m3

0.5 - 5.0 m
> 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
At rest - production equipment installed and operating

In operation - Installed equipment functioning in defined
operating mode and specified number of personnel present
Four grades of clean areas:
Grade D (equivalent to Class 100,000, ISO 8):

Clean area for carrying
y g out less critical stages
g in manufacture of
aseptically prepared products eg. handling of components after washing.
Grade C (equivalent to Class 10,000, ISO 7):
Clean area for carrying out less critical stages in manufacture of
aseptically prepared products eg. preparation of solutions to be filtered.
Grade B (equivalent to Class 100, ISO 5):
Background environment for Grade A zone, eg. cleanroom in which
laminar flow workstation is housed.
Grade A (equivalent to Class 100 (US Federal Standard 209E), ISO 5
(ISO 14644-1):
Local
L
l zone for
f high
hi h risk
i k operations
i
eg. product
d
filling,
filli
stopper bowls,
b l
open vials, handling sterile materials, aseptic connections, transfer of
partially stoppered containers to be lyophilized.
Conditions usually provided by laminar air flow workstation.
Limits for viable particles (microbiological contamination)
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
-
These are average values

Individual settle plates may be exposed for less than 4 hours
Values are for guidance only - not intended to represent specifications
Levels (limits) of detection of microbiological contamination should be
established for alert and action purposes and for monitoring trends of air
quality in the facility
10
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
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
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
Air Changes/Airflow patterns

Air flow over critical areas should be uni-directional
(laminar flow) at a velocity sufficient to sweep particles
away from filling/closing area
for B, C and D rooms at least 20 changes per hour are
ususally required
Clean up time/recovery
Particulate levels for the Grade A at rest state should be
achieved after a short clean-up period of 20 minutes
after completion of operations (guidance value)
Particle counts for Grade A in operation state should be
maintained whenever product or open container is
exposed
14
Temperature and Relative Humidity

Ambient temperature and humidity should not be
uncomfortably high (could cause operators to generate
particles) (18C)
Airflow velocity
Laminar airflow workstation air speed of approx 0.45m/s
20% at working position (guidance value)
15
16
Personnel
Minimum number of personnel in clean areas

especially during aseptic processing
Inspections and controls from outside
Training to all including cleaning and maintenance staff
initial and regular
manufacturing, hygiene, microbiology
should be formally validated and authorized to enter
aseptic area
Special cases
supervision in case of outside staff
decontamination procedures (e.g. staff who worked
with animal tissue materials)
Personnel (2)
High standards of hygiene and cleanliness

should not enter clean rooms if ill or with open
wounds
Periodic health checks
No shedding of particles, movement slow and controlled
No introduction of microbiological hazards
No outdoor clothing brought into clean areas, should be clad
in factoryy clothing
g
Changing and washing procedure
No watches, jewellery and cosmetics
Eye checks if involved in visual inspection
17
18
Personnel (3)
Clothing of appropriate quality:

Grade D
hair, beard, moustache covered
protective clothing and shoes
Grade C
hair, beard, moustache covered
single or 2-piece suit (covering wrists, high neck),
shoes/overshoes
no fibres/particles to be shed
Grade A and B
headgear, beard and moustache covered, masks,
gloves
not shedding fibres, and retain particles shed by
operators
Personnel (4)
Outdoor clothing not in change rooms leading to Grade B and C

rooms
Change at every working session, or once a day (if supportive
data)
Change gloves and masks at every working session
Frequent disinfection of gloves during operations
Washing of garments separate laundry facility
No damage, and according to validated procedures
(washing and sterilization)
Regular microbiological monitoring of operators
19
Aseptic Processing
In aseptic processing, each component is individually sterilized, or

several components are combined with the resulting mixture
sterilized.
Most common is preparation of a solution which is
filtered through a sterilizing filter then filled into sterile
containers (e.g active and excipients dissolved in Water
for Injection)
May involve aseptic compounding of previously sterilized
components which is filled into sterile containers
May involve filling of previously sterilized powder
sterilized by dry heat/irradiation
produced from a sterile filtered solution which is then
aseptically crystallized and precipitated
requires more handling and manipulation with higher
potential for contamination during 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
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
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
Filter must be validated to demonstrate ability to remove bacteria

most common method is to show that filter can retain a
microbiological challenge of 107 CFU of Brevundimonas
diminuta per cm2 of the filter surface
a bioburden isolate may be more appropriate for filter
retention studies than Brevundimonas diminuta
Challenge concentration is intended to provide a margin
of safety well beyond what would be expected in
production
preferably the microbial challenge is added to the fully
formulated product which is then passed through the
filter
14
Aseptic Processing
Filter validation (2)
if the product is bactericidal, product should be passed

through the filter first followed by modified product
containing the microbial challenge (after removing any
bactericidal activity remaining on the filter)
filter validation should be carried out under worst case
conditions e.g. maximum allowed filtration time and
maximum pressure
integrity testing specification for routine filtration should
correlate with that identified during filter validation
29
Aseptic Processing
Equipment/container preparation and sterilization
All equipment (including lyophilizers) and product

containers/closures should be sterilized using
g validated cycles
y
same requirements apply for equipment sterilization that
apply to terminally sterilized product
particular attention to stoppers - should not be tightly
packed as may clump together and affect air removal
during vacuum stage of sterilization process
equipment wrapped and loaded to facilitate air removal
particular attention to filters
filters, housings and tubing
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)
equipment should be designed to be easily assembled and

disassembled,, cleaned,, sanitised and/or sterilized
equipment should be appropriately cleaned - O-rings and
gaskets should be removed to prevent build up of dirt or
residues
rinse water should be WFI grade
equipment should be left dry unless sterilized immediately after
cleaning (to prevent build up of pyrogens)
washing of glass containers and rubber stoppers should be
validated for endotoxin removal
should be defined storage period between sterilization and use
(period should be justified)
16
The Media Fill
33
34
Aseptic Processing
Media Fill
Not possible to define a sterility assurance level for aseptic

p
processing
g
Sterile Process is validated by simulating the manufacturing
process using microbiological growth medium (media fill)
Process simulation includes formulation (compounding),
filtration and filling with suitable media using the same
processes involved in manufacture of the product
modifications must be made for different dosage formats
e.g. lyophilized products, ointments, sterile bulks, eye
drops filled into semi-transparent/opaque containers,
biological products
17
Aseptic Processing
Media Fill (2)
Media fill program should include worst case activities

Factors associated with longest permitted run (e
(e.g.
g
operator fatigue)
Representative number, type, and complexity of normal
interventions, non-routine interventions and events (e.g.
maintenance, stoppages, etc)
Lyophilisation
Aseptic equipment assembly
35
Aseptic Processing
Media Fill (3)
Worst case activities (cont)

No of personnel and their activities,
activities shift changes,
changes breaks,
breaks
gown changes
Representative number of aseptic additions (e.g. charging
containers, closures, sterile ingredients) or transfers
Aseptic equipment connections/disconnections
Aseptic sample collections
Line speed and configuration
36
18
Aseptic Processing
Media Fill (4)
Worst case activities (cont)

Weight checks
Container closure systems
Specific provisions in processing instructions
Written batch record documenting conditions and activities
Should not be used to justify risky practices
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)
Frequency and Number

Three initial
initial, consecutive per shift
Subsequently semi-annual per shift and process
All personnel should participate at least annually,
consistent with routine duties
Changes should be assessed and revalidation carried out

as required
Line Speed
Speed depends on type of process
39
Aseptic Processing
Media Fill (7)
Representative of actual production conditions (no. of personnel, activity levels etc) - no

special precautions (not including adjustment of HVAC)
if nitrogen used for overlaying/purging need to substitute with air
Media
Anaerobic media should be considered under certain circumstances

Should be tested for growth promoting properties (including factory isolates)
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)
Batch Record Review

Process and environmental control activities should be
included in batch records and reviewed as part of batch
release
In-process and laboratory control results
Environmental and personnel monitoring data
Output from support systems(HEPA/HVAC, WFI, steam
generator)
Equipment function (batch alarm reports
reports, filter integrity)
Interventions, Deviations, Stoppages - duration and
associated time
Written instructions regarding need for line clearances
Disruptions to power supply
22
Aseptic Processing
Issues relating to Aseptic Bulk Processing

Applies to products which can not be filtered at point of fill
and require aseptic processing throughout entire
manufacturing process.
Entire aseptic process should be subject to process
simulation studies under worst case conditions (maximum
duration of "open" operations, maximum no of operators)
Process simulations should incorporate storage and
transport of bulk.
Multiple
p uses of the same bulk with storage
g in between
should also be included in process simulations
Assurance of bulk vessel integrity for specified holding
times.
45
46
Aseptic Processing
Bulk Processing (2)

Process simulation for formulation stage should be
performed
pe
o ed at least
east ttwice
ce pe
per yea
year.
Cellular therapies, cell derived products etc
products released before results of sterility tests known
(also TPNs, radioactive preps, cytotoxics)
should be manufactured in a closed system
Additional testing
sterility testing of intermediates
microscopic examination (e.g. gram stain)
endotoxin testing
23
Useful Publications
PIC/S Recommendation on the Validation of Aseptic Processes

FDA Guidance for Industry- Sterile Drug Products Produced by
Aseptic Processing - Current Good Manufacturing Process
ISO 13408 Aseptic Processing of Health Care Products
Part 1: General Requirements
Part 2: Filtration
Part 3: Lyophilization
Part 4: Clean-In-Place Technologies
Part 5: Sterilization-In-Place
Part 6: Isolator Systems
47
48
Using a Risk Based Approach
24
Preventing Contamination: Aseptic

Processing Risk Factors
Risk-based approach
Critical Control Points (CCPs)
Sources
S
off Variability
V i bilit
Holistic Facility
Case studies
Recurring problems underscore importance of CCPs
Five Major Issues for Discussion
49
Risk Analysis FMEA
Reducing Risk Severity Factor:

Process changes or product redesign including development
of an aseptically produced product into one with terminal
sterilization.
Reducing Probability of Occurrence of Risk:
Process automation projects, tighter controls upstream in the

process, and new technologies such as isolators
Probability of Detecting Failures:
Validation is intensified monitoring which should detect flaws or

weaknesses,
ea esses, which
c may
ay not
ot be normally
o a y obse
observable.
ab e A media
ed a fill
is a good example of a validation test.
[Noble, P., PDA Journal of Pharmaceutical Science and Technology, July/August 2001.]
50
25
Risk-Based Approach
Critical Control Points
Causes of Contamination
Where are the potential routes of contamination in an

aseptic process?
Detection of Contamination Problem
What measurements are most valuable in indicating
sterility assurance?
Focus on issues of concern

Influential factors that determine control of the facility and
process
Failure to meet CGMP can impact safety or efficacy
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
Aseptic Processing requires A

A strict design regime,
regime
not only on the process area, but on the interactions
with surrounding areas and the movement of people,
materials and equipment so as not to compromise the
aseptic conditions.
[ISPE Sterile Manufacturing Facilities Guide, Volume 3, January 1999]
53
Personnel
Continued
Continued vigilance throughout the
entire manufacturing process
[Avis, K.,Personnel An academic Approach, PDA Journal, Sept-Oct., 1971]
Unstable situations are, in most

cases, ca
cases
caused
sed b
by the infl
influence
ence of
arms and hands.
[Ljungqvist, B., and Reinmuller, B., Clean Room Design: Minimizing Contamination Through Proper
Design; Interpharm Press,
54
27
Environment
Studies have shown that the level of airborne
microorganisms in the filling environment has a

profound effect on the level of product
contamination.
[Ljungqvist, B., and Reinmuller, B., Clean Room Design: Minimizing Contamination Through
Proper Design; Interpharm Press, 1997]
Researchers found a definable direct relationship
between the fraction of product contaminated and the

level of microorganisms in the air surrounding the
machine
[Sinclair, C.S., and Tallentire, A., J Pharm Sci Tech, 49 (6), 294-299]
55
Environmental Data and State of Line

Qualification
It also may be necessary to requalify with acceptable process

simulation tests in response to adverse trends or failures in the ongoing
monitoring
i i off the
h ffacility
ili or process such
h as: Continued
C i
d critical
i i l area EM
results above action/alert limits
[PDA Technical Report #22 Process Simulation Testing for Aseptically Filled Products, 1996]
Facility and equipment modification, significant changes in personnel,

anomalies in environmental testing results and end product sterility
testing showing contaminated products may all be cause for revalidating
the system.
[FDAs 1987 Guideline

Guideline on Sterile Drug Products Produced by Aseptic Processing]
56
28
Design, Environment, & Personnel: Link to

Sterility
Widely accepted that each of the following is crucial to assuring sterility:

Design
Environment
Personnel
Thats theory, what about actual experiences?

The above principle plays out in the many case studies we see
throughout each year.
Lack of adherence to CGMP in these areas underlies the vast
number of failures in the industry.
57
Case Study
Media Fill Failure
Media Fill Failure:

Approx. 60% contaminated
p
Corrections made to firms satisfaction.
Considered spurious.
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 non-sterility problem still existed.
Root Cause:
Personnel / Aseptic Connection
Isolates in both failures were common skin-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.
|
58
29
A Brief History of Media Fill

Guidance
59
60
30
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62
31
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64
32
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66
33
67
68
34
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70
35
A Media Fill Execution Example
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53
Thank you
Questions / Comments?
Feel free to contact me at
dawn.tavalsky@sanofipaseur.com
107
54
Testing / Sampling -- Drug Product

Manufacturing Process Validation
2011 PROCESS VALIDATION GUIDANCE

APPLICATION TO CLEANING VALIDATION
INCLUDING CASE STUDIES
Paul L. Pluta, PhD
Journal of Validation Technology
Journal of GXP Compliance
University of Illinois at Chicago (UIC) College of Pharmacy
Chicago, IL, USA
OUTLINE / OBJECTIVES
Process Validation General
PV Guidance recommendations Comparison to current
Stages of Process Validation
Stage 1 Process Design (Understanding)

St
Stage
2 Process
P
Q
Qualification
lifi ti (P
(Performance)
f
)
Stage 3 Continued Process Verification (Maintenance)
Lifecycle Approach to Cleaning Validation
Stage activities Stages 1, 2, and 3

Common problems Case studies
Residue
Performance
Equipment
Analytical
Documentation
Interactive discussion
PLEASE PARTICIPATE!
2

Does this make sense?

Cleaning is a process
Validation lifecycle concepts being applied to equipment,
facilities, utilities, computers, etc., by validation and
technical experts
Who can argue with understanding, performing, and
maintaining the validated state?
Consistent with QbD and ICH approaches
pp
Which approach would you rather present to an
auditor?
3
TERMINOLOGY: PROCESS VALIDATION

Process Validation Process Qualification
Process Performance Qualification (PPQ)
Qualification
Equipment #1
UO #1
Equipment #2
Process steps
Equipment #3
Process steps
UO #2
Qualification
HVAC
Utilities
Facilities
Computers
UO #3
Process steps
Analytical methods validation

Cleaning process validation
Packaging process validation
Acceptable lots = Process is validated
4

FDA PROCESS VALIDATION GUIDANCE (2011)

Definition: Collection and evaluation of data, from the process design
stage throughout commercial production, which establishes
scientific evidence that a process is capable of consistently
delivering quality products. Process validation involves a series of
activities over the lifecycle of the product and process.
Three stages of activities:
Stage 1 Process Design Development and scale-up activities
Stage 2 Process Qualification Reproducible manufacturing
Stage 3 Continued Process Verification Maintaining the
validated state during ongoing manufacturing
Other topics in Guidance
Concurrent release
Documentation
Analytical methodology
5
VALIDATION GUIDANCE TRANSITION
1987
Development
Performance Maintenance
2008-2011
Development Performance
f
Maintenance
Above based on RISK

FDA PROCESS VALIDATION GUIDANCE (1-2011)

Stage 1. Process design
R&D / technical development work
Stage 2. Process qualification
Equipment considerations
PQ protocol, testing, results
Stage 3. Continued process verification
Monitoring and maintaining validation
Change control
A l ti l considerations
Analytical
id ti
Documentation
CLEANING IS A PROCESS -APPLICATION OF THE ABOVE TO CLEANING
7
WHAT IS THE CLEANING PROCESS?

Cleaning Process Performance Qualification
Automated CIP System
Process steps
1 Residue on equipment
1.
2. Water rinse
3. Cleaning agent rinse
4. Water rinse
5. Purified Water rinse
6. Dry
Qualification
Equipment
Purified Water
Computer / software
Compressed air
Conductivity
TOC
Equipment is clean -- Process is validated
Process parameters Quality attributes

8

WHAT IS THE CLEANING PROCESS?

Cleaning Process Performance Qualification
Manual Cleaning
Process steps
1 Residue on equipment
1.
2. Water rinse
3. Scrub
4. Cleaning agent rinse
5. Scrub
6. Water rinse
7. Purified
u ed Water
ate rinse
se
8. Dry
Qualification
Personnel
Purified Water
Compressed air
Equipment is clean -- Process is validated

Process parameters Quality attributes
9
CLEANING VALIDATION OVERVIEW

1990s 2008
1. Defined cleaning procedure (basis?)
2 Product A batch does not contaminate subsequent
2.
Product B batch
3. Acceptance limit calculated
4. Assume uniform contamination of all equipment
5. Three conformance lots = Validated cleaning procedure
6. Validated analytical method (original API)
7. Worst-case matrix approach
10

FDA PROCESS VALDIATION GUIDANCE TRANSITION

APPPLICATION TO CLEANING VALIDATION
Pre 2008
Cl
Cleaning
i method
th d d
development
l
t (?)
PQ Maintenance (change control)

Post 2008 (Draft 2008, finalized 2011)
Development PQ Maintenance
INCREASED SPECIFIC REQUIREMENTS
11
STAGE 1, PROCESS DESIGN (PROCESS UNDERSTANDING)

APPLICATION TO CLEANING
1. Building and capturing process knowledge and understanding.
2. Establishing a strategy for process control.
Understand residue chemistry (solubility, stability)
Determine cleaning agent based on chemistry
Determine cleaning process
Determine process parameters
Lab scale and pilot scale experiments
Designed experiments
Define commercial-scale process
Identify and understand sources of variability
Establish methods to control variability
Process Analytical Technology
DOCUMENT ALL OF THE ABOVE

12

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
RESIDUE PROPERTIES AS BASIS FOR CLEANING

Example: Antibiotic suspension containing basic API
Original cleaning method: Water, PurW, dry
No documented cleaning validation for many years
Unknown
U k
peaks
k on original
i i l cleaning
l
i validation
lid ti attempts
tt
t
Basic API insoluble
Second method: Alkaline soap wash, water, PurW, dry

Unknown peaks again
Basic API insoluble
Final method: Acid wash, alkaline soap wash, water, PurW, dry
No residues. Unknown peaks determined to be flavors.
Basic API dissolves
Consider active drug and other residue chemistry in

development of cleaning process
14

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
pH SOLUBILITY PROFILE, pH 1-12

Solubility
mg/ml
Drug A
Drug B
pH 1
12
16

RESIDUE SOLUBILITY AND STABILITY FOR

DETERMINING WORST-CASE SOILS
Solubility considerations
Hydrophilic
y p
and hydrophobic
y p
molecules
Ionization Effect of pH
Effect of temperature
Surface active molecules
Liquid and semisolid product vehicle polarity
Stability considerations
Hydrolysis, oxidation, photolysis, physical changes
What residue is really present?
Consider chemistry of residues.
17
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
Automated cleaning vs. manual cleaning

Manual cleaning process variation
Human physical variation
Cleaning between same-product batches
Campaign length
Time to initiate cleaning (Dirty hold time)
Equipment storage (Clean hold time)
20
10

STAGE 2, PROCESS QUALIFICATION

(VALIDATION PERFORMANCE)
APPLIUCATION TO CLEANING
1.
2.
3.
4.
Design of a facility and qualification of utilities and equipment

Process performance qualification
PPQ protocol
PPQ protocol execution and report
Qualification of equipment, utilities, facilities

Cleaning equipment (CIP)
Equipment to be cleaned
Product contact materials composition/surface polish
Most difficult to clean locations
Process Performance Qualification commercial scale
Conclusion that process consistently produces clean equipment
Conformance batches
All support systems,
systems documents
documents, training
training, personnel
personnel, etc.
etc in place
Target / nominal operating parameters within design space
Additional testing (swab / rinse)
Decision to release cleaning process for routine commercial use
Post validation monitoring plan Based on risk
Drug residue properties
Manual or CIP
21
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)
(IQ/OQ/PQ for manufacturing process application)

23
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

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
PROCEDURE TO DETERMINE SAMPLING

LOCATIONS
Specific procedure recommended
Equipment
E i
t ttechnical
h i l evaluation
l ti
Observation of equipment after processing
Equipment disassembly review
Cleaning procedure review
p
interviews
Operator
SOP describing above
Documentation of above for equipment sampling
26
13

CLEANING PROCESS DOCUMENTATION (Cleaning batch record)

SOP
Fill tank half full
Add half scoop of soap
Scrub as needed
Rinse until clean
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 Part B. Steps 1,2,3,4,5
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
27
TIME TO INITIATE CLEANING

DIRTY HOLD TIME
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

How to determine Dirty Hold Time (DHT)

Lot
#1
#2
#3
Time to initiate cleaning

3d
days
7 days
5 days
What is DHT?
3 days unless other data available.
29
LABORATORY STUDY DIRTY HOLD TIME

1.
2.
3.
4.
5.
Develop simulated cleaning process

Coupon in beaker with stirrer
Weigh coupons. Pour residue onto coupon surface per time
schedule Allow to air dry
schedule.
dry. Weigh coupons
coupons.
Example time schedule:
1-1-2011
Day 30
1-10-2011
Day 20
1-20-2011
Day 10
1-25-2011
Day 5
1-28-2011
Day 2
1-29 2011
Dayy 1
1-30-2011
Day 0
Perform simulated cleaning. Observe. Air dry. Observe. Swab
coupons if needed (quantitative analysis).
Weigh dry coupons. Calculate residuals.
30
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
EQUIPMENT STORAGE (CLEAN HOLD TIME)

How long can equipment be stored without recleaning?
Storage location?
Storage conditions?
What type of testing?

Do not test for residual drug
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
Manual cleaning is high risk
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?
Q to management: Do you know that your equipment is not clean?
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
STAGE 3, CONTINUED PROCESS VERIFICATION

(VALIDATION MONITORING AND MAINTENANCE)
APPLICATION TO CLEANING
Activities to assure process remains in validated state

Change
g control -- evaluate impact
p
of change
g and validate
(test) as necessary
Trend and assess data
Study OOS and OOT (Out of Trend) data
Improve process
Improve control to detect and reduce variability
Cleaning non-conformances and deviations
Re validation definition: Actual batch or paper
Re-validation
Is re-testing necessary?
When should re-testing be considered?
Periodic Management Review
36
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
Risk analysis -- cleaning method (CIP or manual), residue

toxicity, etc.
37
POST VALIDATION MONITORING
Residue toxicity risk

Residue that can be visually seen
Room lighting must be adequate
Provide additional lighting if necessary
Residue that cannot be visually seen
38
19

DOCUMENTATION
Stages 1, 2, 3
Cleaning process development reports
Equipment qualification
Cleaning equipment
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
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
pH / cleaning agent-solubility profile
pH / cleaning agent-stability profile
What can happen to residue?
Oxidation
Hydrolysis
Photolysis
Physical change
Bi t h protein
Biotech
t i residue
id d
degraded
d d iin cleaning
l
i process

42
21

ANALYTICAL RECOVERY STUDIES

Identify all product-contact materials to be swabbed
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
Factor data based on recovery results if necessary
Done in analytical laboratory by lab personnel

API (actual) and cleaning agent
43
SAMPLING PERSONNEL TRAINING

Representative sampling sites
Use of auxiliary equipment
Representative of most difficult analytical methods

Volatile solvents time constraints
Retraining considerations
Who does sampling?
Personnel skills
44
22

EXAMPLE CLEANING VALIDATION DATA

HPLC method
Equipment sample #
1
2
3
4
5
6
7
..
24
Residue analysis (per swab)

< 1 mcg
< 1 mcg
< 1 mcg
< 1 mcg
< 1 mcg
< 1 mcg
< 1 mcg
..
< 1 mcg
Conclusion: Cleaning is validated?

Reality: API completely degraded, API not recoverable
45
SUMMARY
WHERE WE ARE -- CURRENT PRACTICE
R&D
Validation
Commercialization
46
23

SUMMARY -- WHERE WE ARE GOING

LIFECYCLE APPROACH TO PROCESS VALIDATION
Objectives:
Scientific and technical process

Demonstrate process works as intended
Process must remain in control throughout lifecycle
Cleaning equipment
Effective documents consistent with the above
Analytical methods validated (includes sampling)
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
2011
Development
p
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

Swab / rinse testing on equipment

Most difficult to clean sampling sites
Use of auxiliary sampling equipment (extension pole)
Swab / rinse training of sampling person

53
SUMMARY
DOCUMENTATION
Document everything
Documentation must be readily available
Documentation must be
Scientific and technical
Thorough and clear
Simple sentences, good grammar
54
27

POTENTIAL PROBLEM AREAS

Stage 1. Development
Understand residue properties
Stage 2. Performance
Cleaning procedure records (Cleaning batch records)
Non-uniform contamination
Most difficult-to-clean locations in the equipment
Risk in manual cleaning procedures, evaluation, and training
Dirty and clean hold times
Stage 3. Maintenance
Change control
g
review -- deviations,, non-conformances,, re-cleaning,
g,
Periodic management
changes, trends, etc.
Analytical
Residue properties analytical methods for actual residue
Recovery studies
Swab sampling training
55
WHAT TO DO NEXT?
1.
Plan implementation strategy

Deliberate program guarantee success
2.
Get upper management agreement

Management sets direction
3.
Get Validation Approval Committee agreement

Standards and responsibilities
4.
Get QA agreement
5.
6.
7
7.
8.
9.
Train development group (Stage 1)

Train Annual Product Review group (Stage 3)
Train site on validation lifecycle approach
Train protocol writers
Start slowly Pilot approach Build on continuing success
QA has GMP responsibility
Opportunity for validation leadership!

56
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

PAUL L. PLUTA, PhD

Editor-in-Chief
Ad
Advanstar
t Communications,
C
i ti
Iselin,
I li NJ,
NJ USA
Adjunct Associate Professor

Chicago, IL, USA
Editor and Chapter Author

Cleaning and Cleaning Validation
Validation, Volume 1
1. Basics
Basics,
Expectations, and Principles
PDA and Davis Healthcare International (DHI) Publishing, 2009
Contact: paul.pluta@comcast.net
59
30
10/5/2011
Organization Training and Process Flow

Organization,
for Sanitization of an Aseptic Facility
Robert Pallo
10/5/2011
Organization, Training and Process Flow for

Sanitization of an Aseptic Facility -- Robert Pallo
Organization, Training and Process

Flow for Sanitization of an Aseptic
Facility
Robert Pallo
Manager PSO Fill and Finish Operations
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

10/5/2011
Organization, Training and Process

Flow for Sanitization of an Aseptic
Facility
TRAINING STRATEGIES
10/5/2011
TYPES OF TRAINING METHODS

HOW TO BE SUCCESSFUL AT TRAINING
TRAINING FOR THE NON MICROBIOLOGIST
GOWNING TRAINING
ASEPTIC TECHNIQUE TRAINING
THE IMPORTANCE OF MONITORING


CLASSROOM TRAINING
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

CLASSROOM TRAINING
VESTIBULE TRAINING
10/5/2011


CLASSROOM TRAINING
VESTIBULAR TRAINING
Classroom is created as close to the production
facility as conditions allow
Same equipment, machinery, and environment
10/5/2011

10/5/2011

VESTIBULAR TRAINING
ADVANTAGES
CAN TRAIN LARGE NUMBER OF PEOPLE QUICK
DOES NOT INTERFERE WITH PRODUCTION OPS
GOOD HANDS ON EXPERIENCE
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

CLASSROOM TRAINING
VESTIBULAR TRAINING
ON THE JOB TRAINING
10/5/2011


ON THE JOB TRAINING
ADVANTAGES
GOOD HANDS ON EXPERIENCE
LEARN TO USE THE EXACT EQUIPMENT IN
THE EXACT FACILITY
10/5/2011

10/5/2011

ON THE JOB TRAINING
DISADVANTAGES
CAN GET IN THE WAY OF PRODUCTION
CAN RUIN EXPENSIVE EQUIPMENT
CAN CAUSE A BATCH REJECT
SAFETY?
10/5/2011


TRAINING FOR SUCCESS
START OUT WITH CLASS ROOM TRAINING
10/5/2011
VIDEOS
DEMONSTRATIONS
SLIDE PRESENTATIONS
LET THE STUDENT PRACTICE OUTSIDE THE AREA

10/5/2011

TRAINING FOR SUCCESS
VESTIBULE TRAINING (MODIFIED!)
ENTER THE FACILITY DURING OFF HOURS
PRACTICE GOWNING
10/5/2011


ON THE JOB TRAINING (AS AN
APPRENTICE)
ENTER THE FACILITY, BUT DONT TOUCH W/O
PERMISSION
HAVE A VETERAN INSTRUCT (LET THE
STUDENT PUSH SOME BUTTONS))
HAVE THE STUDENT REMAIN OUT OF THE
WAY DURING HECTIC PERIODS
10/5/2011

10/5/2011

Sanitization of an Aseptic Facility
Microbiology for the Non Microbiologist
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


The Gram Test

1 In the gram test
1.
test, a special dye (known as crystal
violet) is dropped on the bacteria.
2. Then the bacteria is rinsed and another dye (known
as methyl red) is dropped on the bacteria.
3. Gram positive
positive bacteria will accept the crystal violet
dye and appear as purple/brown under the
microscope.
4. Gram negative bacteria will not accept the crystal
violet dye, but will accept the methyl red dye.
These appear as red under the microscope.
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


Gram Positive Rods have a
rod shaped. They come
from the environment. An
example of a Gram Positive
Rod is Bacillus. Bacillus
can form a hard outer cover
p
that p
protects
called a spore
it from damage from heat
and disinfectants. Thats
why hypochlorite is needed
to kill a gram positive rod.
10/5/2011

10
10/5/2011

Gram Negative Rods also
have a rod shape. But
they do not have a hard
outer cover. An example
of a Gram Negative Rod is
Pseudomonas.. This
Pseudomonas
microbe can be found in
water, in wet areas, or
dried areas that were
previously wet.
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

Why should we worry about microbes in

the
th ffacility?
ilit ?
Bacteria can double themselves by splitting in
half. This doubling time varies with the type
of bacteria. E. coli has a doubling, or
generation time of 20 minutes. With this
generation speed
speed, a single E.
E coli bacteria cell
can grow as indicated in this table:
10/5/2011


E. coli BACTERIAL CELL GROWTH RATES
20 minutes
2 cells (double from start)
7 hours
1 million cells
10 hours
1 billion cells
24 hours
1 x 1021 cells (1 sextillion)
10/5/2011
12
10/5/2011

Sources of bacteria
Humans
10/5/2011
1 gram of fecal matter contains 109 bacteria.

40% of fecal matter is microbial matter.
Our body has 1 Kg of bacteria at any one time.
Th
These
are reasons we humans
h
are the
th greatest
t t contributor
t ib t to
t
contamination in the clean room. We can slough off bacteria
from our skin, and we can carry soil in with us.


Other sources of bacteria

Bioburden is the bacteria in the environment.
These come from water, air, personnel, raw
materials, working surfaces, and the manufacturing
area.
10/5/2011

13
10/5/2011

To control bioburden
bioburden::
10/5/2011
Practice aseptic technique

Follow the rules and guidelines
Practice good personnel control
controlgowning
and hygiene
good environmental control
Have g


What can you do?
10/5/2011
A quiet person sheds 100,000

100 000 particles per minute
minute.
A walking person sheds 5 million particles per
minute. Be careful how you walk.
Hand washing is a critical process. This is because
gloves are no longer sterile the minute they come
out of the package. The purpose of gloves is to
contain particles; not to replace aseptic technique
technique.
Wipe gloves with 70% IPA often.

14
10/5/2011

The FDA Requirement

FDA requires us to prevent objectionable
bacterial from entering non sterile
batches; and to prevent any bacteria
from entering sterile batches
batches.
21 CFR 211.113.
10/5/2011


The difference between sterilizing, disinfecting, or

sanitizing:
g
10/5/2011
Sterilizing destroys all life

Disinfection destroys pathogens
pathogens.. These are bacteria that are
known to cause diseases, such as streptococcus, and
staphylococcus. Disinfection does not destroy sporespore-forming
bacteria. Spore formers change to a hard bacterial cell that
becomes immune to boiling water, alcohol, or even Vesphene
or LpH. For spore formers, like Bacillus
Bacillus,, it is necessary to use
hypochlorite.
yp
Sanitization (with alcohol) reduces the amount of bioburden to
safe standards.

15
10/5/2011

The 7 steps to good aseptic technique:
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.


Behavior in the Cleanroom
10/5/2011

16
10/5/2011
Organization, Training and Process Flow for Sanitization of

an Aseptic Facility
Particle Generators
Machines
10/5/2011

Organization, Training and Process Flow for Sanitization of

an Aseptic Facility
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
Aerodynamic position
10/5/2011

22
10/5/2011

Vortices
Aerodynamic position
Slow, deliberate movements
10/5/2011


10/5/2011

23
10/5/2011

Aseptic Gowning
10/5/2011


Gowning
Pre requisites
Basic Microbiology for the non Microbiologist

Hygiene, illness, skin lesions
Particulation from People
Jewelry and Makeup
Sterile facility rules and regulations
10/5/2011

24
10/5/2011

Gowning
Step One:
Demonstration
Step Two
Practice
Step Three:
Visual check of Gowning technique
Step Four:
More practice
Step Five:
Aseptic Qualification: Three runs
10/5/2011


Gowning
Dr. Aseptic, your aseptic trainer

Stays current with latest techniques
Provides hands on training and guidance
10/5/2011

25
10/5/2011

Gowning
10/5/2011


Gowning
10/5/2011

26
10/5/2011

Gowning
10/5/2011


Gowning
10/5/2011

27
10/5/2011

Gowning
10/5/2011


Gowning
10/5/2011

28
10/5/2011

Facility Sanitization
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

Lint-free disposable mop

LintNon shedding wipes
Buckets made of stainless steel or plastic
Sterile sanitizing solutions
Process grade water
10/5/2011


Requirements for Sanitizing Agents

Must
M t establish
t bli h and
d maintain
i t i procedures
d
ffor
the preparation and usage of sanitizing
agents.
Sanitizing agents must meet worker safety
requirements.
Material
M t i lS
Safety
f t Data
D t Sheets
Sh t (MSDS) are
required to be kept on site for the sanitizing
agents used.
10/5/2011

30
10/5/2011

1. WATER RINSE OF THE FLOOR

2. PHENOLIC DISINFECTOR
LOW pH or High pH
0.5% HYPOCHLORITE Once a month
10/5/2011


FILL TWO BUCKETS WITH YOUR
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

RED BUCKET IS FOR WRINGING.

WHITE AND BLUE BUCKETS ARE FOR
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

REPLENISH THE MOP

ONE STROKE TOP TO BOTTOM
REVERSE MOP
ONE STROKE TOP TO BOTTOM
DOUBLE BUCKET
10/5/2011


10/5/2011

33
10/5/2011
10/5/2011


AFTER FILLING
PHENOLICS ARE USED IMMEDIATELY AFTER BATCH
OPERATIONS
70% IPA IS USED IMMEDIATELY BEFORE BATCH OPERATIONS
AFTER MAJOR CONTAMINATION EVENTS:

1. FACILITY: 1 X with 0.5% HYPOCHLORITE
2. EQUIPMENT: 1 X with 0.5% HYPOCHLORITE AND 2 X PHENOLICS
3. FACILITY: TWO PASSES WITH PHENOLICS
10/5/2011

34
10/5/2011

USE STERILE POLYPROPYLENE WASTE BAGS

DISCARD AND REPLENISH DISINFECTOR AFTER
EVERY ROOM.
DISINFECT THE ISO CLASS 5 ROOMS
FIRSTWORK FROM CLEANER TO DIRTIER
ROOMS
WASH THE MOP AND BUCKET HARDWARE
BEFORE AUTOCLAVING FOR THE NEXT USE
10/5/2011


MONTHLY: FULL FACILITY ((CEILING, WALLS, FLOOR)) DISINFECTION
with 0.5% SODIUM HYPOCHLORITE
WEEKLY:
(or after each batch operation):

WALLS, FLOOR AND FIXTURES with PHENOLIC
DAILY:
If NO batch operations were conducted in the room:

FLOOR ONLY with PHENOLIC
MAJOR CONTAMINATION OR HEPA SHUTDOWN: FULL FACILITY WITH

0.5% SODIUM HYPOCHLORITE FOLLOWED BY TWO FULL
FACILITY DISINFECTIONS WITH PHENOLICS
10/5/2011

35
10/5/2011

Room No.
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
USP Water drop

QTY Water
Initials
Date
APPROVAL
OPERATIONS
10/5/2011
QUALITY ASSURANCE


Time Savers??
10/5/2011

36
10/5/2011

Time Savers??
10/5/2011


Time Savers??
10/5/2011

37
10/5/2011

Material Handling
Step 1 Wash the parts
10/5/2011


Material Handling
Step 2 Disinfect on Entry side of

cleanroom
l
10/5/2011

38
10/5/2011

Material Handling
Step 3 Disinfect on Clean side of

cleanroom
l
10/5/2011


Material Handling
10/5/2011

39
10/5/2011

Material Handling
10/5/2011

THE NUTS AND BOLTS:

MATERIAL PREPARATION
STEP 1
MAKE THE BUCKET BE YOUR PARTS
TRAY
FILTER WITH TUBING ATTACHED
WRINGER
WIPER BUCKET
40
10/5/2011
THE NUTS AND BOLTS:

MATERIAL PREPARATION
STEP 2
AUTOCLAVE YOUR PARTS.
TRANSFER YOUR PRE STERILIZED
ITEMS AND DISINFECTORS
THE NUTS AND BOLTS:

MAKING THE DISINFECTOR
FILTER THE WATER INTO TWO BUCKETS
ADD THE UNIT DOSE PHENOLIC TO EACH
BUCKET
MIX WITH A MOP
1 SET OF BUCKETS
COVERS 300
300--500 sf.
41
10/5/2011
THE NUTS AND BOLTS:

WALL--CEILING AND WALLWALL
WALL-FLOOR
CORNERS
USE THE MEGA TIP MOP TO

DISINFECT THE CORNERS
TOP CORNERS FIRST

FIRSTTHEN
THEN THE BOTTOM
SWEEP THE PARTICLES TOWARD THE DOOR
THE NUTS AND BOLTS:

WALL--CEILING AND WALLWALL
WALL-FLOOR
CORNERS
MEGA TIP MOP
MOP- SEQUENCE OF CORNER DISINFECTION
3
2
42
10/5/2011
THE NUTS AND BOLTS:

DISINFECTING THE WALLS
MOP-SEQUENCE
Q
OF WALL DISINFECTION
FIRST
PASS
DOWN
REVERSE
MOP
DOUBLE
BUCKET
THEN
NEXT
PASS
DOWN
THEN
NEXT
PASS
DOWN

PROCESS FLOW
USE STERILE POLYPROPYLENE WASTE BAGS
DISCARD AND REPLENISH DISINFECTOR AFTER EVERY ROOM
.
DISINFECT THE CLASS 100 ROOMS FIRSTWORK FROM
CLEANER TO DIRTIER ROOMS
WASH THE MOP AND BUCKET HARDWARE BEFORE
AUTOCLAVING FOR THE NEXT USE
10/5/2011

43
10/5/2011
THE NUTS AND BOLTS:

DISINFECTING THE FLOORS
REPLENISH THE MOP
START FROM THE BACK OF THE ROOM AND
MOP TOWARDS THE BACK WALL
REVERSE MOP
Repeat
DOUBLE BUCKET
THE NUTS AND BOLTS:

DISINFECTION OF WALLS
START AT THE WALL FURTHEST FROM THE DOOR

USE THE DOUBLE BUCKET METHOD
MOVE THE MOP IN ONE DIRECTION ONLY
RINSE AND REPLENISH USING THE DOUBLE
BUCKET METHOD AFTER EVERY ROW
44
10/5/2011
THE NUTS AND BOLTS:

FREQUENCIES
MONTHLY: FULL FACILITY (CEILING, WALLS, FLOOR) DISINFECTION
with 0.5% SODIUM HYPOCHLORITE
WEEKLY:
(or after each batch operation):

WALLS, FLOOR AND FIXTURES with PHENOLIC
DAILY:
If NO batch operations were conducted in the room:

FLOOR ONLY with
ith PHENOLIC
MAJOR CONTAMINATION OR HEPA SHUTDOWN: FULL FACILITY WITH

0.5% SODIUM HYPOCHLORITE FOLLOWED BY TWO FULL
FACILITY DISINFECTIONS WITH PHENOLICS
THE NUTS AND BOLTS:

DOCUMENTATION
Room No.
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
USP Water drop

QTY Water
Initials
Date
APPROVAL
OPERATIONS
QUALITY ASSURANCE
45
10/5/2011

Sanitization of an Aseptic Facility :
FINAL WORDS
CONTROL WHAT ENTERS YOUR FACILITY

PERFORM A REGULAR EM PROGRAM
VALIDATE YOUR DISINFECTORS
WRITE GOOD SOPs AND TRAIN TRAIN TRAIN
(especially with gowning!)
MONITOR TO ASSURE YOUR SOPs ARE FOLLOWED
10/5/2011


Sanitization of an Aseptic Facility :
FINAL WORDS
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
Conducting a Gap Analysis

of your sterile operations
For IVT Aseptic Processing Program
Amsterdam, October 2011
compared to a standard / guide / SOP /

practice
"The only man I know who

behaves sensibly is my tailor; he
takes my measurements anew
each time he sees me. The rest
go on with their old
measurements and expect me
t fit them"
to
th "
- George Bernard Shaw
2/68
9/26/2011
y
y
y
y
y
Review
Refresh
Renew
Refine and
apply your
knowledge base for aseptic
processing

Guidance
y Regulatory requirements for audits
processing and recent revisions

processing: February 2008 revision
y PIC/s Guidance
y ISO guidance
y Inspectional Observations
4
9/26/2011
II. Designing and Conducting a Gap

Analysis
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
IV Monitoring the Efficacy of CAPA

y One month,
month three months and one
year later methods for following up

on the effectiveness of the corrective
and preventive action programs.
y Documenting follow up
y Management review as a tool for
escalating tough open issues.
7
Interactive Bit!
y (to
(t b
be d
done allll along
l
th
the way))
y develop a gap analysis checklist
for sterile operations based on

regulations, guidance, inspectional
fi di
findings
and
d observations
b
ti
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!
Regulatory Requirement for Auditing

EU GMPs
10/68
9/26/2011

EU GMPs
11/68
9.3 All self inspections should be

recorded
d d
y Reports should contain all the
observations made during the
inspections and, where
applicable, proposals for
corrective measures
y Statements on the actions
subsequently taken should also
be recorded
Q10 Pharmaceutical Quality System on

Auditing
y Under Quality
Quality System
Elements:
y Process Performance and Product
12/68
Quality Monitoring System:

(5) Include feedback on product
quality from both internal and
external sources e.g. complaints, product
rejections, non-conformances, recalls, deviations, audits and
regulatory inspections and findings
9/26/2011

Auditing
y Under CAPA:
13/68

Auditing
y Under Management Review:
14/68
9/26/2011

Auditing
y Under Continual Improvement:
15/68
What is an Audit / Gap

Analysis
An in
in-depth
depth examination of:
y procedures
y systems
y documentation
In depth means:
y review a cross-section or 100% of
the information ?
16/68
9/26/2011
21 CFR Subpart C Buildings and Facilities

Para 211.42 Design and Construction Features
17

18

drug products
the
9/26/2011

regulations

19

y Trends on incoming materials /
components
t - going
i up / d
down /
static
20
10
9/26/2011

21

Israelsimply
Ltd
Accordingly,
this rule

22
y Industry Objections Risk Management

y Where containers and closures are actively
y
rendered non-pyrogenic by a designated
depyrogenation process, the depyrogenation
process shall be validated
y Not ALL containers and closures require active
depyrogenation
y Some containers and closures are non-pyrogenic
by nature and/or design of their manufacturing
process(es) or have been qualified not to require
active depyrogenation
y Handling procedures are also designed and
controlled (e.g., bulk packaging, incoming parts
control, storage, personnel control) to minimize the
risk of pyrogen contamination during finished
11
9/26/2011

tunnel
y Temperature
y Time
y Air quality (post cycle: particles)
y Line speed
tunnel
23

y Paragraph (a) of 211.110 Sampling and

y The revised regulation will add bioburden
listed)
24
12
9/26/2011

Control
y Paragraph (b) of 211.113 Control of microbiological
25
contamination is being revised to include validation of

aseptic processes for drug products that are purported
to be sterile
y The current regulation mentions only validation of
sterilization processes, not aseptic processes
y Even before 1987, when the Guideline for Sterile Drug
Products Produced by Aseptic Processing was issued,
industry routinely conducted validation studies that
substituted microbiological media for the actual product
to demonstrate that its aseptic processes were
validated. These parts of validation studies are often
referred to as media fills. We believe that this revision
clarifies existing practices and serves to harmonize the
CGMP requirements with Annex 1 of the EU GMPs,
which
requires
such
validation
PCI Pharmaceutical
Consulting
Israel
Ltd

Control
y Industry objections: - Loss of clarity
y The change of wording might be interpreted
as media fills being the ONLY validation

that is required for an aseptic process
therefore better to leave the wording as is
(especially since FDA admits in the
preamble that industry is already doing
media fills)
26
13
9/26/2011
27

y Trending of personnel
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
29
Existing
New
30
15
9/26/2011


31

32
16
9/26/2011
Sample Size
33
Media Simulations: Current Acceptance Criteria
y The target should be zero
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
17
9/26/2011
Media Simulations: New Acceptance Criteria
35


p
y filled and
intervals
y For p
y
, bioburden
36
18
9/26/2011

Text
vials
i l should
h ld b
be maintained
i t i d
inserted
37

Guide
38
19
9/26/2011

Guide
39

40
previous
y Velocity
specification
g y test
y Efficacy
ofConsulting
disinfectants
with our isolates
PCI
Pharmaceutical
Israel Ltd
20
9/26/2011

Guide
41

production

periods
g y of p
package
g
integrity
42
21
9/26/2011
KPIs for personnel

y Monitoring
y Supervision
p
y Media fills

some kinds
y On-the-job
l ti
with
ith respectt tto
43

Guide
44
22
9/26/2011

Guide
45

46

records
supports this
23
9/26/2011

Guide
47

itself
y Steam (autoclave)
y Ethylene oxide

shift
y Filtration
y
y
y
y
y
y
y

Integrity
Time of filtration
Volume of filtrate
bioburden
y gamma
48
24
9/26/2011
PIC/s
49
PIC/s
50
25
9/26/2011
ISPE Baseline Guides
26
9/26/2011
ISO cleanrooms
Part II Designing and Conducting

a Gap Analysis
9Preparing an assessment checklist
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

currentt product
d t and
d process
drug
gp
p
PCIcontrol
Be Empathetic and Be systematic

Know the Guidance
y EU oriented or USA or both
y Quality systems must always be
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!
28
9/26/2011
Be systematic Know the Guidance

y Facility use your eyes and logic: if it
looks wrong it probably is so ASK

y Equipment: calibration, qualification,
maintenance, cleaning and malfunctions
y Processes: follow batch records
y Laboratory: follow sample and dont forget
about sampling process but if aseptic
FOCUS on MICROBIOLOGY (and if you
dont have expertise get in someone who
does
to coach you)
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
How do you proceed ?

58/68
29
9/26/2011
Risk Ranking Table

Risk Category
Ranking /
Definition
Severity
SEV
Likelihood of
Occurrence
OCC
Low
Medium
High
If the event occurs

and is not
detected it is NOT
likely to harm the
patient
If the event occurs

may cause
moderate harm to
the patient
Direct and severe

impact to the
patient; life
threatening
There is a
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
If the event occurs

there is a HIGH
it might be
it probably will
likelihood of
detected
NOT be detected
DET
59
Likelihood of
Detection

Scale 1 - 5
RPN
< 10 ?
SEV x
OCC X
DET
11 29 ?
30 ?
60
30
9/26/2011
Risk Priority Ranking

Detection
High
(Risk)
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
Critical / Major / Significant (minor?)
31
9/26/2011
Report Writing
y Provide time frames
y The detailed audit observations
63/68
are listed below. Please provide

a response within 30 days of
issuance of this report
report,
addressing corrective / preventive
actions for each finding and a
target date for implementation
III CAPA
analysis
program
y Preparing
P
i a preventive
ti action
ti
64
32
9/26/2011
Correction and Corrective

Action
y Correct the items identified in
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
any gap analysis is only as good as

the auditor
y A formal risk mapping study where
the process is mapped on a flow chart
and risks systematically identified and
controls provided is a proactive
measure to ensure the needed
controls have been designed into the
system
y What questions will you now add to
th
l i h kli t?
33
9/26/2011
IV Monitoring the Efficacy of

CAPA
y One month,

67
Thank you for your participation

Questions?
Contact me at: pcikaren@netvision.net.il
68
34
9/26/2011
Personnel Training - KPIs

y Deviation operator error: recurrence
y Sterile Product
y (Capacity data)
y Testing of employee training
y On the Job evaluation
y Compliance to curriculum
y Certification
y Gowning results / EM data
y Media fill participation
y Health Reporting
69
Validation - KPIs
70
35
9/26/2011
EM - KPIs
71
Deviations, Complaints, Rejected Batches KPIs
72
36
10/3/2011
Conducting a Gap Analysis

of your sterile operations
For IVT ACE
Amsterdam, Netherlands
compared to a standard / guide / SOP /

practice
"The only man I know who

behaves sensibly is my tailor; he
takes my measurements anew
each time he sees me. The rest
go on with their old
measurements and expect me
t fit them"
to
th "
- George Bernard Shaw
2/68
10/3/2011
y Be able to audit a sterile
operation and identify gaps

against regulations

Guidance
y Regulatory requirements for audits
processing
processing:
p
g
y PIC/s Guidance
y ISO guidance
y Inspectional Observations
10/3/2011
II. Designing and Conducting a Gap

Analysis
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
analysis
program
y Preparing
P
i a preventive
ti action
ti
6
10/3/2011

CAPA
y One month,

7
Interactive Bit!
y (to be done all along the way)
y develop a gap analysis checklist
for sterile operations based on

regulations, guidance,
inspectional findings and
observations
10/3/2011
Your Bonus.Toolkit
y Template for conducting risk
assessmentt off sterile

t il operations
ti
(we develop it as we work)
y .to work!

EU GMPs
10/68
10/3/2011

EU GMPs
11/68
9.3 All self inspections should be

recorded
d d
y Reports should contain all the
observations made during the
inspections and, where
applicable, proposals for
corrective measures
y Statements on the actions
subsequently taken should also
be recorded

Auditing
y Under Quality
Quality System
Elements:
y Process Performance and Product
12/68
Quality Monitoring System:

(5) Include feedback on product
quality from both internal and
external sources e.g. complaints, product
rejections, non-conformances, recalls, deviations, audits and
regulatory inspections and findings
10/3/2011

Auditing
y Under CAPA:
13/68

Auditing
y Under Management Review:
14/68
10/3/2011

Auditing
y Under Continual Improvement:
15/68
What is an Audit / Gap

Analysis
An in
in-depth
depth examination of:
y procedures
y systems
y documentation
In depth means:
y review a cross-section or 100% of
the information ?
16/68
10/3/2011
21 CFR Subpart C Buildings and Facilities

Para 211.42 Design and Construction Features
17

18

drug products
the
10/3/2011

regulations

19

y Trends on incoming materials /
components
t - going
i up / d
down /
static
20
10
10/3/2011

21

Israelsimply
Ltd
Accordingly,
this rule

tunnel
y Temperature
y Time
y Air quality (post cycle: particles)
y Line speed
tunnel
22
11
10/3/2011

y Paragraph (a) of 211.110 Sampling and

y The revised regulation will add bioburden
listed)
23

Control
y Paragraph (b) of 211.113 Control of microbiological
24
contamination is being revised to include validation of

aseptic processes for drug products that are purported
to be sterile
y The current regulation mentions only validation of
sterilization processes, not aseptic processes
y Even before 1987, when the Guideline for Sterile Drug
Products Produced by Aseptic Processing was issued,
industry routinely conducted validation studies that
substituted microbiological media for the actual product
to demonstrate that its aseptic processes were
validated. These parts of validation studies are often
referred to as media fills. We believe that this revision
clarifies existing practices and serves to harmonize the
CGMP requirements with Annex 1 of the EU GMPs,
which
requires
such
validation
PCI Pharmaceutical
Consulting
Israel
Ltd
12
10/3/2011

Control
y Industry objections: - Loss of clarity
y The change of wording might be interpreted
as media fills being the ONLY validation

that is required for an aseptic process
therefore better to leave the wording as is
(especially since FDA admits in the
preamble that industry is already doing
media fills)
25
26
13
10/3/2011

y Trending of personnel
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
28
14
10/3/2011
Particulate Classes
29


30
15
10/3/2011

31
Media Simulations: Acceptance Criteria
32
16
10/3/2011


p
y filled and
intervals
y For p
y
, bioburden
33

Text
vials
i l should
h ld b
be maintained
i t i d
inserted
34
17
10/3/2011

Guide
35

Guide
36
18
10/3/2011

previous
y Velocity
37

specification
g y test
y Efficacy
ofConsulting
disinfectants
with our isolates
PCI
Pharmaceutical
Israel Ltd

Guide
38
19
10/3/2011

production

periods
g y of p
package
g
integrity
39
KPIs for personnel

y Monitoring
y Supervision
p
y Media fills

some kinds
y On-the-job
l ti
with
ith respectt tto
40
20
10/3/2011

Guide
41

Guide
42
21
10/3/2011

43

records
supports this

Guide
44
22
10/3/2011

itself
y Steam (autoclave)
y Ethylene oxide

shift
y Filtration
y
y
y
y
y
y
y

Integrity
Time of filtration
Volume of filtrate
bioburden
y gamma
45
PIC/s
46
23
10/3/2011
PIC/s
47
24
10/3/2011
ISO cleanrooms
25
10/3/2011
Part II Designing and Conducting

a Gap Analysis
9Preparing an assessment checklist
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

currentt product
d t and
d process
drug
gp
p
PCIcontrol
26
10/3/2011
Be Empathetic and Be systematic

Know the Guidance
y EU oriented or USA or both
y Quality systems must always be
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!
Be systematic Know the Guidance

y Facility use your eyes and logic: if it
looks wrong it probably is so ASK

y Equipment: calibration, qualification,
maintenance, cleaning and malfunctions
y Processes: follow batch records
y Laboratory: follow sample and dont forget
about sampling process but if aseptic
FOCUS on MICROBIOLOGY (and if you
dont have expertise get in someone who
does
to coach you)
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
How do you proceed ?

55/68
Risk Ranking Table

Risk Category
Ranking /
Definition
Severity
SEV
Likelihood of
Occurrence
OCC
Low
Medium
High
If the event occurs

and is not
detected it is NOT
likely to harm the
patient
If the event occurs

may cause
moderate harm to
the patient
Direct and severe

impact to the
patient; life
threatening
There is a
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
If the event occurs

there is a HIGH
it might be
it probably will
likelihood of
detected
NOT be detected
DET
56
Likelihood of
Detection
28
10/3/2011

Scale 1 - 5
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
Critical / Major / Significant (minor?)
29
10/3/2011
Report Writing
y Provide time frames
y The detailed audit observations are
59/68
listed below. Please provide a

response within 30 days of issuance
of this report,
report addressing correcti
corrective
e/
preventive actions for each finding
and a target date for implementation
and the name of responsible person
III CAPA
analysis
program
y Preparing
P
i a preventive
ti action
ti
60
30
10/3/2011
Correction and Corrective

Action
y Correct the items identified in
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
any gap analysis is only as good as

the auditor
y A formal risk mapping study where
the process is mapped on a flow chart
and risks systematically identified and
controls provided is a proactive
measure to ensure the needed
controls have been designed into the
system
y What questions will you now add to
th
l i h kli t?
31
10/3/2011

CAPA
y One month,

63
Thank you for your participation

Questions?
Contact me at: pcikaren@netvision.net.il
64
32

CLEANING VALIDATION DOCUMENTATION -LIFECYCLE AND ASSOCIATED DOCUMENTS

Paul L. Pluta, PhD
Chicago, IL, USA
OUTLINE / OBJECTIVES
Overview
FDA Process Validation Guidance 2011
Cleaning Validation Policy
Cleaning Validation Master Plan
Stage 1 Documents -- Cleaning Process Development
Stage 2 Documents
Cleaning Validation Requests and Plans

Cleaning Validation Protocols, Results, and Reports
Equipment qualification
Stage 3 Continued Process Verification

Analytical
Associated Documents
Document Outlines / Templates
Document Problems
Implementation of PV Guidance Recommendations
PLEASE PARTICIPATE
2

IMPORTANCE OF VALIDATION DOCUMENTS

Always requested in regulatory audits
Lasting documentation
Documents reviewed long after people are gone
Documents must stand alone
Early documents (Request, Plan, Protocol) reviewed

when project is in-progress or not completed
FDA auditors often focus on documentation validation
documents often requested ahead of audit
Comparison to EU auditors
Above sometimes difficult for technical people
IMPORTANCE OF VALDIATION DOCUMENTS

NEW PROCESS VALDIATION GUIDANCE
FDA Process Validation Guidance has greatly expanded the scope of
validation
Lifecycle approach documents from development through

commercialization
Traditional validation documents (protocol and results) less important
Validation organizations should lead sites in transition to lifecycle

approach
Multiple groups at site must now contribute to process validation lifecycle

approach
pp
and p
provide applicable
pp
documents
Lifecycle approach being applied to all validation and qualification

(equipment, facilities, cleaning, etc.)

TERMINOLOGY: PROCESS VALIDATION

Process Validation Process Qualification
Process Performance Qualification (PPQ)
Qualification
Equipment #1
UO #1
Equipment #2
UO #2
Equipment #3
UO #3
Qualification
HVAC
Utilities
Facilities
Computers
Analytical methods validation

Cleaning process validation
Packaging process validation
Process is validated
5
FDA PROCESS VALIDATION GUIDANCE (2011)

Definition: Collection and evaluation of data, from the
process design stage throughout commercial production,
which establishes scientific evidence that a process is
capable of consistently delivering quality products
products.
Process validation involves a series of activities over the
lifecycle of the product and process.
Three stages of activities:
Stage 1 Process Design Development and scale-up activities
Stage 2 Process Qualification Reproducible manufacturing
Stage 3 Continued Process Verification Routine manufacturing
STAGE 1 AND STAGE 3 EMPHASIS NEW PARADIGM
VALIDATION FORMERLY STAGE 2 ONLY
6

FDA PROCESS VALIDATION GUIDANCE

Before commercial distribution to consumers, a manufacturer should
have gained a high degree of assurance in the performance of the
manufacturing processconsistently produce
Manufacturers should:
Understand the sources of variation
Detect the presence and degree of variation
Understand the impact of variation on the process and product
attributes
Control the variation in a manner commensurate with risk to process
and product.
p
to justify commercial distribution of the product.
use ongoing programs to collect and analyze product and process
data state if control of the process.
7
FDA PROCESS VALIDATION GUIDANCE

Good project management and good archiving to capture scientific
knowledge.
Enhance accessibility of information later in lifecycle.
Integrated team approach: Process engineering,
engineering industrial pharmacy,
pharmacy
analytical chemistry, microbiology, statistics, manufacturing, and
quality assurance.
Scientific studies throughout the product lifecycle planned,
documented, and approved.
Greater control over higher-risk attributes.
Re-evaluate risks throughout product/process lifecycle.
Homogeneity with batch and consistency between batches are goals of
process validation.
Note key words: Information, risk, documents, archiving, statistics,
consistency
8

STAGE 1, PROCESS DESIGN

(PROCESS UNDERSTANDING)
1. Building and capturing process knowledge and
understanding.
2 E
2.
Establishing
t bli hi a strategy
t t
ffor process control.
t l
Define commercial-scale process
Define unit operations and process parameters
Identify and understand sources of variability
Identify critical process parameters
Studies to understand effects of scale
Establish mechanisms to control variability
Process Analytical Technology
Designed experiments
Lab scale and pilot scale experiments
9
PROCESS DESIGN (PROCESS UNDERSTANDING)

Objective
API and excipient pharmaceutics
Quality attributes
Risk analysis
Process parameters
Design of experiments
Design space
Normal operating range
In-process controls
Product development key inputs to design stage
Variability by different component lots, production operators,
environmental conditions, and measurement systems
Use risk analysis tools to screen variables
Establish a strategy for process control
10

QUALITY BY DESIGN (QbD)

1. Quality target product profile (QTTP)
2. Critical quality attributes (CQA), critical material
attrib tes (CMA)
attributes
3. Critical process parameters (CPP)
4. Design space
5. Scale-up and technology transfer
y input
p variables
6. Identify
7. Input variable control strategy
8. Continuous improvement
Other considerations: PAT, Risk analysis
11

(VALIDATION PERFORMANCE)
1.
2.
3.
4.
Design of a facility and qualification of utilities and equipment

Process performance qualification
PPQ protocol
PPQ protocol execution and report
Confirmation at commercial scale of process design information

Qualification of equipment, utilities, facilities
Performance qualification
Conclusion that process consistently produces quality product.
Conformance batches
All support systems, documents, training, personnel, etc. in place
Target / nominal operating parameters within design space
Additional testing
Decision to release process for routine commercial manufacturing
12


Conformance Lots
Procedures
Validation plans
Protocols (PPQ)
Sampling
Testing
Results
Plan to maintain validation
alidation
ALL EQUIPMENT, ANALYTICAL, AND SUPPORTING
SYSTEMS MUST BE QUALIFIED.
13
PERFORMANCE QUALIFICATION APPROACH

Higher level of sampling, testing, and scrutiny of process performance.
Protocol should address:
Operating parameters, processing limits, and raw material inputs
Data to be collected and how evaluated
Test to be performed and acceptance criteria
Sampling plan sampling points, number of samples, frequency
Statistical methods used
Statistical confidence levels
Provisions to address deviations and non-conformances
Facility, utility, and equipment qualification
Personnel training
Status of analytical method validation
Review and approval by appropriate departments and quality unit
DETAILS FROM PV GUIDANCE
14

PERFORMANCE QUALIFICATION APPROACH

The PPQ lots should be manufacturer under normal conditions by
personnel expected to routinely perform each step of each unit
operation in the process. Normal operating conditions should cover
the utility systems (air handling and water purification), material,
personnel environment
environment, and manufacturing procedures.
procedures
PQ report:
Discuss all aspects of protocol
Summarize and analyze data as specified in protocol
Evaluate unexpected observations and additional data
Summarize and discuss non-conformances
Describe
D
ib corrective
ti actions
ti
or changes
h
Clear conclusions
Approval by appropriate departments and quality unit
15
STAGE 3, CONTINUED PROCESS VERIFICATION

(VALIDATION MONITORING AND MAINTENANCE)
Activities to assure process remains in validated state

Annual Product Review
Trend and assess data
Study OOS and OOT (Out of Trend) data
Timely monitoring of critical operating and performance
parameters.
Monitor product characteristics, materials, facilities,
equipment, and SOP changes
Establish process history based on ongoing process
performance
Improve process
Improve control to detect and reduce variability
Change control; evaluate impact of change and test as
necessary
16

CONTINUED PROCESS VERIFICATION

Monitoring
Statistical process control
Trend analysis
Change control
Continuous improvement
Revalidation
Management review
STATISTICIAN RECOMMENDED BY FDA
17

ITEMS TO BE REVIEWED
Product and process data
Relevant process trends
Quality of incoming materials or components
In-process
p
material
Finished products
Defect complaints
OOS findings
Deviations
Yield variations
Batch records
Incoming raw material records
Adverse event reports
Production operator and quality staff feedback
Above should help identify possible product / process improvements
18

SUMMARY OF GUIDANCE RECOMMENDATIONS

Stage 1: Product Design
QTPP, Development information, Identification of CQA, CMA, and CPP
Identification of sources of variation and control plan
Experimental studies
Technology transfer / scale up
Stage 2: Process Qualification
Protocol requirements
Statistical sampling and acceptance criteria
Equipment qualification and analytical method validation
Stage 3: Continued Process Verification
Post PQ plan
APR,
APR batch
b t h data,
d t yields,
i ld deviations,
d i ti
OOS,
OOS non-conformances,
f
etc.
t
Incoming material data
Change control
Statistical analysis of data / control charting
Product complaints
19
PROCESS VALIDATION HISTORY

1978
CGMP includes Validation

1987
Development -- VALIDATION -- Control
2008-2011
Lifecycle approach
Continuum of understanding validation maintenance
UNDERSTANDING -- VALIDATION -- MAINTENANCE
20
10

VALIDATION PHILOSOPHY
Validation is based on science and understanding.

Validation is confirmation.
Acceptable results are expected
expected.
Validation is not
R&D
Final stage of development
Optimization
Fine-tuning
g
Debugging
Validation must be maintained throughout the product
commercial life.
21
VALIDATION GUIDANCE KEY POINTS

Comprehensive and integrated approach
Development, performance, and maintenance of
validation throughout
g
p
product/process
p
lifecycle
y
FDA defined and detailed recommendations for all
stages of validation
Risk management key component of all activities
Variation identification and control important
Documentation addressing the above concepts is
necessary for successful validation programs.
22
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
Spelling and grammar correct

N
Need
d good
d writers
it
Simple sentences
Simple words
23
APPLICATION OF PV GUIDANCE TO CLEANING VALIDATION -CLEANING VALDIATION DOCUMENTS

Validation policy Reference PV Guidance approach
Corporate templates
Cleaning Validation Master Plan (CVMP) or section in VMP

Stage 1 Design and Development R&D responsible
Stage 2 Performance
Validation Request / Plan Reference PV Guidance
Validation Protocol(s) Reference PV Guidance
Engineering Studies
Other requirements
Validation Results / Report Reference PV Guidance
Equipment -- Joint responsibilities

Analytical -- Stage 1 activities. Assay and sampling
Stage 3 Maintenance QA responsible, Validation supportive
Associated documents
24
12

VALIDATION POLICY (CORPORATE OR COMPANY)

Describe validation approach
Design and development . Science-based
Performance
Maintain validated state through monitoring, change control, and
management review
Risk analysis
Variation identification and control
Continuing improvements
Specific corporate requirements

Corporate
C
policies
li i and
d procedures
d
Regulatory requirements (local and global) and industry
expectations
25
CLEANING VALIDATION MASTER PLAN

Program description at site
Comprehensive lifecycle approach

Science and technical basis
Risk analysis
Variation identification and control
Policy and procedures listing site program control
Product cleaning matrix

Equivalent equipment
Equipment surface area calculations
Residue calculations methods
Templates
Cleaning validation specific references

Equipment qualification specific references
Improvement projects and timelines
Update as necessary (annual, quarterly, monthly, etc.)
MAY ALSO BE A CHAPTER IN THE SITE VMP
26
13

STAGE 1 DOCUMENTS PROCESS DESIGN AND DEVELOPMENT

R&D / Technical group reports
API solubility and stability
Residue studies
Rationale for selection of cleaning agent
Laboratory studies, process studies, DOE
Cleaning process development and scale-up
Technical information (solubility, stability) part of new product
development
R&D scientists not accustomed to providing technical reports for
cleaning audit
Information must be readily available
VALIDATION PROFESSIONALS MUST ASSURE STAGE 1
DOCUMENTATION AVAILABILITY
27
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

CLEANING VALIDATION REQUEST / PLAN

Request: Statement of recommended validation
What?
Why needed?
Wh acceptable?
Why
t bl ?
Impact of validation risk analysis
Approach to accomplish Cleaning validation plan
Approval
Plan: Details of work to accomplish cleaning validation

Description of strategy and approach
References from Stage 1 work supporting information
Approval
Above may be combined into one document
29
CLEANING VALIDATION REQUEST OUTLINE
Objective of cleaning validation

Why needed?
Justification -- Why acceptable? See Validation Plan
Impact of validation
Risk analysis
Approach to accomplish validation

Compliance to internal requirements, policies, engineering standards,
etc.
Regulatory impact (usually no submission involved)
Other systems or product impacted
Procedure changes or other document changes
Notifications to affected groups (internal, external, labs)
Above applicable to equipment and other qualification

HAVE MODEL DOCUMENTS AVAILABLE
30
15

CLEANING VALIDATION REQUEST -- PROBLEMS

Poorly written
Inadequate information
Prematurelyy written
Written to meet individual or business goals
Written to demonstrate future intent
Written in advance of regulatory audit
Amendments necessary -- changes usually required

Cleaning Validation requests should be submitted for approval only
after objective and scope of validation is determined and work
details (risk/testing/sampling) determined.
Amendments are a planning failure regardless of justification.
31
CLEANING VALIDATION REQUEST TERMINOLOGY

EXAMPLES
Validation request:
Cleaning validation of Product A
System: New product cleaning validation
Change impact: High impact. New product
Reason: New product to be manufactured at site
J tifi ti
Justification:
S V
See
Validation
lid ti Pl
Plan
SIMPLE AND CLEAR MINIMAL WORDS
32
16

CLEANING VALIDATION PLAN OUTLINE
Introduction
Technical information
Cleaning procedure (finalized)
Complex processes may have multiple procedures
Cleaning validation strategy, sampling, and testing

Cleaning validation documentation
Manufacturing process and equipment
List of required protocols, reports, procedures, etc.

Administrative benefit
References
List of reports and scientific references (including Stage 1 reports)
33
CLEANING VALIDATION PLAN

INTRODUCTION
Overview describing cleaning validation / product /
process / equipment / etc.
etc
Cleaning procedure(s)
Requirements to complete cleaning validation
Conformance to regulations and internal policy

Impact of change
Impact on regulatory submission
Impact of change on procedures,
procedures drawings
drawings, other documents
Notifications to other areas internal and external
Notification to test labs and other areas impacted by validation
34
17


TECHNICAL INFORMATION
Basic product / process / equipment description
Product, formula, manufacturing process, equipment
Include non-technical description information
Technical aspects of validation / qualification

Residue properties
Cleaning agent
Cleaning process May have multiple processes
Reference to technical reports from Design Stage

Validation approach
Experimental studies
Past data or related product data
Validation protocols
New procedures
Residue limits calculation
Number of lots related to impact of change and risk

WRITTEN FOR THE READER
35

CLEANING PROCEDURE(S)
Finalized approved cleaning procedures should be
pp
to cleaning
g validation p
plan
appended
These are processes being validated
Complex products (e.g., tablets) using multiple
equipment will require multiple cleaning
procedures
DO NOT APPROVE PLAN
IF CLEANING PROCEDURES ARE NOT
FINALIZED AND APPROVED
36
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


VALIDATION STRATEGY AND TESTING
Prospective validation only
Types of testing -- general
Visual cleanliness
Analytical testing
Tests and rationale general

Based on risk analysis
Sampling and rationale general

Swab and rinse sampling based on impact and risk analysis
Uniform and non-uniform contamination potential
Data treatment
Acceptance criteria general
DETAILS OF ABOVE PROVIDED IN PROTOCOLS
39

DOCUMENTATION REQUIREMENTS
Doc #
Title
Date closed
01
Validation Request / Plan
02
CIP Equipment Qualification
03
Cleaning Validation Protocol
04
Cleaning Procedure
05
Cleaning Validation Results
06
07
Update Validation Master Plan Product ,

equipment, and cleaning sections
08
Project Summary Report

40
20


REFERENCES
R&D Reports
Published literature
Scientific and technical support to cleaning
validation plan
Report copies should be stored in validation area
or readily accessible (within 30 minutes)
41
PRODUCT / PROCESS CLEANING DESIGN

INFORMATION
Technical reports from R&D

Pharmaceutics (solubility / stability) reports
Cleaning process and procedure
Technology transfer / Scale-up reports
Identification of sources of variation
Variation control plans
Other technical reports
REPORTS SHOULD BE REVIEWED FOR CONSISTENCY

BETWEEN GROUPS
REPORTS SHOULD BE REFERENCED IN CLEANING VALIDATION
PLAN
42
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
CLEANING VALIDATION PROTOCOLS
Execution of the Validation Plan

Overview
Testing details
Sampling details
Acceptance criteria
Minimal text repetition from Validation Plan
PROTOCOL EASILY WRITTEN IF VALIDATION PLAN IS

THOROUGH
DO NOT INITIATE PROTOCOL IF SUCCESS IS NOT
EXPECTED
44
22

CLEANING VALIDATION PROTOCOL
Objective of validation specific protocol

Validation description specific
Validation approach
T ti and
Testing
d rationale
ti
l -- specific
ifi
Sampling and rationale specific
Equipment sampling documents
Data treatment -- specific

Acceptance criteria specific
All testing must have acceptance criteria
No FYI testing in validation
Data sheets specific

CLEANING VALIDATION MUST BE APPROACHED AS
CONFIRMATION OF EXPECTED RESULTS.
45
CLEANING VALIDATION PROTOCOL

TESTING AND SAMPLING
Based on risk analysis
Product
P d
residue
id lilimits
i
Visually clean and analytical testing
Consider the following:
CIP cleaning
Manual cleaning
Drug
Dr g potenc
potency
RISK ANALYSIS IN ABOVE
46
23

CLEANING VALIDATION SAMPLING

What is routine QA sampling?
Visual
Analytical
Risk analysis
High risk
Medium risk
Low risk
SAMPLING PAGES AVAILABLE
RISK LEVEL MUST BE ACKNOWLEDGED
47
ENGINEERING STUDY
Conducted in advance of validation

Test swabbing and rinsing procedure
Test analytical procedure
No acceptance criteria
Trial run
Can Engineering Study be conducted concurrently

with cleaning validation? NO!
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
DATA SHEET EXAMPLE

PRODUCT LOT l# ________________
UNIT OPERATION: Mixing / blending
EQUIPMENT: Mixer / blender, # ___________
SAMPLES: See sampling page
Sampling by _______________ Date _______________
p g by
y _______________ Date _______________
Sampling
TEST RESULTS
Sample #1
Sample #2
Sample #3
Sample #4
Sample #5
Sample #6
Acceptance Limit
__________
__________
__________
__________
__________
__________
Actual Data
__________
__________
__________
__________
__________
__________
Pass / Fail (Circle)

P / F
P / F
P / F
P / F
P / F
P / F
Recorded by _______________ Date _______________

Verified by ________________ Date ________________
Attach original laboratory data
50
25

PROCESS VALDIATION PROTOCOL (PPQ)

FDA GUIDLINE RECOMMENDATIONS
APPLICATIONS TO CLEANING VALDIATION
Higher level of sampling, testing, and scrutiny of process performance.
Protocoll should
P
h ld address:
dd
Operating parameters and processing limits
Data to be collected and how evaluated
Test to be performed and acceptance criteria
Sampling plan sampling points, number of samples
Provisions to address deviations and non-conformances
Facility, utility, and equipment qualification
Status of analytical method validation
Review and approval by appropriate departments and quality unit
51
CLEANING VALIDATION PROTOCOL OUTLINE

Overview
Unit operations
Cleaning
Cl
i procedures
d
(if not iin V
Validation
lid i Pl
Plan))
Testing with justification

Sampling with justification
Equipment sampling pages
Data sheets
Acceptance criteria with calculations
52
26

CLEANING VALIDATION PLAN / PROTOCOL -PROBLEMS

Inadequate plan or missing information
No basic explanation of specific cleaning validation
N strategy
No
t t
and
d approach
h
No test rationale
No sampling rationale
Vague sampling directions
No acceptance criteria rationale
Incorrect calculations
Poorly written
53
CLEANING VALIDATION PROTOCOL -- PROBLEMS

How many lots should be tested?
May not test if product is within matrix
Worst-case matrix subject to audit
Consider impact of change.

Consider product.
Consider process.
Is product within matrix?
Consider risk.
Written justification
ABOVE DISCUSSED IN VALDIATION PLAN
54
27

CLEANING VALIDATION RESULTS
Compilation of testing required in protocol

Compilation of data sheets
Deviations or adverse events
Discussion
Conclusion
WRITE GOOD PLAN
PROTOCOL CONSISTENT WITH PLAN
RESULTS CONSISTENT WITH PROTOCOL
WRITE DISCUSSION FIRST MOST IMPORTANT SECTION
55
CLEANING VALIDATION RESULTS OUTLINE

Introduction
Data sheets compiled
Results
Deviations, Non-conformances, etc. discussion
Discussion of results
Results pass is not sufficient.
Validation statement:
Results indicate that the cleaning process is validated.
Post-validation monitoring plan
WRITE DISCUSSION SECTION FIRST MOST IMPORTANT
SECTION
56
28

CLEANING VALIDATION RESULTS -PROBLEMS

No basic explanation of specific cleaning validation
I
Incomplete
l t data
d t
No discussion or inadequate discussion of results
Results pass is not adequate.
No validation statement
P l written
Poorly
itt
57
CLEANING VALIDATION REPORT

Recommended for complex projects
Recommended for multiple protocol projects
PRIMARY REPORT FOR AUDIT
Cut and Paste exercise from multiple
p documents
Best approach to avoid inconsistency
58
29

CLEANING VALIDATION REPORT FORMAT
Introduction
Key information from Validation Plan
Supporting information
Protocol #1 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
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

CLEANING EQUIPMENT QUALIFICATION

IQ, OQ, PQ or ASTM E2500
Same approach as with processes (Lifecycle approach)
Same philosophy (confirmation), requirements, and
approval
Critical tests only
Non-critical tests in FAC, SAC, etc.
Do as much as possible in commissioning
Qualification protocol: Do tests only once
Validation statement
Results indicate that _____is qualified.
QUALIFICATION DOCUMENTS AVAILABLE AND
REFERENCED IN VMP
61
Information for cleaning validation

Product-contact materials
Surface area of product-contact materials
Compatibility with pH or cleaning agents
Equivalent to other equipment at site
IQ / OQ/ PQ or ASTM E2500 (for manufacturing process)
Obtain coupons of product-contact materials from
manufacturer for future analytical work
62
31

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
______ sq. cm.
Material B
Material C
Equipment total surface area
______ sq. cm.

______ sq.cm.
______ sq. cm.
EQUIVALENT SURFACE AREA CALCULATIONS FILED IN EQUIPMENT IQ

63
PRODUCT-CONTACT MATERIALS
1.
2
2.
3.
4.
Determine all product-contact materials

V if compatibility
Verify
tibilit with
ith cleaning
l
i agents
t
Record in equipment IQ
If material is to be swabbed for cleaning
validation, obtain identical (representative)
coupons of material from manufacturer
5. Analytical to conduct recovery studies.
64
32

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.
EQUIVALENT EQUIPMENT DOCUMENT REFERENCED

IN CLEANING VALIDATION MASTER PLAN
65
ANALYTICAL METHOD
Residue chemistry understanding
Method must measure actual residue

Material coupons should be identical to equipment material
Swab sampling training

Sampling personnel must provide reliable samples
Analytical instrument qualification expected Fundamental

requirement
66
33

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
67
ANALYTICAL METHOD RECOVERY STUDIES

Swab and rinse sampling must be able to recover residue from
equipment surfaces.
Trained lab analysts demonstrate that drug may be quantitatively
recovered for equipment
q p
surface coupons.
p
All equipment surfaces to be swabbed or rinsed in cleaning validation
should be tested.
Residue must be soluble in solvent or water for recovery.
Coupons must be identical or representative of equipment surfaces
Coupons should be requested from equipment manufacturers
If recovery is not quantitative, data are factored based on recovery
data.
data
Recovery studies are part of Stage 1 design and development.
Recovery study data must be readily available for audit.
Raw data must be available and consistent with technical reports.
68
34

TRAINING SWAB SAMPLING

Sampling personnel must provide good swab samples for
analysis.
Sampling personnel must be appropriately trained and
qualified.
qualified
Training should be representative of worst case sampling
(e.g., sampling using volatile solvents, sampling using
extension poles).
Retraining must be considered at appropriate intervals.
Swab sampling training records must be readily
available for audit.
69
ASSOCIATED TRAINING RECORDS

Site training records reviewed for cleaning competency
Manufacturing operators
Manufacturing supervisors
QA inspectors
Sampling personnel
Analytical personnel
Environmental personnel (if appropriate)
Validation Approval Committee members
Others
70
35

STAGE 3 DOCUMENTS
Two categories
1 Special requirements based on PPQ results
1.
High result on certain equipment

Other high risk consideration
Require post validation testing
2. Routine monitoring.
71
STAGE 3 DOCUMENTS
MAINTAINING CLEANING VALDIATAION
Compilation of
Post validation monitoring results

Change control validation results/reports and monitoring
Cleaning non-conformances
Cleaning deviations
Cleaning process monitoring (control charts)
Trend assessment
Cleaning process changes

Improvement projects instituted
Other changes
Record of management review of above information

72
36

STAGE 3 CLEANING VALIDATION MAINTENANCE

RESPONSIBILITIES
RESPONSIBILITY
Postt validation
P
lid ti monitoring
it i results
lt
Cleaning deviations
Other changes
Record of management review
QA
Validation
Production
Production
QA
Production
Validation
___
QA
73
VALIDATION DOCUMENT APPROVAL

STANDARDS FOR APPROVAL
VALIDATION APPROVAL COMMITTEE (VAC)
VAC must review documents with perspective of an
external regulatory auditor
Assure acceptability of technical cleaning validation
Assure compliance with regulations, policies, and
industry expectations
p
y of documentation.
Assure acceptability
Spelling and grammar
VAC IMPORTANT PARTNER WITH VALDIATION
74
37

VALIDATION DOCUMENT APPROVAL

Technical validation
Scientific and technical principles

Consistent approach
Supports objective of validation
Supports routine manufacturing in type of testing and
sampling
Results and discussion support data
Correct technical conclusions
Equipment testing support entire manufacturing process
75
DOCUMENT OUTLINES / TEMPLATES

Document templates very difficult
Labor intensive
Do not fit every situation
Suggested approach
Document outline of major sections

Document outline evolves
Model approved documents available
Model approved documents improve and are replaced
76
38

IMPLEMENTATION
Deliberate strategy must be successful
Meet with affected groups Engineering, Technical Support, others
Meet with Validation Approval Committee
Upper management approval

General training on validation all involved in validation
General training on cleaning validation all involved in cleaning
Protocol writer training
Expectations for documents
Validation Approval Committee responsibilities / training
Science and technical basis

Compliance with procedures
Documentation quality
Surrogate regulatory auditor
Develop model documents

Continually improve these documents
77
SUMMARY
WHERE WE ARE -- CURRENT PRACTICE
CLEANING VALIDATION
R&D
Validation
Commercialization
78
39

SUMMARY -- VALIDATION
CURRENT PRACTICE
Emphasis on repeatability (3x)
One-time effort
Documentation important
Last step in development basis?
Hope we can pass validation
79
SUMMARY -- WHERE WE ARE GOING

LIFECYCLE APPROACH TO CLEANING VALIDATION
Lifecycle approach:
Validation is never completed
Validation is always ongoing
Objectives:
Scientific and technical process
Demonstrate process works as intended
Process must remain in control throughout lifecycle
Effective documents consistent with the above
Comprehensive approach
80
40

LIFECYCLE APPROACH TO PROCESS VALIDATION

Process Design
Studies to establish process
Identify critical process parameters
Identify sources of variation
Consider range of variation possible in processes
Process
P
understanding
d
t di
Process Qualification
Equipment, facilities, and utilities
Confirm commercial process design
Validation performance
Continued process verification
Monitor, collect information, assess
Maintenance, continuous verification, process improvement
Change
g control
Validation maintenance
The process of process validation.
81
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
82
41

SUMMARY
CLEANING VALIDATION -- FUTURE
Development
Stage 1
Performance
Stage 2
Maintenance
Stage 3
83
SUMMARY
EFFECTIVE CLEANING VALIDATION DOCUMENTS
HIGH LEVEL DOCUMENTS
Corporate Policies
Company-wide requirements
Cleaning Validation Master Plan (or VMP)
Site requirements
Reference to validation documents
Cleaning
g matrix
Equivalent equipment
Cleaning project commitments
84
42

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
85
SUMMARY
STAGE 1 DOCUMENTS
Residue chemistry
Cleaning agent selection
Process development
Analytical method development
Residue chemistry
Recovery studies
Sampling training
86
43

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
87
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
88
44

SUMMARY STAGE 2
VALIDATION RESULTS
Data sheets
Discussion of results Evaluate results
Additional post-validation testing if necessary
Validation statement ___ is validated.

Summary report for multiple protocol validation
or complex projects
Stage 3 Plan included in results document
Most important validation document
Simple sentences, simple words
Written for the reader
89
SUMMARY STAGE 2
Operator
p
cleaning
g training
g
Manual cleaning requires appropriate training (not read
and sign)
Retraining (annual?) must be considered.
90
45

SUMMARY STAGE 3
Specific Post-PPQ requirements
Compilation of Stage 3 post-validation maintenance
Post validation monitoring results

Cleaning deviations
Trend assessment

Other changes
Record of management review of above information

91
SUMMARY OTHER CONSIDERATIONS

Follow intent of FDA PV Guidance
Use outlines or templates
Based on guidance requirements
Example information to provide expectations for writers and
approvers
Have model documents available
Model documents evolve and improve
Provide model documents to protocol writers

Write most important document sections first
Consider problem examples

Training records consistent with responsibilities
92
46

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
93
IMPLEMENTATION
Deliberate strategy must be successful
Meet with affected groups and with Validation Approval Committee
Upper management approval

Training
Validation general
Cleaning validation
Protocol writers
Validation Approval Committee responsibilities / training

Surrogate regulatory auditor
Develop model documents

Continually improve these documents
94
47

PAUL L. PLUTA, PhD

Editor-in-Chief
Advanstar Communications
Adjunct Associate Professor

Chicago, IL, USA
Editor and Chapter Author

Cleaning and Cleaning Validation, Volume 1. Basics, Expectations, and
Principles PDA and Davis Healthcare International (DHI) Publishing
Principles.
Publishing, 2009
Cleaning and Cleaning Validation, Volume 2 . Applications of Basics and
Principles. PDA and Davis Healthcare International (DHI) Publishing, 2011
(expected)
Contact: paul.pluta@comcast.net
95
48

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