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Preliminary Concept Paper

Not for Implementation


Sterile Drug Products
Produced by
Aseptic Processing
Draft
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TABLE OF CONTENTS
DRAFT............................................................................................................................................1
I. INTRODUCTION...............................................................................................................1
II. BACKGROUND..................................................................................................................1
III. SCOPE....................................................................................................................................2
I. BUI!DINGS AND "ACI!ITI#S................................................................................2
A. Critic$l Are$ %Cl$ss &''(.............................................................................. 3
B. Supporting Cle$n Are$s............................................................................... 4
C. Cle$n Are$ Sep$r$tion................................................................................. 5
D. Air "iltr$tion.................................................................................................. 5
1. Membrane (Compressed Gases)......................................................................5
2. High Efciency Paric!"ae #ir (HEP#)..............................................................$
#. Design............................................................................................................ %
V. PERSONNEL TRAINING, QUALIFICATION, & MONITORING...................................9
A. )$nu*$cturing Personnel.......................................................................... 1&
B. !$bor$tory Personnel................................................................................ 12
C. )onitoring Progr$+................................................................................... 12
I. CO)PON#NTS AND CONTAIN#R,C!OSUR#S...............................................12
A. Co+ponents................................................................................................ 12
B. Cont$iners,Closures................................................................................... 13
1. Preparaion.................................................................................................... 14
2. 'nspecion o( Conainer)C"os!re *ysem.......................................................15
II. #NDOTO-IN CONTRO!...........................................................................................15
III. TI)# !I)ITATIONS....................................................................................................1
I-. PROC#SS A!IDATION AND #.UIP)#NT .UA!I"ICATION..................1!
A. Process Si+ul$tions................................................................................... 1%
1. *!dy +esign............................................................................................... 1,
2. -re.!ency and n!mber o( r!ns....................................................................1,
3. *i/e and +!raion o( r!ns............................................................................. 10
4. 1ine *peed.................................................................................................... 2&
5. En2ironmena" Condiions............................................................................ 2&
$. Media............................................................................................................ 2&
%. 'nc!baion and E3aminaion o( Media -i""ed 4nis........................................21
,. 'nerpreaion o( 5es 6es!"s.......................................................................22
B. "iltr$tion #/c$cy....................................................................................... 23
C. Sterili0$tion o* #1uip+ent $nd Cont$iner,Closures..............................24
1. *eri"i/er 7!a"i8caion and 9a"idaion............................................................25
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2. E.!ipmen Conro"s and 'nsr!men Ca"ibraion............................................2$
-. !ABORATOR2 CONTRO!S..........................................................................................2!
A. #n3iron+ent$l )onitoring........................................................................ 2%
1. Genera" :rien Program............................................................................. 2%
2. Esab"ishing 1imis and a 5rending Program................................................2,
3. *anii/aion Efcacy.................................................................................... 20
4. Monioring Mehods..................................................................................... 20
B. )icrobiologic$l )edi$ $nd Identi4c$tion...............................................3&
C. Pre54ltr$tion Bioburden............................................................................ 31
D. P$rticul$te )onitoring............................................................................... 31
"I. STERILIT# TESTING.........................................................................................................$1
A. C6oice o* )et6ods...................................................................................... 32
B. )edi$............................................................................................................ 32
C. Personnel..................................................................................................... 33
D. S$+pling $nd Incub$tion.......................................................................... 33
#. In3estig$tion o* Sterility Positi3es..........................................................33
"II. BATC% RECORD REVIE&' PROCESS CONTROL DOCUMENTATION..............$
APPENDI" 1' ASEPTIC PROCESSING ISOLATORS........................................................$!
A( )$inten$nce.................................................................................................. 3%
1. Genera"......................................................................................................... 3%
2. G"o2e 'negriy.............................................................................................. 3%
B( Design............................................................................................................ 3%
1. #ir;o<........................................................................................................... 3%
2. Maeria"s o( Consr!cion............................................................................... 3,
3. Press!re +i=erenia"...................................................................................... 3,
4. C"ean #rea C"assi8caions............................................................................. 3,
C( Tr$ns*er o* )$teri$ls,Supplies...................................................................3,
1. 'nrod!cion>.................................................................................................. 30
2. +ischarge>..................................................................................................... 30
D( Decont$+in$tion.......................................................................................... 30
1. *!r(ace E3pos!re......................................................................................... 30
2. Efcacy......................................................................................................... 30
3. -re.!ency..................................................................................................... 4&
#( "illing !ine Sterili0$tion.............................................................................. 4&
"( #n3iron+ent$l )onitoring.......................................................................... 4&
G( Personnel...................................................................................................... 4&
APPENDI" 2' BLO&(FILL( SEAL TEC%NOLOG#...........................................................)1
A( #1uip+ent Design $nd Air .u$lity............................................................41
B( $lid$tion,.u$li4c$tion............................................................................... 42
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C( B$tc6 )onitoring $nd Control....................................................................42
APPENDI" $' PROCESSING PRIOR TO FILLING*SEALING OPERATIONS...............)$
A( Aseptic processing *ro+ e$rly +$nu*$cturing steps.............................43
B( Aseptic processing o* cell5b$sed t6er$py products %or o* products
intended *or use $s cell b$sed t6er$pies(.....................................................44
REFERENCES............................................................................................................................)5
R#!#ANT GUIDANC# DOCU)#NTS.........................................................................)
DRA"T G!OSSAR2...............................................................................................................)!
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Sterile Drug Products Produced by Aseptic Processing
Draft

I. INTRODUCTION
II. BACKGROUND
There are basic diferences between the production of sterile drug products
by aseptic processing and by terminal sterilization.
Terminal sterilization usually involves flling and sealing product containers
under conditions of a high uality environment! the product" container" and
closure in most cases have low bioburden but are not sterile. The
environment in which flling and sealing is performed is of high uality in
order to minimize the microbial content of the in#process product" and to
help ensure that the subseuent sterilization process is successful. The
product in its fnal container is then sub$ected to a sterilization process such
as heat or radiation.
%n aseptic processing" the drug product" container" and closure are sub$ected
to sterilization processes separately" as appropriate" and then brought
together.
1
&ecause there is no further processing to sterilize the product
after it is in its fnal container" it is critical that containers be flled and sealed
in an environment of e'tremely high uality. (anufacturers should be aware
that there are more variables associated with aseptic processing than
terminal sterilization. &efore aseptic assembly" diferent parts of the fnal
product are generally sub$ected to diferent sterilization processes" such as
dry heat for glass containers" moist heat sterilization for rubber closures" and
sterile fltration for a liuid dosage form. )ach of the processes of the
aseptic manufacturing operation reuires thorough validation and control.
)ach also introduces the possibility of error that might ultimately lead to the
distribution of contaminated product. Any manual or mechanical
manipulation of the sterilized drug" components" containers" and closures
prior to or during aseptic assembly poses a ris* of contamination and thus
necessitates careful control. The terminally sterilized drug product" on the
other hand" undergoes a single sterilization process in a sealed container"
thus limiting the possibilities for error.
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Due to their nature, certain products are aseptically processed from an earlier stage in the process, or in their
entirety. Cell-based therapy products are an example. All components and excipients for these products are rendered
sterile, and release of the final product is contingent on determination of sterility. See Appendix III.
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(anufacturers should have a *een awareness of the public health implication
of distributing a non#sterile drug purporting to be sterile. Poor +,(P
conditions at a manufacturing facility can ultimately pose a life threatening
health ris* to a patient.
III. SCOPE
This document discusses only selected issues and thus does not address all
aspects of aseptic processing. -inished drug product +,(P issues are
primarily addressed" with only limited guidance regarding upstream bul*
processing steps. .pdates relative to the /012 document include guidance
on3 personnel ualifcation" clean room classifcations under dynamic
conditions" room design" uality control" environmental monitoring" and
review of production records. The aseptic processing isolator is also
discussed.
Although this document discusses +,(P issues relating to the sterilization of
components" containers" and closures" terminal sterilization of the drug
product is not addressed. %t is a well#accepted principle that sterile drugs
should be manufactured by aseptic processing only when terminal
sterilization is not feasible. 4owever" unacceptable degradation of the
product can occur as a result of terminal sterilization" or the mar*et
presentation can aford some uniue and substantial clinical advantage not
possible if terminal sterilization were employed. %n such cases" ad$unct
processing steps 5e.g." heat e'posure conditions which provide some -
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increase the level of sterility confdence should be considered.
A list of references" which may be of value to the reader" is included at the
conclusion of this document.
I. BUI!DINGS AND "ACI!ITI#S
2
8early all drugs recalled due to 8on#sterility or 9ac* of Sterility Assurance in the period
spanning /016#:666 were produced via aseptic processing.
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Section ://.;: 5design and construction features7 reuires" in part" that aseptic
processing operations be <performed within specifcally defned areas of adeuate size.
There shall be separate or defned areas for the frm=s operations to prevent
contamination or mi'ups.> Aseptic processing operations must also <include" as
appropriate" an air supply fltered through high e?ciency particulate air 54)PA7 flters
under positive pressure"> as well as systems for <monitoring environmental
conditions@>and <maintaining any euipment used to control aseptic conditions.>
Section ://.;A 5ventilation" air fltration" air heating and cooling7 states" in part" that
<euipment for adeuate control over air pressure" microorganisms" dust" humidity"
and temperature shall be provided when appropriate for the manufacture" processing"
pac*ing or holding of a drug product.> This regulation also states that <air fltration
systems" including pre#flters and particulate matter air flters" shall be used when
appropriate on air supplies to production areas.>
%n aseptic processing" there are various areas of operation which reuire
separation and control" with each area having diferent degrees of air uality
depending on the nature of the operation. Area design is based upon
satisfying microbiological and particulate standards defned by the
euipment" components" and products e'posed" as well as the particular
operation conducted" in the given area.

+ritical and support areas of the aseptic processing operation should be
classifed and supported by microbiological and particulate data obtained
during ualifcation studies. Bhile initial clean room ualifcation includes
some assessment of air uality under as#built and static conditions" the fnal
room or area classifcation should be derived from data generated under
dynamic conditions" i.e." with personnel present" euipment in place" and
operations ongoing. The aseptic processing facility monitoring program
should assess conformance with specifed clean area classifcations under
dynamic conditions" on a routine basis.
The following table summarizes clean area air classifcations 5Cef. /7.
TAB!# &5 Air Cl$ssi4c$tions
$
+lean Area
+lassifcation
D 6.E um
particlesFft
G
D 6.E um
particlesFm
G
(icrobiological 9imit
b

cfuF/6 ft
G
cfuFm
G
/66 /66 G"E66 H/
c
HG
c
/666 /666 GE"666 H : H2
/6"666 /6"666 GE6"666 H E H /1
/66"666 /66"666 G"E66"666 H:E H 11
a# All classifcations based on data measured in the vicinity of e'posed articles during periods of activity.
b# Alternate microbiological standards may be established where $ustifed by the nature of the operation. c#
Samples from class /66 environments should normally yield no microbiological contaminants.
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Two clean areas are of particular importance to sterile drug product uality3
the critical area and the supporting clean areas associated with it.
A. Critic$l Are$ %Cl$ss &''(
A critical area is one in which the sterilized drug product" containers" and
closures are e'posed to environmental conditions designed to preserve
sterility. Activities conducted in this area include manipulations 5e.g." aseptic
connections" sterile ingredient additions7 of sterile materials prior to and
during flling and closing operations.
This area is critical because the product is not processed further in its
immediate container and is vulnerable to contamination. %n order to maintain
product sterility" the environment in which aseptic operations are conducted
should be of appropriate uality throughout operations. Ine aspect of
environmental uality is the particulate content of the air. Particulates are
signifcant because they can enter a product and contaminate it physically
or" by acting as a vehicle for microorganisms" biologically. Particle content in
critical areas should be minimized by efective air systems.
Air in the immediate pro'imity of e'posed sterilized containersFclosures and
fllingFclosing operations is of acceptable particulate uality when it has a
per#cubic#foot particle count of no more than /66 in a size range of 6.E
micron and larger 5+lass /667 when counted at representative locations
normally not more than one foot away from the wor* site" within the airJow"
and during fllingFclosing operations. Deviations from this critical area
monitoring parameter should be documented as to origin and signifcance.
(easurements to confrm air cleanliness in aseptic processing zones should
be ta*en with the particle counting probe oriented in the direction of
oncoming airJow and at specifed sites where sterilized product and
container#closure are e'posed. Cegular monitoring should be performed
during each shift. 8onviable particulate monitoring with a remote counting
system is generally less invasive than the use of portable particle counting
units and provides the most comprehensive data. See Section K.D"
LParticulate (onitoring.L
Some powder flling operations can generate high levels of powder
particulates that" by their nature" do not pose a ris* of product
contamination. %t may not" in these cases" be feasible to measure air uality
within the one foot distance and still diferentiate Lbac*ground noiseL levels
of powder particles from air contaminants. %n these instances" air should be
sampled in a manner that" to the e'tent possible" characterizes the true level
of e'trinsic particulate contamination to which the product is e'posed. %nitial
certifcation of the area under dynamic conditions without the actual powder
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flling function should provide some baseline information on the non#product
particle generation of the operation.
Air in critical areas should be supplied at the point of use as 4)PA fltered
laminar Jow air at a velocity su?cient to sweep particulate matter away
from the fllingFclosing area and maintain laminarity during operations. The
velocity parameters established for each processing line should be $ustifed"
and appropriate to maintain laminarity and air uality under dynamic
conditions within a defned space 5Cef. :7.



Proper design and control should prevent turbulence or stagnant air in the
aseptic processing line or clean zone. Ince relevant parameters are
established" airJow patterns should be evaluated for turbulence. Air pattern
or <smo*e> studies demonstrating laminarity and sweeping action over and
away from the product under dynamic conditions should be conducted. The
studies should be well#documented with written conclusions. Mideotape or
other recording mechanisms have been found to be useful in assessing
airJow initially as well as facilitating evaluation of subseuent euipment
confguration changes. 4owever" even successfully ualifed systems can be
compromised by poor personnel" operational" or maintenance practices.
Active air monitoring of critical areas should normally yield no microbiological
contaminants. +ontamination in this environment should receive
investigative attention.
B. Supporting Cle$n Are$s
Supporting clean areas include various classifcations and functions. (any
support areas function as zones in which non#sterile components" formulated
product" in#process materials" euipment" and containerFclosures are
prepared" held" or transferred. These environments should be designed to
minimize the level of particulate contaminants in the fnal product and
control the microbiological content 5bioburden7 of articles and components
that are subseuently sterilized.
The nature of the activities conducted in a supporting clean area should
determine its classifcation. An area classifed at +lass /66"666 would be
used for less critical activities 5such as initial euipment preparation7. The
area immediately ad$acent to the aseptic processing line should" at a
minimum" meet +lass l6"666 standards 5see Table /7 under dynamic
conditions. Depending on the operation" manufacturers can also classify this
area as +lass /666 or maintain the entire aseptic flling room at +lass /66.

A !elocity from "# to 1## feet per minute is generally established, $ith a range of plus or minus 2#% around the
setpoint. &igher !elocities may be appropriate in operations generating high le!els of particulates.
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C. Cle$n Are$ Sep$r$tion
Adeuate separation is necessary between areas of operation to prevent
contamination 5://.;:7. %n order to maintain air uality in areas of higher
cleanliness" it is important to achieve a proper airJow and a positive pressure
diferential relative to ad$acent less clean areas. Cooms of higher
classifcation should have a positive pressure diferential relative to ad$acent
lower classifed areas of generally at least 6.6E inch of water 5with doors
closed7. Bhen doors are open" outward airJow should be su?cient to
minimize ingress of contamination 5Cef. G7. Pressure diferentials between
clean rooms should be monitored continuously throughout each shift and
freuently recorded" and deviations from established limits investigated.
An adeuate air change rate should be established for a cleanroom. -or
+lass /66"666 supporting rooms" airJow su?cient to achieve at least :6 air
changes per hour is typically acceptable.
-acility monitoring systems should be established to rapidly detect atypical
changes that can compromise the facility=s environment. Iperating
conditions should be restored to established" ualifed levels before reaching
action levels. -or e'ample" pressure diferential specifcations should enable
prompt detection 5i.e." alarms7 of any emerging low pressure problem in
order to preclude ingress of unclassifed air into a classifed room.
D. Air "iltr$tion
1. Membrane (Compressed Gases)
A compressed gas should be of appropriate purity 5e.g." free from oil and
water vapor7 and its microbiological and particulate uality should be eual
to or better than air in the environment into which the gas is introduced.
+ompressed gases such as air" nitrogen" and carbon dio'ide are often used
in clean rooms and are freuently employed in operations involving purging
or overlaying.
(embrane flters allow for the fltration of compressed gases to meet an
appropriate high uality standard" and can be used to produce a sterile
compressed gas. A sterile#fltered gas is used when the gas contacts a
sterilized material. +ertain euipment also should be supplied with a sterile#
fltered gas. -or e'ample" sterile bacterial retentive membrane flters should
be used for autoclave air lines" lyophilizer vacuum brea*s" vessels containing
sterilized materials" and hot air sterilizer vents. Sterilized tan*s or liuids
should be held under continuous overpressure to prevent microbial
contamination. Safeguards should be in place to prevent a pressure change
that can result in contamination due to bac* Jow of non#sterile air or liuid.
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,as flters 5including vent flters7 should be dry. +ondensate in a gas flter
can cause bloc*age or microbial contamination. -reuent replacement"
heating" and use of hydrophobic flters prevent moisture residues in a gas
supply system. These flters also should be integrity tested upon installation"
and periodically thereafter 5e.g." including at end of use7. %ntegrity test
failures should be investigated.
2. High Efciency Paric!"ae #ir (HEP#)
4
An essential element in ensuring aseptic conditions is the maintenance of
4)PA flter integrity. %ntegrity testing should be performed at installation to
detect lea*s around the sealing gas*ets" through the frames or through
various points on the flter media. Thereafter" integrity tests should be
performed at suitable time intervals for 4)PA flters in the aseptic processing
facility. -or e'ample" such testing should be performed twice a year for the
aseptic processing room. Additional testing may be needed when air uality
is found to be unacceptable" or as part of an investigation into a media fll or
drug product sterility failure. Among the flters that should be integrity
tested are those installed in dry heat depyrogenation tunnels commonly
used to depyrogenate glass vials.
Ine recognized method of testing the integrity of 4)PA flters is use of a
dioctylphthalate 5DIP7 aerosol challenge. 4owever" alternative aerosols may
be acceptable. Poly#alpha#olefn can also be used" provided it meets
specifcations for critical physicochemical attributes such as viscosity. Some
alternative aerosols are problematic because they pose a ris* of microbial
contamination of the environment being tested. -irms should ensure that
any alternative does not promote microbial growth.
An intact 4)PA flter is capable of retaining at least 00.02 percent of
particulates greater than 6.G micron in diameter. %t is important to ensure
that the aerosol used for the challenge has a su?cient number of particles of
this size range. Performing an integrity test without introducing particles of
*nown size upstream of the flter is inefective for detecting lea*s. The DIP
challenge should introduce the aerosol upstream of the flter in a
concentration of 16 to l66 microgramsFliter of air at the flterNs designed
airJow rating. The downstream side of the flter is then scanned with an
appropriate photometer probe at a sampling rate of at least one cubic foot
per minute. Scanning should be conducted on the entire flter face and
frame at a position about one to two inches from the face of the flter. This
comprehensive scanning of 4)PA flters should be fully documented. Bhile
vendors often provide these services" the drug manufacturer is responsible
for ensuring that these essential certifcation activities are conducted
satisfactorily. A single probe reading euivalent to 6.6/ percent of the
'
(he same broad principles can be applied to )*+A filters.
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upstream challenge should be considered as indicative of a signifcant lea*
and should result in replacement of the 4)PA flter or perhaps repair in a
limited area. A subseuent confrmatory re#test should be performed in the
area of any repair.
There is a ma$or diference between flter integrity testing and e?ciency
testing. The purpose of regularly scheduled integrity testing is to detect
lea*s from the flter media" flter frame and seal. The challenge is a
polydispersed aerosol usually composed of particles ranging in size from one
to three microns. The test is done in place and the flter face is scanned with
a probe! the measured downstream lea*age is ta*en as a percent of the
upstream challenge. The e?ciency test" on the other hand" is a test used
only to determine the rating of the flter.
,

4)PA flter integrity testing alone is not su?cient to monitor flter
performance. This testing is usually done only on a semi#annual basis. %t is
important to conduct periodic monitoring of flter attributes such as
uniformity of velocity across the flter 5and relative to ad$acent flters7.
Mariations in velocity generally increase the possibility of contamination" as
these changes 5e.g." velocity reduction7 can have an efect on the laminarity
of the airJow. AirJow velocities are measured si' inches from the flter face
or at a defned distance pro'imal to the wor* surface for each 4)PA flter.
-or e'ample" velocity monitoring as freuently as wee*ly may be appropriate
for the clean zone in which aseptic processing is performed. 4)PA flters
should be replaced when inadeuate airJow 5e.g." due to bloc*age7 or non#
uniformity of air velocity across an area of the flter is detected.
#. Design
,
The e?ciency test uses a monodispersed aerosol of 6.G micron size particles" relates to
flter media" and usually reuires specialized testing e-uipment. Do$nstream readings represent an
a!erage o!er the entire filter surface. (herefore, the efficiency test is not intended to test for lea.age in a filter.
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Section ://.;: reuires that aseptic processing operations be <performed within specifcally
defned areas of adeuate size. There shall be separate or defned areas for the frm=s
operations to prevent contamination or mi'ups.>
Section ://.;: states that <Jow of components" drug products containers" closures" labeling" in#
process materials" and drug products through the building or building shall be designed to
prevent contamination.> 4)PA fltered air as appropriate" as well as <Joors" walls and ceilings of
smooth" hard surfaces that are easily cleanable> are some additional reuirements of this
section.
Section ://.AG states that euipment <shall be of appropriate design" adeuate size" and
suitably located to facilitate operations for its intended use and for its cleaning and
maintenance.>
Section ://.AE states that >euipment shall be constructed so that surfaces that contact the
components" in#process materials" or drug products shall not be reactive" additive" or absorptive
so as to alter the safety" identity" strength" uality" or purity of the drug product beyond the
o?cial or other established reuirements.>
Section ://.A1 includes reuirements for <automatic" mechanical and electronic euipment.>
Section ://.//G states that <appropriate written procedures" designed to prevent
microbiological contamination of drug products purporting to be sterile" shall be established and
followed.>
An aseptic process is designed to minimize e'posure of sterile articles to
dynamic conditions and potential contamination hazards presented by the
operation. 9imiting the duration of open container e'posure" providing the
highest possible environmental control" and designing euipment to prevent
entrainment of lower uality air into the +lass /66 zone are essential to this
goal 5Cef. G7.
Any intervention or stoppage during an aseptic process can increase the ris*
of contamination. Personnel and material Jow should be optimized to
prevent unnecessary activities that increase the potential for introducing
contaminants to e'posed product" container#closures" or the surrounding
environment. The layout of euipment should provide for ergonomics that
optimize comfort and movement of operators. The Jow of personnel should
be designed to limit the freuency with which entries and e'its are made to
and from the aseptic processing room and" more signifcantly" its critical
area. %n order to prevent changes in air currents that introduce lower uality
air" movement ad$acent to the critical area should be limited. -or e'ample"
personnel intervention can be reduced by integrating an on#line weight
chec* device" thus eliminating a repeated manual activity within the critical
zone. %t is also important to minimize the number of personnel in the aseptic
processing room.
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Transfer of products should be performed under appropriate clean room
conditions. -or e'ample" lyophilization processes include transfer of
aseptically flled product in partially#sealed containers. To prevent
contamination" partially#closed sterile product should be staged and
transferred only in critical areas. -acility design should assure that the area
between a flling line and the lyophilizer" and the transport and loading
procedures" provide +lass /66 protection.
The sterile product and container#closures should also be protected from
activities occurring ad$acent to the line. +arefully designed curtains" rigid
plastic shields" or other barriers should be used in appropriate locations to
partially segregate the aseptic processing line.
Airloc*s and interloc*ing doors facilitate better control of air balance
throughout the aseptic processing area. Airloc*s should be installed between
the aseptic processing area entrance and the ad$oining uncontrolled area.
Ither interfaces such as personnel entries" or the $uncture of the aseptic
processing room and its ad$acent room" are also appropriate locations for air
loc*s.
+lean rooms are normally designed as functional units with specifc
purposes. A well#designed clean room is constructed with material that
allows for ease of cleaning and sanitizing. )'amples of adeuate design
features include seamless and rounded Joor to wall $unctions as well as
readily accessible corners. -loors" walls" and ceilings are constructed of
smooth" hard surfaces that can be easily cleaned 5://.;:7. +eilings and
associated 4)PA flter ban*s should be designed to protect sterile materials
from contamination. +lean rooms also should not contain unnecessary
euipment" f'tures" or materials.
Processing euipment and systems should be euipped with sanitary fttings
and valves. Drains are not considered appropriate for rooms in classifed
areas of the aseptic processing facility.
Bhen applicable" euipment must be suitably designed for ease of
sterilization 5://.AG7. The efect of euipment layout and design on the
clean room environment should be addressed. -lat surfaces or ledges that
accumulate dust and debris should be avoided. )uipment should not
obstruct airJow and" in critical zones" its design should not perturb airJow.
V. PERSONNEL TRAINING, QUALIFICATION, & MONITORING
Sections 211.22 states that /the -uality control unit shall ha!e the responsibility for appro!ing or re0ecting all
procedures or specifications impacting on the identity, strength, -uality, and purity of the drug product.1
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Section 211.112b3 addresses the procedures designed to pre!ent microbiological contamination, stating that
/appropriate $ritten procedures, designed to pre!ent microbiological contamination of drug products purporting to
be sterile, shall be established and follo$ed.1
Section ://.:E" Personnel Oualifcations reuires that <each person engaged in
manufacture" processing" pac*ing or holding of a drug product shall have education" training
and e'perience" or any combination thereof" to enable that person to perform the assigned
functions@)ach person responsible for supervising the manufacture" processing" pac*ing" or
holding of a drug product shall have the education" training" and e'perience" or any
combination thereof" to perform assigned functions in such a manner as to provide
assurance that the drug product has the safety" identity" strength" uality" and purity that it
purports or is represented to possess.> This section also reuires <an adeuate number of
ualifed personnel to perform and supervise the manufacture" processing" pac*ing or
holding of each drug product.> Section ://.:E also reuires that continuing training in
+,(P <shall be conducted by ualifed individuals on a continuing basis and with su?cient
freuency to assure that employees remain familiar with +,(P reuirements applicable to
them.> The training <shall be in the particular operations that the employee performs and in
current good manufacturing practice 5including the current good manufacturing practice
regulations in this chapter and written procedures reuired by these regulations7" as they
relate to the employeeNs functions.>
Section ://.:1" Personnel Cesponsibilities states" that <personnel engaged in the
manufacture" processing" pac*ing or holding of a drug product shall wear clean clothing
appropriate for the duties they perform.> %t also states that <personnel shall practice good
sanitization and health habits> and specifes that <protective apparel" such as head" face"
hand" and arm coverings" shall be worn as necessary to protect drug products from
contamination.> %t also states that <any person shown at any time 5either by medical
e'amination or supervisory e'amination7 to have an apparent illness or open lesions that
may adversely afect the safety or uality of drug products shall be e'cluded from direct
contact with components" drug product containers" closures" in#process materials" and drug
products until the condition is corrected or determined by competent medical personnel not
to $eopardize the safety or uality of drug products. All personnel shall be instructed to
report to supervisory personnel any health conditions that may have an adverse efect on
drug products.>
This section also addresses restrictions on entry into limited access areas3 <4nly personnel
authori5ed by super!isory personnel shall enter those areas of the buildings and facilities designated as
limited-access areas.1
Section ://.;: reuires the establishment of a <system for monitoring environmental
conditions.>
A. )$nu*$cturing Personnel
A well#designed aseptic process minimizes personnel intervention. As
operator activities increase in an aseptic processing operation" the ris* to
fnished product sterility also increases. %t is essential that operators
involved in aseptic manipulations adhere to the basic principles of aseptic
techniue at all times to assure maintenance of product sterility.
Appropriate training should be conducted before an individual is permitted to
enter the aseptic processing area and perform operations. -or e'ample"
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such training should include aseptic techniue" clean room behavior"
microbiology" hygiene" gowning" and patient safety hazard posed by a non#
sterile drug product" and the specifc written procedures covering aseptic
processing area operations. After initial training" personnel should be
updated regularly by an ongoing training program. Supervisory personnel
should routinely evaluate each operator=s conformance to written procedures
during actual operations. Similarly" the uality control unit should provide
regular oversight of adherence to established" written procedures and basic
aseptic techniues during manufacturing operations.
Adherence to basic aseptic techniue is a continuous reuirement for
operators in an aseptic processing operation. Some of these techniues
aimed at maintaining sterility of sterile items and surfaces include3
/. Conacing seri"e maeria"s on"y <ih seri"e insr!mens. Sterile
instruments 5e.g." forceps7 are should always be used in the handling
of sterilized materials. &etween uses" instruments should be placed
only in sterilized containers. These instruments should be replaced as
necessary throughout the operation.
After initial gowning" sterile gloves should be regularly sanitized to
minimize the ris* of contamination. Personnel should not directly
contact sterile products" containers" closures" or critical surfaces.
:. Mo2ing s"o<"y and de"iberae"y. Capid movements can create
unacceptable turbulence in the critical zone. Such movements disrupt
the sterile feld" presenting a challenge beyond intended cleanroom
design and control parameters. The principle of slow" careful
movement should be followed throughout the cleanroom.
G. ?eeping he enire body o! o( he pah o( "aminar air. 9aminar
airJow design is used to protect sterile euipment surfaces" container#
closures" and product. Personnel should not disrupt the path of
laminar Jow air in the aseptic processing zone.
;. #pproaching a necessary manip!"aion in a manner ha does no
compromise seri"iy o( he prod!c. %n order to maintain sterility of
nearby sterile materials" a proper aseptic manipulation should be
approached from the side and not above the product 5in vertical
laminar Jow operations7. Also" spea*ing when in direct pro'imity to an
aseptic processing line is not an acceptable practice.
Personnel who have been ualifed and permitted access to the aseptic
processing area should be appropriately gowned. An aseptic processing area
gown should provide a barrier between the body and e'posed sterilized
materials" and prevent contamination from particles generated by" and
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microorganisms shed from" the body. ,owns need to be sterile and non#
shedding" and should cover the s*in and hair. -ace mas*s" hoods"
beardFmoustache covers" protective goggles" elastic gloves" clean room
boots" and shoe overcovers are e'amples of common elements of gowns. An
adeuate barrier should be created by the overlapping of gown components
5e.g." gloves overlapping sleeves7. %f an element of the gown is found to be
torn or defective" it should be changed immediately.
There should be an established program to regularly assess or audit
conformance of personnel to relevant aseptic manufacturing reuirements.
An aseptic gowning ualifcation program should assess the ability of a
cleanroom operator to maintain the sterile uality of the gown after
performance of gowning procedures. ,owning ualifcation should include
microbiological surface sampling of several locations on a gown 5e.g." glove
fngers" facemas*" forearm" chest" other sites7. -ollowing an initial
assessment of gowning" periodic reualifcation should monitor various
gowning locations over a suitable period to ensure the consistent
acceptability of aseptic gowning techniues. Semi#annual or yearly
reualifcation is acceptable for automated operations where personnel
involvement is minimized.
To protect e'posed sterilized product" personnel are e'pected to maintain
sterile gown uality and aseptic method standards in a consistent manner.
Britten procedures should adeuately address circumstances under which
personnel should be retrained" reualifed" or reassigned to other areas.
B. !$bor$tory Personnel
The basic principles of training" aseptic techniue" and personnel
ualifcation in aseptic manufacturing are eually applicable to those
performing aseptic sampling and microbiological laboratory analyses.
Processes and systems cannot be considered to be in control and
reproducible if there is any uestion regarding the validity of data produced
by the laboratory.
C. )onitoring Progr$+
Personnel can have substantial impact on the uality of the environment in
which the sterile product is processed. A vigilant and responsive personnel
monitoring program should be established. (onitoring should be
accomplished by obtaining surface samples of each aseptic processing
operatorNs gloves on an at least a daily basis" or in association with each
batch. This sampling should be accompanied by an appropriate sampling
freuency for other strategically selected locations of the gown 5Cef. 27. The
uality control unit should establish a more comprehensive monitoring
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program for operators involved in operations which are especially labor
intensive" i.e. those reuiring repeated or comple' aseptic manipulations.
Asepsis is fundamental to an aseptic processing operation. An ongoing goal
for manufacturing personnel in the aseptic processing room is to maintain
contamination#free gloves throughout operations. Sanitizing gloves $ust prior
to sampling is inappropriate because it can prevent recovery of
microorganisms that were present during an aseptic manipulation. Bhen
operators e'ceed established levels or show an adverse trend" an
investigation should be conducted promptly. -ollow#up actions may include
increased sampling" increased observation" retraining" gowning
reualifcation" and in certain instances" reassignment of the individual to
operations outside of the aseptic processing area. (icrobiological trending
systems" and assessment of the impact of atypical trends" are discussed in
more detail under Section K%." 9aboratory +ontrols.
I. CO)PON#NTS AND CONTAIN#R,C!OSUR#S
A. Co+ponents
Section :/6.G5b75G7 defnes a LcomponentL as <any ingredient intended for use in the manufacture
of a drug product" including those that may not appear in such drug product.>
Section ://.16" ,eneral Ceuirements" reuires" in part" the establishment of written procedures
<describing in su?cient detail the receipt" identifcation" storage" handling" sampling" sampling"
testing" and approval or re$ection of components and drug product containers and closures@
+omponents and drug product containers and closures shall at all times be handled and stored in a
manner to prevent contamination.>
Section ://.1;" Testing and approval or re$ection of components" drug product containers" and
closures" reuires that <each lot of a component" drug product container" or closure that is liable to
microbiological contamination that is ob$ectionable in view of its intended use shall be sub$ected to
microbiological tests before use.>
A drug product produced by aseptic processing can become contaminated by
use of one or more components 5e.g." active ingredients" e'cipients" Bater
for %n$ection7 that are contaminated with microorganisms or endoto'ins. %t is
important to characterize the microbial content of each component liable to
contamination and establish appropriate acceptanceFre$ection limits based
on information on bioburden. Pnowledge of bioburden is critical in assessing
whether the sterilization process is adeuate.
%n aseptic processing" each component is individually sterilized or several
components are combined" with the resulting mi'ture sterilized.
6
There are
several methods to sterilize components 5see relevant discussion in Section
6
See Appendix III for discussion of certain biologic components that are aseptically handled from the start of the
process.
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%K7. A widely used method is fltration of a solution formed by dissolving the
component5s7 in a solvent such as .SP Bater -or %n$ection 5B-%7. The
solution is passed through a sterilizing membrane or cartridge flter. -ilter
sterilization is used where the component is soluble and is li*ely to be
adversely afected by heat. A variation of this method involves sub$ecting
the fltered solution to aseptic crystallization and precipitation of the
component as a sterile powder. 4owever" this method involves more
handling and manipulation and therefore has a higher potential for
contamination during processing. %f a component is not adversely afected
by heat" and is soluble" it may be made into a solution and sub$ected to
steam sterilization" typically in an autoclave or a pressurized vessel.
Dry heat sterilization is a suitable method for components that are heat
stable and insoluble. 4owever" carefully designed heat penetration and
distribution studies should be performed for powder sterilization because of
the insulating efects of the powder.
)thylene o'ide 5)tI7 e'posure is often used for surface sterilization. Such
methods should be carefully controlled and validated if used for powders to
evaluate whether consistent penetration of the sterilant is achieved and to
minimize residual ethylene o'ide and by#products.
Parenteral products are intended to be non#pyrogenic. There should be
written procedures and appropriate specifcations for acceptance or re$ection
of each lot of components that might contain endoto'ins. Any components
failing to meet endoto'in specifcations should be re$ected.
B. Cont$iners,Closures
Section ://.0; 5drug product containers and closures7 states that <drug product containers and
closures shall be clean and" where indicated by the nature of the drug" sterilized and processed to
remove pyrogenic properties to assure that they are suitable for their intended use.> %t also states
that <Standards or specifcations" methods of testing" and" where indicated" methods of cleaning"
sterilizing and processing to remove pyrogenic properties shall be written and followed for drug
product containers and closures.>

Section ://.//G5b7 reuires <validation of any sterilization process> as part of designing procedures
<to prevent microbiological contamination of drug products purporting to be sterile.>
1. Preparaion
+ontainers and closures should be rendered sterile and" for parenteral drug
products" pyrogen#free. The type of processes used will depend primarily on
the nature of the material comprising the container andFor closure. The
validation study for any such process should be adeuate to demonstrate its
ability to render materials sterile and pyrogen#free. Britten procedures
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should specify the freuency of revalidation of these processes as well as
time limits for holding sterile" depyrogenated containers and closures.
Presterilization preparation of glass containers usually involves a series of
wash and rinse cycles. These cycles serve an important role in removing
foreign matter. Cinse water should be of high purity so as not to
contaminate containers. -or parenteral products" fnal rinse water should
meet the specifcations of Bater for %n$ection" .SP.
The adeuacy of the depyrogenation process can be assessed by spi*ing
containers or closures with *nown uantities of endoto'in" followed by
measuring endoto'in content after depyrogenation. The challenge studies
should be performed with a reconstituted endoto'in solution applied directly
onto the surface being tested and air#dried. Positive controls should be used
to measure the percentage of endoto'in recovery by the test method.
Malidation study data should demonstrate that the process reduces the
endoto'in content by at least 00.0Q 5G logs7.
,lass containers are generally sub$ected to dry heat for sterilization and
depyrogenation. Malidation of dry heat sterilizationFdepyrogenation should
include appropriate heat distribution and penetration studies as well as the
use of worst#case process cycles" container characteristics 5e.g." mass7" and
specifc loading confgurations to represent actual production runs. See
Section %K.+.

Pyrogen on plastic containers can be generally removed by multiple B-%
rinses. Plastic containers can be sterilized with an appropriate gas"
irradiation or other suitable means. -or gases such as )tI" the parameters
and limits of the )tI sterilization cycle 5e.g. temperature" pressure" humidity"
gas concentration" e'posure time" degassing" aeration" and determination of
residuals7 should be specifed and monitored closely. &iological indicators
are of special importance in demonstrating the efectiveness of )tI and
other gas sterilization processes.
Cubber closures 5e.g." stoppers and syringe plungers7 are cleaned by
multiple cycles of washing and rinsing prior to fnal steam or irradiation
sterilization. At minimum" the initial rinses for the washing process should
employ Purifed Bater .SP of minimal endoto'in content" followed by fnal
rinse5s7 with B-% for parenteral products. 8ormally" depyrogenation is
achieved by multiple rinses of hot B-%. The time between washing and
sterilizing should be minimized because moisture on the stoppers can
support microbial growth and the generation of endoto'ins. &ecause rubber
is a poor conductor of heat" e'tra attention should be given to the validation
of processes that use heat to sterilize rubber stoppers. Malidation data
should also demonstrate successful endoto'in removal from rubber
materials.
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A potential source of contamination is the siliconization of rubber stoppers.
Silicone used in the preparation of rubber stoppers should be rendered
sterile and should not have an adverse efect on the safety" uality" or purity
of the drug product.
See Section M%%% for discussion of the need to establish production time limits
for the holding of sterilized containers and closures.
+ontract facilities that perform sterilization and depyrogenation of containers
and closures are sub$ect to the same +,(P reuirements as those
established for in#house processing. The fnished dosage form manufacturer
is responsible for the review and approval of the contractorNs validation
protocol and fnal validation report.
2. 'nspecion o( Conainer)C"os!re *ysem
A container#closure system that permits penetration of air" or
microorganisms" is unsuitable for a sterile product. Any damaged or
defective units should be detected" and removed" during inspection of the
fnal sealed product. Safeguards should be implemented to strictly preclude
shipment of product that may lac* container#closure integrity and lead to
non#sterility. )uipment suitability problems or incoming container or closure
defciencies have caused loss of container#closure system integrity. As
e'amples" failure to detect vials fractured by faulty machinery" or by
mishandling of bul* fnished stoc*" has led to drug recalls. %f damage that is
not readily detected leads to loss of container#closure integrity" improved
procedures should be rapidly implemented to prevent and detect such
defects.
-unctional defects in delivery devices 5e.g." syringe device defects" delivery
volume7 can also result in product uality problems" and should be monitored
by appropriate in#process testing.
Any defects or results outside the specifcations established for in#process
and fnal inspection should be investigated in accord with Section ://./0:.
II. #NDOTO-IN CONTRO!
Section ://.AG" euipment design" size" and location" states that euipment <shall be of
appropriate design" adeuate size" and suitably located to facilitate operations for its intended
use and for its cleaning and maintenance.L
Section 211.6,, e-uipment construction re-uires, in part, that /e-uipment shall be constructed so that surfaces that contact
the components, in-process materials, or drug products shall not be reacti!e, additi!e, or absorpti!e so as to alter the safety,
identity, strength, -uality or purity of the drug product beyond the official or other established re-uirements.1
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Section ://.A2" euipment cleaning and maintenance reuires" states that <euipment and
utensils shall be cleaned" maintained" and sanitized at appropriate intervals to prevent
malfunctions or contamination that would alter the safety" identity" strength" uality" or purity of
the drug product beyond the o?cial or other established reuirements.>
Section ://.0; states that <drug product containers and closures shall be clean" and where
indicated by the nature of the drug" sterilized and processed to remove pyrogenic properties to
assure that they are suitable for their intended use.>
Section ://./A2 states3 <-or each batch of drug product purporting to be sterile andFor
pyrogen#free" there shall be appropriate laboratory testing to determine conformance to such
reuirements. The test procedures shall be in writing and shall be followed.>
)ndoto'in contamination of an in$ectable product can be a result of poor
+,(P controls. +ertain patient populations 5e.g." neonates7" those receiving
other in$ections concomitantly" or those administered a parenteral in
atypically large volumes or doses can be at greater ris* for pyrogenic
reaction than anticipated by the established limits based on body weight of a
normal healthy adult 5Cef. A"27. Such clinical concerns reinforce the need for
appropriate +,(P controls to prevent generation of endoto'in. Drug product
components" container#closures" euipment" and storage time limitations are
among the concerns to address in establishing endoto'in control.
Adeuate cleaning" drying" and storage of euipment provides for control of
bioburden and prevents contribution of endoto'in load. )uipment should be
designed to be easily assembled and disassembled" cleaned" sanitized"
andFor sterilized. )ndoto'in control should be e'ercised for all product
contact surfaces both prior to and after sterile fltration.
)ndoto'in on euipment surfaces is inactivated by high temperature dry
heat" or removed from euipment surfaces by validated cleaning procedures.
Some clean#in#place procedures employ initial rinses with appropriate high
purity water andFor a cleaning agent 5e.g." acid" base" surfactant7" followed
by fnal rinses with heated B-%. )uipment should be dried following
cleaning. Sterilizing flters and moist heat sterilization have not been shown
to be efective in removing endoto'ins. Processes that are designed to
achieve depyrogenation should demonstrate a G#log reduction of endoto'in.
III. TI)# !I)ITATIONS
Section ://./// 5time limitations on production7 states3 <Bhen appropriate" time limits for
the completion of each phase of production shall be established to assure the uality of the
drug product.>
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Time limits should be established for each phase of aseptic processing. Time
limits should include" for e'ample" the period between the start of bul*
product compounding and its fltration" fltration processes" product e'posure
while on the processing line" and storage of sterilized euipment" containers
and closures. (aintenance of in#process uality at diferent production
phases should be supported by data. &ioburden and endoto'in load should
be assessed when establishing time limits for stages such as the formulation
processing stage.
The total time for product fltration should be limited to an established
ma'imum in order to prevent microorganisms from penetrating the flter.
Such a time limit should also prevent a signifcant increase in upstream
bioburden and endoto'in load. Sterilizing flters should generally be replaced
following each manufactured lot. &ecause they can provide a substrate for
microbial attachment" ma'imum use times for those flters used upstream
for solution clarifcation or particle removal should also be established and
$ustifed.
I-. PROC#SS A!IDATION AND #.UIP)#NT .UA!I"ICATION
Section ://.//G5b7 5control of microbiological contamination7 states7 /Appropriate $ritten
procedures, designed to pre!ent microbiological contamination of drug products purporting to be sterile, shall be
established and follo$ed. Such procedures shall include !alidation of any sterili5ation process.1
Sections ://.AG" ://.AE" and ://.A2 address" respectively" <)uipment" design" size" and
location"> <)uipment construction"> and <)uipment cleaning and maintenance.>
Section ://.1;5c75G7 states that <sterile euipment and aseptic sampling techniues shall
be used when necessary.>
The following sections primarily discuss routine ualifcation and validation
study e'pectations. +hange control procedures are only brieJy addressed"
but are an important part of the uality systems established by a frm. A
change in euipment" process" test method" or systems reuires evaluation
through the written change control program" and should trigger an
evaluation of the need for revalidation or reualifcation.
A. Process Si+ul$tions
%n order to ensure the sterility of products purporting to be sterile" both
sterilization and aseptic fllingFclosing operations must be adeuately
validated 5://.//G7. The goal of even the most efective sterilization
processes can be defeated if the sterilized elements of a product 5the drug"
the container and the closure7 are brought together under conditions that
contaminate those elements. Similarly" product sterility is compromised
when the product elements are non#sterile at the time they are assembled.
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The validation of an aseptic processing operation should include the use of a
microbiological growth nutrient medium in place of product. This has been
termed a <media fll> or <process simulation.> The nutrient medium is
e'posed to product contact surfaces of euipment" container systems"
critical environments" and process manipulations to closely simulate the
same e'posure that the product itself will undergo. The sealed containers
flled with the media are then incubated to detect microbial contamination.
The results are interpreted to determine the potential for any given unit of
drug product to become contaminated during actual operations 5e.g." start#
up" sterile ingredient additions" aseptic connections" flling" closing7.
)nvironmental monitoring data is integral to the validation of an aseptic
processing operation.
1. *!dy +esign
A validation protocol should detail the overall strategy" testing reuirements"
and acceptance criteria for the media fll. (edia fll studies should simulate
aseptic manufacturing operations as closely as possible" incorporating a
Lworst#caseL approach. A media fll study should address applicable issues
such as3
a7 factors associated with the longest permitted run on the processing line
b7 ability to produce sterile units when environmental conditions impart a
greater ris* to the product
c7 number and type of normal interventions" atypical interventions"
une'pected events 5e.g." maintenance7" stoppages" euipment ad$ustments
or transfers
d7 lyophilization" when applicable
e7 aseptic assembly of euipment 5e.g." at start#up" during processing7
f7 number of personnel and their activities
g7 number of aseptic additions 5e.g." charging containers and closures as well
as sterile ingredients7
h7 shift changes" brea*s" and gown changes 5when applicable7
i7 number and type of aseptic euipment disconnectionsFconnections
$7 aseptic sample collections
*7 line speed and confgurations
l7 manual weight chec*s
m7 operator fatigue
n7 container#closure systems 5e.g." sizes" type" compatibility with euipment7
o7 consideration of temperature and humidity set point e'tremes
p7 specifc provisions of aseptic processing related Standard Iperating
Procedures 5conditions permitted before line clearance is mandated" etc.7.
A written batch record" documenting conditions and activity simulated"
should be prepared for each media fll run. The same vigilance should be
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observed in both media fll and routine production runs. (edia flls cannot be
used to LvalidateL an unacceptable practice.
2. -re.!ency and n!mber o( r!ns
Bhen a processing line is initially validated" separate media flls should be
repeated enough times to ensure that results are consistent and meaningful.
This approach is important because a single run can be inconclusive" while
multiple runs with divergent results signal a process that is not in control. A
minimum of three consecutive separate successful runs should be performed
during initial line ualifcation. Subseuently" routine semi#annual
revalidation runs should be conducted for each shift and processing line to
evaluate the state of control of the aseptic process. All personnel who enter
the aseptic processing area" including technicians and maintenance
personnel" should participate in a media fll at least once a year
)ach change to a product or line change should be evaluated using a written
change control system. Any changes or events that appear to afect the
ability of the aseptic process to e'clude contamination from the sterilized
product should be assessed through additional media flls. -or e'ample"
facility and euipment modifcation" line confguration change" signifcant
changes in personnel" anomalies in environmental testing results" container#
closure system changes or" end product sterility testing showing
contaminated products may be cause for revalidation of the system.
Bhere a media fll=s data indicates the process may not be in control" a
comprehensive documented investigation should be conducted to determine
the origin of the contamination and the scope of the problem. Ince
corrections are instituted" multiple repeat process simulation runs should be
performed to confrm that defciencies in practices and procedures have
been corrected and the process has returned to a state of control. 4owever"
when an investigation fails to reach well#supported" substantive conclusions
as to the cause of the media fll failure" three consecutive successful runs
and increased scrutiny 5i.e." e'tra supervision" monitoring7 of the production
process should be implemented.
3. *i/e and +!raion o( r!ns
The duration of aseptic processing operations is a ma$or consideration in
determining the size of the media fll run. Although the most accurate
simulation model would be the full batch size and duration because it most
closely simulates the actual production run" other appropriate models can be
$ustifed. %n any study protocol" the duration of the run and the overall study
design should adeuately mimic worst#case operating conditions and cover
all manipulations that are performed in the actual processing operation.
Adeuate batch sizes are needed to simulate commercial production
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conditions and accurately assess the potential for commercial batch
contamination. The number of units flled should be su?cient to reJect the
efects of potential operator fatigue" as well as the ma'imum number of
interventions and stoppages. The run should be large enough to accurately
simulate production conditions and sensitive enough to detect a low
incidence of contaminated units. -or batches produced over multiple shifts
or yielding an unusually large number of units" the media fll protocol should
adeuately encompass conditions and any potential ris*s associated with the
larger operation.
Bhile conventional manufacturing lines are highly automated" often operate
at relatively high speeds" and are designed to limit operator intervention"
there are some processes that include considerable operator involvement.
Bhen aseptic processing employs manual flling or closing" or e'tensive
manual manipulations" the duration of the process simulation should
generally be no less than the length of the actual manufacturing process in
order to best simulate operator fatigue.
-or simulation of lyophilization operations" unsealed containers should be
e'posed to pressurization and partial evacuation of the chamber in a manner
that is representative of process stresses. Mials should not be frozen" as this
may inhibit the growth of microorganisms.
4. 1ine *peed
The media fll program should adeuately address the range of line speeds
5e.g." by brac*eting all vial sizes and fll volumes7 employed during
production. %n some cases" more than one line speed should be evaluated in
the course of a study.
)ach individual media fll run should evaluate a single worst#case line speed
and the speed chosen for each batch during a study should be $ustifed. -or
e'ample" use of high line speed is $ustifed for manufacturing processes
characterized by freuent interventions or a signifcant degree of manual
manipulation. .se of slow line speed is $ustifed for manufacturing processes
characterized by prolonged e'posure of sterile components in the aseptic
area
5. En2ironmena" Condiions
(edia flls should be conducted under environmental conditions that
simulate normal as well as Lworst caseL conditions of production. An
inaccurate assessment 5ma*ing the process appear LcleanerL than it actually
is7 can result from conducting a media fll under e'traordinary air particulate
and microbial uality" or under production controls and precautions ta*en in
preparation for the media fll. To the e'tent standard operating procedures
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Preliminary Concept Paper
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permit stressful conditions" it is crucial that media flls should include
rigorous challenges in order to support the validity of these studies.
$. Media
%n general" a microbiological growth medium such as soybean casein digest
medium should be used. .se of anaerobic growth media 5such as -luid
Thioglycollate (edium7 is appropriate in special circumstances. (edia
selected should be demonstrated to promote growth of .SP H2/D indicator
microorganisms as well as isolates that have been identifed by
environmental monitoring" personnel monitoring" and positive sterility test
results. Positive control units should be inoculated with a H/66 +-.
challenge and incubated. -or those instances in which the growth promotion
testing fails" the origin of any contamination found during the simulation
should nonetheless be investigated and the media fll should be promptly
repeated.
The production process should be accurately simulated using media and
conditions that optimize detection of any microbiological contamination.
)ach unit should be flled with an appropriate uantity and type of microbial
growth medium to contact the inner container#closure surfaces 5when the
unit is inverted and swirled7 and permit visual detection of microbial growth.
Some drug manufacturers have e'pressed concern over the possible
contamination of the facility and euipment with the nutrient media during
media fll runs. 4owever" if the medium is handled properly and is promptly
followed by the cleaning" sanitizing" and" where necessary" sterilization of
euipment" subseuently processed products are not li*ely to be
compromised.
%. 'nc!baion and E3aminaion o( Media -i""ed 4nis
(edia units should be incubated for a su?cient time 5a period of not less
than /; days7 at a temperature adeuate to enhance detection of organisms
that can otherwise be di?cult to culture.
)ach media flled unit should be e'amined for contamination by personnel
with appropriate education" training and e'perience in microbiological
techniues. There should be direct uality control unit oversight throughout
any such e'amination. +lear containers with otherwise identical physical
properties should be used as a substitute for amber or other opaue
containers to allow visual detection of microbial growth.
Bhen a frm performs a fnal product inspection of units immediately
following the media fll run" all integral units should proceed to incubation.
.nits found to have defects not related to integrity 5e.g." cosmetic defect7
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should be incubated! units that lac* integrity should be re$ected.
8

)rroneously re$ected units should be returned promptly for incubation with
the media fll lot.
After incubation is underway" any unit found to be damaged should be
included in the data for the media fll batch" because the incubation of the
units simulates release to the mar*et. Any decision to e'clude such
incubated units 5i.e." non#integral7 from the fnal batch tally should be fully
$ustifed" and the deviation e'plained in the media fll report. %f a correlation
emerges between di?cult to detect damage and microbial contamination" a
thorough investigation should be conducted to determine its cause 5See
Section M%.&7.
Britten procedures regarding aseptic interventions should be clear and
specifc 5e.g." intervention type! uantity of units removed7" providing for
consistent production practices and assessment of these practices during
media flls. %f written procedures and batch documentation are adeuate,
these inter!ention units do not need to be incubated during media fills. Bhere procedures
lac* specifcity" there would be insu?cient $ustifcation for e'clusion of units
removed during an intervention from incubation. As an example, if a production
procedure reuires removal of ten units after an intervention at the stoppering
station infeed" batch records 5i.e." for production and media flls7 should
clearly document conformance with this procedure. %n no case should more
units be removed during a media fll intervention than would be cleared
during a production run. The ability of a media fll run to detect potential
contamination from a given simulated activity should not be compromised by
a large scale line clearance" which can result in removal of a positive unit
caused by an unrelated event or intervention. %f unavoidable" appropriate
study provisions should be made to compensate in such instances.
Appropriate criteria should be established for yield and accountability. &atch
record reconciliation documentation should include an accurate accounting
and description of units re$ected from a batch.
,. 'nerpreaion o( 5es 6es!"s
The process simulation run should be observed" and contaminated units
should be reconcilable with the appro'imate time and the activity being
simulated during the media fll. Mideotaping of a media fll has been found to
be useful in identifying personnel practices which could negatively impact on
the aseptic process.
8
Separate incubation of certain categories of re$ected units may nonetheless provide
valuable information with respect to contamination that may arise from containerFclosure
integrity defciencies.
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Any contaminated unit should be considered as ob$ectionable and fully
investigated. The microorganisms should be identifed to species level. %n
the case of a media fll failure" a comprehensive investigation should be
conducted" surveying all possible causes of the contamination. The impact
on commercial drugs produced on the line since the last successful media fll
should also be assessed.
Bhenever contamination e'ists in a media fll batch" it should be considered
as indicative of a potential production problem. The use of statistics has
limitations for media fll evaluation in that the number of contaminated units
should not be e'pected to increase in a directly proportional manner with the
number of vials in the media fll run. Test results should show" with a high
degree of confdence" that the units produced by an aseptic processing
operation are sterile. (odern aseptic processing operations in suitably
designed facilities have demonstrated a capability of meeting contamination
levels approaching zero 5Cef.17 and should normally yield no media fll
contamination. -or e'ample" a single contaminated unit in a /6"666 unit
media fll batch should be fully investigated" but is normally not considered
on its own to be su?cient cause for line revalidation. 4owever" intermittent
incidents at this media fll contamination level can be indicative of a
persistent low level contamination problem. Accordingly" any pattern of
media fll batches with such low level contamination should be
comprehensively investigated and would be cause for line revalidation.
A frmNs use of media fll acceptance criteria allowing infreuent
contamination does not mean that a distributed lot of drug product
purporting to be sterile may contain a non#sterile unit. The purpose of an
aseptic process is to prevent any contamination. A manufacturer is fully
liable for the shipment of any non#sterile unit" an act that is prohibited under
the -DR+ Act. -DA also recognizes that there might be some scientifc and
technical limitations on how precisely and accurately validation can
characterize a system of controls intended to e'clude contamination.
As with any validation batch" it is important to note that LinvalidationL of a
media fll run should be a rare occurrence. A media fll lot should be aborted
only under circumstances in which written procedures reuire commercial
lots to be eually handled. Supporting documentation and $ustifcation
should be provided in such cases.
B. "iltr$tion #/c$cy
-iltration is a common method of sterilizing drug product solutions. An
appropriate sterilizing grade flter is one which reproducibly removes all
microorganisms from the process stream" producing a sterile eSuent. Such
flters usually have a rated porosity of 6.: micron or smaller. Bhatever flter
or combination of flters is used" validation should include microbiological
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challenges to simulate Lworst caseL production conditions regarding the size
of microorganisms in the material to be fltered and integrity test results of
the flters used for the study. The microorganisms should be small enough to
both challenge the nominal porosity of the flter and simulate the smallest
microorganism that may occur in production. The microorganism
@re2!ndimonas dimin!a 5AT++ /0/;A7 when properly grown" harvested and
used" can be satisfactory in this regard because it is one of the smallest
bacteria 56.G micron mean diameter7. &ioburden of unsterilized bul*
solutions should be determined" in order to trend the characteristics of
potentially contaminating organisms. %n certain cases" when $ustifed as
euivalent or better than use of @re2!ndimonas dimin!a" it may be
appropriate to conduct bacterial retention studies with a bioburden isolate.
The number of microorganisms in the challenge is important because a flter
can contain a number of pores larger than the nominal rating which have
potential to allow passage of microorganisms 5Cef. 07. The probability of
such passage is considered to increase as the number of organisms
5bioburden7 in the material to be fltered increases 5Cef. /67. A challenge
concentration of at least /6
2
organisms per cm
:
of efective fltration area of
@. dimin!a is generally used. A commercial lotNs actual inJuent bioburden
should not include microorganisms of a size andFor concentration that would
present a challenge beyond that considered by the validation study.
Direct inoculation into the drug formulation provides an assessment of the
efect of drug product on the flter matri' and on the challenge organism.
4owever" directly inoculating @. dimin!a into products with inherent
bactericidal activity or into oil#based formulations can lead to erroneous
conclusions. Bhen su?ciently $ustifed" the efects of the product
formulation on the membraneNs integrity can be assessed using an
appropriate alternate method. -or e'ample" the drug product could be
fltered in a manner in which the worst#case combination of process
specifcations and conditions are simulated. This step could be followed by
fltration of the challenge organism for a signifcant period of time" under the
same conditions" using an appropriately modifed product 5e.g." lac*ing an
antimicrobial preservative or other antimicrobial component7 as the vehicle.
Any divergence from a simulation using the actual product and conditions of
processing should be $ustifed. -actors which can afect flter performance
normally include3 5/7 viscosity of the material to be fltered! 5:7 p4! 5G7
compatibility of the material or formulation components with the flter itself!
5;7 pressures! 5E7 Jow rates! 5A7 ma'imum use time! 527 temperature! 517
osmolality! 507 and the efects of hydraulic shoc*. Bhen designing the
validation protocol" it is important to address the efect of the e'tremes of
processing factors on the flter capability to produce sterile eSuent. -ilter
validation should be conducted using the worst case conditions" such as
ma'imum flter use time and pressure 5Cef. //7. -ilter validation
e'periments" including microbial challenges" need not be conducted in the
actual manufacturing areas. 4owever" it is essential that laboratory
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e'periments simulate actual production conditions. The specifc type of flter
used in commercial production should be evaluated in flter validation
studies. Bhen the more comple' flter validation tests go beyond the
capabilities of the flter user" tests are often conducted by outside
laboratories or by flter manufacturers. 4owever" it is the responsibility of
the flter user to review the validation data on the e?cacy of the flter in
producing a sterile eSuent. The data should be applicable to the userNs
products and conditions of use because flter performance may difer
signifcantly for various conditions and products.
After a fltration process is properly validated for a given product" process
and flter" it is important to ensure that identical flter replacements
5membrane or cartridge7 used in production runs will perform in the same
manner. Sterilizing flters should be routinely discarded after processing of a
single batch. 8ormally" integrity testing of the flter is performed after the
flter unit is assembled and sterilized prior to use. %t is important that the
integrity testing be conducted after fltration in order to detect any flter
lea*s or perforations that might have occurred during the fltration. <-orward
Jow> and <bubble point> tests" when appropriately employed" are two
acceptable integrity tests. A production flter=s integrity test specifcation
should be consistent with data generated during fltration e?cacy studies.
C. Sterili0$tion o* #1uip+ent $nd Cont$iner,Closures
%n order to maintain sterility" euipment surfaces that contact sterilized drug
product or sterilized containerFclosure surfaces must be sterile so as not to
alter purity of the drug 5://.AG and ://.//G7. Those surfaces that are in the
vicinity of sterile product or container#closures" but do not directly contact
product should also be rendered sterile where reasonable contamination
potential e'ists. %t is as important in aseptic processing to properly validate
the processes used to sterilize such critical euipment as it is to validate
processes used to sterilize the drug product and its containerFclosure. (oist
heat and dry heat sterilization are most widely used and the primary
processes discussed in this document. %t should be noted that many of the
heat sterilization principles discussed in this document are also applicable to
other sterilization methods.
Sterility of aseptic processing euipment 5e.g." stopper hoppers7 should be
maintained by batch#by#batch sterilization. -ollowing sterilization of
euipment" containers" or closures" any transportation or assembly needs to
be performed in a manner in which its sterile state is protected and
sustained" with adherence to strict aseptic methods.
1. *eri"i/er 7!a"i8caion and 9a"idaion
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Malidation studies should be conducted demonstrating the e?cacy of the
sterilization cycle. Ceualifcation studies should also be performed on a
periodic basis. -or both the validation studies and routine production" use of
a specifed load confguration should be documented in the batch records.
.nevacuated air=s insulating properties prevent moist heat from penetrating
or heating up materials" and achieving the lethality associated with
saturated steam. +onseuently" there is a far slower thermal energy transfer
and rate of *ill from the dry heat in insulated locations in the load. %t is
important to remove all of the air from the autoclave chamber during the
sterilization cycle. Special attention should be given to the nature or type of
the materials to be sterilized and the placement of biological indicator within
the sterilization load. D#value of the biological indicator can vary widely
depending on the material 5e.g." glass versus TeJon7 to be sterilized. Di?cult
to reach locations within the sterilizer load and specifc materials should be
an important part of the evaluation of sterilization cycle e?cacy. Thereafter"
reualifcationFrevalidation should continue to focus on load areas identifed
as the most di?cult to penetrate or heat 5e.g." worst#case locations of tightly
wrapped or densely pac*ed supplies" securely fastened load articles" lengthy
tubing" the sterile flter apparatus" hydrophobic flters" stopper load7.
The formal program providing for regular 5i.e." semiannual" annual7
revalidation should consider the age of the sterilizer and its past
performance. +hange control procedures should adeuately address issues
such as a load confguration change or a modifcation of the sterilizer.
a7 Oualifcation3 )mpty +hamber
Temperature distribution studies evaluate numerous locations
throughout an empty sterilizing unit 5e.g." steam autoclave" dry heat
oven7 or euipment train 5e.g." large tan*s" immobile piping7. %t is
important that these studies assess temperature uniformity at various
locations throughout the sterilizer to identify potential Lcold spotsL
where there can be insu?cient heat to attain sterility. These heat
uniformity or Ltemperature mappingL studies should be conducted by
placing calibrated temperature measurement devices in numerous
locations throughout the chamber.
b7 Malidation3 9oaded +hamber
4eat penetration studies should be performed using the established
sterilizer load5s7. Malidation of the sterilization process with a loaded
chamber demonstrates the efects of loading on thermal input to the
items being sterilized" and may identify <cold spots> where there is
insu?cient heat to attain sterility. The placement of biological
indicators 5&%7 at numerous positions in the load" including the most
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di?cult to sterilize places" is a direct means of demonstrating the
e?cacy of any sterilization procedure. %n general" the thermocouple
5T+7 is placed ad$acent to the &% so as to assess the correlation
between microbial lethality and thermal input. Malidation of
sterilization can be performed using a partial or half#cycle approach. %n
some cases" the <bioburden> based cycle is used for sterilization
validation. -or further information on validation using moist heat
sterilization" please refer to -DA guidance" <,uideline for the
Submission of Documentation for Sterilization Process Malidation in
Applications for 4uman and Meterinary Drug Products> 58ovember"
/00;7.
Sterilization cycle specifcations are based upon the delivery of
adeuate thermal input to the slowest to heat locations. Bhen
determining which articles are most di?cult to sterilize" special
attention should be given to the sterilization of flters. -or e'ample"
some flter installations in piping cause a signifcant pressure
diferential across the flter" resulting in a signifcant temperature drop
on the downstream side. &iological indicators should be placed at
appropriate downstream locations of this euipment to determine if
the drop in temperature afects the thermal input at these sites.
)stablished load confguration should be part of batch record
documentation. A sterility assurance level of /6
#A
or better should be
demonstrated for the sterilization process.
2. E.!ipmen Conro"s and 'nsr!men Ca"ibraion
-or both validation and routine process control" the reliability of the data
generated by sterilization cycle monitoring devices should be considered to
be of the utmost importance. Devices that measure cycle parameters should
be routinely calibrated. Britten procedures should be established to ensure
these devices are maintained in a calibrated state. -or e'ample3
Temperature monitoring devices for heat sterilization should be
calibrated at suitable intervals" as well as before and after validation
runs.
Devices used to monitor dwell time in the sterilizer should be
periodically calibrated.
The microbial count and D#value of a biological indicator should be
confrmed before a validation study.
%nstruments used to determine the purity of steam should be
calibrated.
-or dry heat depyrogenation tunnels" devices 5e.g. sensors and
transmitters7 used to measure belt speed should be routinely
calibrated.
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Sterilizing euipment should be properly maintained to allow for consistently
satisfactory function. )valuation of sterilizer performance attributes such as
euilibrium 5<come up>7 time studies should be helpful in assessing if the
unit continues to operate properly.
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-. !ABORATOR2 CONTRO!S
Section ://./A6 5,eneral Ceuirements7 states <9aboratory controls shall include the
establishment of scientifcally sound and appropriate specifcations" standards" sampling
plans" and test procedures designed to assure that components" drug product containers"
closures" in#process materials" labeling" and drug products conform to appropriate standards
of identity" strength" uality" and purity.>
Sections ://./AE and ://./0; reuire that validation of test methods be established and
documented.
Sections ://.:: 5c7 states that <the uality control unit shall have the responsibility for
approving or re$ecting all procedures and specifcations impacting on the identity" strength"
uality" and purity of the drug product.>
Section ://.;: reuires" for aseptic processes" the establishment of a <system for monitoring
environmental conditions.>
Section ://.EA reuires" <written procedures assigning responsibility for sanitation and
describing in su?cient detail the cleaning schedules" methods" euipment" and materials to
be used in cleaning the buildings and facilities.> The <written procedures shall be designed to
prevent the contamination of euipment" components" drug product containers" closures"
pac*aging" labeling materials" or drug products and shall be followed.> Section ://.//G 5b7
reuires that <appropriate written procedures" designed to prevent microbiological
contamination of drug products purporting to be sterile" shall be established and followed.>
Section 211.1"2 states that /all drug product production and control records, including those for pac.aging and
labeling, shall be re!ie$ed and appro!ed by the -uality control unit to determine compliance $ith all established,
appro!ed, $ritten procedures before a batch is released or distributed.1
A. #n3iron+ent$l )onitoring
1. Genera" :rien Program
%n aseptic processing" one of the most important laboratory controls is the
establishment of an environmental monitoring program. This monitoring
provides meaningful information on the uality of the aseptic processing
environment when a given batch is being manufactured as well as
environmental trends of the manufacturing area. An adeuate program
identifes potential routes of contamination" allowing for implementation of
corrections before product contamination occurs 5://.;: and ://.//G7.
)valuating the uality of air and surfaces in the cleanroom environment
should start with a well#defned written program and validated methods. The
monitoring program should cover all production shifts and include air" Joors"
walls" and euipment surfaces" including the critical surfaces in contact with
product and containerFclosures. Britten procedures should include a list of
locations to be sampled. Sample timing" freuency" and location should be
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carefully selected based upon its relationship to the operation performed.
Samples should be ta*en throughout the aseptic processing facility 5e.g."
aseptic corridors! gowning rooms7 using appropriate" scientifcally sound
sampling procedures" standards" and test limits.
9ocations posing the most microbiological ris* to the product are a critical
part of the program. %t is especially important to monitor the microbiological
uality of the aseptic processing clean zone to determine whether or not
aseptic conditions are maintained during fllingFclosing activities. +ritical
surfaces which contact sterile product should be sterile. +ritical surface
sampling should be performed at the conclusion of the aseptic processing
operation to avoid direct contact with sterile surfaces during processing. Air
and surface samples should be ta*en at the actual wor*ing site and at
locations where signifcant activity or product e'posure occurs during
production.
)nvironmental monitoring methods do not always recover microorganisms
present in the sampled area. %n particular" low level contamination can be
particularly di?cult to detect. &ecause of the li*elihood of false negatives"
consecutive growth results are only one type of adverse trend. %ncreased
incidence of contamination over a given period in comparison to that
normally detected is an eually signifcant trend to be trac*ed.
All environmental monitoring locations should be described in SIPs with
su?cient detail to allow for reproducible sampling of a given location
surveyed. Britten SIPs should also address areas such as3 5/7 freuency of
sampling! 5:7 when the samples are ta*en 5i.e." during or at the conclusion of
operations7! 5G7 duration of sampling! 5;7 sample size 5e.g." surface area" air
volume7! 5E7 specifc sampling euipment and techniues! 5A7 alert and
action limits! and 527 appropriate response to deviations from alert or action
limits.
2. Esab"ishing 1imis and a 5rending Program
(icrobiological monitoring limits should be established based on the
relationship of the sampled location to the operation. The limits should be
based on the need to maintain adeuate microbiological control throughout
the entire sterile manufacturing facility. Ine should also consider
environmental monitoring data from historical databases" media flls"
cleanroom ualifcation" and sanitization procedure studies in developing
monitoring limits.
(icrobiological environmental monitoring should include both alert and
action limits. )ach individual sample result should be evaluated for its
signifcance by comparing to the alert or action limits. Averaging of results
can mas* unacceptable localized conditions. A result at the alert limit urges
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attention to the approaching action conditions. A result at the action level
should prompt a more thorough investigation. Britten procedures should be
established" detailing data review freuency" identifcation of contaminants"
and actions to be ta*en. The uality control unit should provide routine
oversight of near term 5e.g." daily" wee*ly" monthly" uarterly7 and long term
trends in environmental and personnel monitoring data.
Trend reports should include data generated by location" shift" lot" room"
operator" or other search parameters. The uality control unit is responsible
for producing specialized data reports 5e.g." a search on a particular atypical
isolate over a year period7 in order to investigate results beyond established
limits and identify any appropriate follow#up actions. %n addition to microbial
counts beyond alert and action limits" the presence of any atypical
microorganisms in the cleanroom environment should be investigated" with
any appropriate corrective action promptly implemented.
Britten procedures should defne the system whereby the most responsible
managers are regularly informed and updated on trends and investigations.
3. *anii/aion Efcacy
The suitability" e?cacy" and limitations of sanitization agents should be
assessed with their implementation for use in clean areas. The
efectiveness of these sanitization procedures should be measured by their
ability to ensure that potential contaminants are adeuately removed from
surfaces 5i.e." via obtaining samples before and after sanitization7.
.pon preparation" disinfectants should be rendered sterile" and used for a
limited time" as specifed by written procedures. Disinfectants should retain
e?cacy against the normal microbial Jora and be efective against spore#
forming microorganisms. (any common sanitizers are inefective against
spores" for e'ample" 26Q isopropyl alcohol is not efective against @aci""!sA
spp. spores. A sporicidal agent should be used regularly to prevent
contamination of the manufacturing environment with otherwise di?cult to
eradicate spore forming bacteria or fungi.
After the initial assessment of sanitization procedures" ongoing sanitization
e?cacy should be freuently monitored through specifc provisionsin the
environmental monitoring program" with a defned course of action in the
event samples are found to e'ceed limits.
4. Monioring Mehods
Acceptable methods of monitoring the microbiological uality of the
environment include3
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a. Surface (onitoring#
)nvironmental monitoring should include testing of various surfaces for
microbiological uality. -or e'ample" product contact surfaces" Joors"
walls" ceilings" and euipment should be tested on a regular basis.
Coutinely used for such tests are touch plates" swabs" and contact
plates. Ither surfaces in controlled areas should be tested to show the
adeuacy of cleaning and sanitizing procedures.
b. Active Air (onitoring#
The method of assessing the microbial uality of air should involve the
use of LactiveL devices such as slit to agar samplers" " those using
liuid impingement and membrane fltration" or centrifugal samplers.
)ach device has certain advantages and disadvantages" although all
allow a uantitative testing of the number of organisms per volume of
air sampled. The use of such devices in aseptic areas is considered an
essential part of evaluating the environment during each production
shift" at carefully chosen critical locations. (anufacturers should be
aware of a deviceNs air monitoring capabilities" and should determine
suitability of any new or current devices with respect to sensitivity and
limit of uantifcation.
c. Passive Air (onitoring 5Settling Plates7#
Another method is the use of passive air samplers such as settling
plates 5petri dishes containing nutrient growth medium e'posed to the
environment7. These settling plates lac* value as uantitative air
monitors because only microorganisms that settle onto the agar
surface will be detected. Their value as ualitative indicators in critical
areas is enhanced by positioning plates in locations posing the greatest
ris* of product contamination. As part of methods validation" the
uality control laboratory should evaluate what media e'posure
conditions optimize recovery of low levels of environmental isolates.
)'posure conditions should preclude desiccation 5e.g." caused by
lengthy sampling periods andFor high airJows7" which inhibits recovery
of microorganisms. The data generated by passive air sampling can be
useful when considered in combination with results from other types of
air samples.
B. )icrobiologic$l )edi$ $nd Identi4c$tion
The environmental monitoring program should include routine
characterization of recovered microorganisms. (onitoring of critical and
immediately surrounding areas as well as personnel should include routine
identifcation of microorganisms to the species 5or" where appropriate"
genus7 level.
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%n some cases" environmental trending data has revealed migration of
microorganisms into the aseptic processing room from either uncontrolled or
lesser#controlled areas. To detect such trends" an adeuate program of
diferentiating microorganisms in lesser#controlled environments 5e.g." +lass
/66"6667 should be in place. At minimum" the program should reuire
species 5or" where appropriate" genus7 identifcation of microorganisms in
ancillary environments at freuent intervals to establish a valid" current
database of contaminants present in the facility during processing 5and to
demonstrate that cleaning and sanitization procedures continue to be
efective7. )nvironmental isolates often correlate with the contaminants
found in a media fll or product sterility testing failure" and the overall
environmental picture provides valuable information for the associated
investigation.
The goal of microbiological monitoring is to reproducibly detect
microorganisms for purposes of monitoring the state of environmental
control. +onsistent methods will yield a database that allows for sound data
comparisons and interpretations. The microbiological culture media used in
environmental monitoring should be validated as capable of detecting fungi
5i.e." yeasts and molds7 as well as bacteria" and incubated at appropriate
conditions of time and temperature. Total aerobic bacterial count can be
obtained by incubating at G6 to GE
o
+ for ;1 to 2: hours. Total combined
yeast and mold count is generally obtained by incubating at :6 to :E
o
+ for E
to 2 days.
%ncoming lots of environmental monitoring media should include positive and
negative controls. ,rowth promotion testing should be performed on all lots
of prepared media. Bhere appropriate" inactivating agents should be used
to prevent inhibition of growth by clean room disinfectants.
C. Pre54ltr$tion Bioburden
-or any parenteral manufacturing process" pre#fltration bioburden should be
minimal. %n addition to increasing the challenge to the sterilizing flter" high
bioburden can contribute endoto'in or other impurities to the drug
formulation. An in#process limit for bioburden level for each formulated
product 5generally sampled immediately preceding sterile fltration7 should
be established.
D. P$rticul$te )onitoring
Coutine particle monitoring is useful in detecting signifcant deviations in air
cleanliness from ualifed processing norms 5e.g." clean area classifcation7.
A result outside the established specifcations at a given location should be
investigated consistent with the severity of the Le'cursion.L Appropriate
corrective action should be implemented to prevent future deviations.
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See Section %M.A for additional guidance on particulate monitoring.
"I. STERILIT# TESTING
Section ://./A2 5Special Testing Ceuirements7 states3 <-or each batch of drug product
purporting to be sterile andFor pyrogen#free" there shall be appropriate laboratory testing
to determine conformance to such reuirements. The test procedures shall be in writing
and shall be followed.>
Section ://./AE states <-or each batch of drug product" there shall be appropriate
laboratory determination of satisfactory conformance to fnal specifcations for the drug
product @prior to release.>
Section ://./AE5e7 reuires methods for testing to be validated as reliable and
reproducible 5e.g." bacteriostasisFfungistasis" method robustness" etc.7" stating3 <The
accuracy" sensitivity" specifcity" and reproducibility of test methods employed by the
frm shall be established and documented. Such validation and documentation may be
accomplished in accordance with Sec. ://./0;5a75:7.>
Section ://.//6 reuires" in part" that sampling procedures are established in order to
ensure batch uniformity3 The Lcontrol procedures shall be established to monitor the
output and to validate the performance of those manufacturing processes that may be
responsible for causing variability in the characteristics of in#process material and the
drug product.L
Section ://./A6 reuires the establishment of sound and appropriate sampling plans
which are representative of the batch.
Section :/6 defnes <representative sample> as one based on rational criteria that
provide an <accurate portrayal> of the material or batch being sampled.
Section ://./16 states a review of, 9at least annually, the -uality standards of each drug product
to determine the need for changes in drug product specifications or manufacturing or control
procedures.9 %nvestigations conducted under Section ://./0: for each drug product are
reuired to be addressed within this annual review.
+ertain aspects of sterility testing are of particular importance" including
control of the testing environment" understanding the test limitations" and
the investigation of manufacturing systems following a positive test.
The testing laboratory environment should employ facilities and controls
comparable to those used for fllingFclosing operations. Poor or defcient
sterility test facilities or controls can result in a high rate of test failures. %f
production facilities and controls are signifcantly better than those for
sterility testing there is the danger of attributing the cause of a positive
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sterility test result to the faulty laboratory even when the product tested
could have" in fact" been non#sterile. Therefore" some manufacturing
defciency may go undetected. The use of isolators to perform sterility
testing is a well#established means for minimizing false positives.
A. C6oice o* )et6ods
Sterility testing methodologies are reuired to be accurate and reproducible"
in accord with ://./0; and ://./AE. The methodology selected should
present the lowest potential for yielding a false positive. The .SP specifes
membrane fltration as the method of choice" when feasible.
As a part of methods validation" appropriate bacteriostasisFfungistasis testing
should be conducted. Such testing should demonstrate reproducibility of the
method in reco!ering each of a panel of representative microorganisms. Study
documentation should include evaluation of whether microbial recovery from
inoculated controls and product samples is comparable throughout the
incubation period. %f growth is inhibited" modifcations 5e.g." increased
dilution" additional membrane flter washes" addition of inactivating agents7
in the methodology should be implemented to optimize recovery. .ltimately"
methods validation studies should demonstrate that the methodology does
not provide an opportunity for Lfalse negatives.L
B. )edi$
%t is essential that the media used to perform sterility testing be rendered
sterile and demonstrated as growth promoting.
C. Personnel
Personnel performing sterility testing should be ualifed and trained for the
tas*. A written program should be in place to regularly update training of
personnel and confrm acceptable sterility testing practices.
D. S$+pling $nd Incub$tion
Sterility tests are limited in their ability to detect low levels of contamination.
-or e'ample" statistical evaluations indicate that the .SP sterility test
sampling plan has been described by .SP as Lonly enabling the detection of
contamination in a lot in which /6Q of the units are contaminated about nine
times out of ten in ma*ing the testL 5Cef. /:7. To further illustrate" if a /6"666
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unit lot with a 6./Q contamination level was sterility tested using :6 units"
there is a 01Q chance that the batch would pass the test.
This limited sensitivity ma*es it necessary to ensure that for batch release
purposes an appropriate number of units are tested and that the samples
uniformly represent the3
5/7 )ntire batch#
Samples should be ta*en at the beginning" middle" and end of the
aseptic processing operation!
5:7 &atch processing circumstances#
Samples should be ta*en in con$unction with processing interventions
or e'cursions.
&ecause of the limited sensitivity of the test" any positive result is considered
a serious +,(P issue and should be thoroughly investigated.
#. In3estig$tion o* Sterility Positi3es
+are should be ta*en in the performance of the sterility test to preclude any
activity that allows for possible sample contamination. Bhen microbial
growth is observed" the lot should be considered to be non#sterile. %t is
inappropriate to attribute a positive result to laboratory error on the basis of
a retest that e'hibits no growth.
:
The evaluation of a positive sterility test
result should include an investigation to determine whether the growth
observed in the test arose from product contamination or from laboratory
error.
Although it is recognized that such a determination may not be reached with
absolute certainty" it is usually possible to acuire persuasive evidence
showing that causative laboratory error is absent. Bhen available evidence
is inconclusive" batches should be re$ected as not conforming to sterility
reuirements.
%t would be di?cult to support invalidation of a positive sterility test. Inly if
conclusive and documented evidence clearly shows that the contamination
occurred as part of testing should a new test be performed.
After considering all relevant factors concerning the manufacture of the
product and testing of the samples" the comprehensive written investigation
should include specifc conclusions" and identify corrective actions. The
investigationNs persuasive evidence of the origin of the contamination should
be based upon at least the following3
:
)nderscoring this regulatory standard, )S+ ;;<, section =81>, states that an initial positi!e test is in!alid only in
an instance in $hich 9microbial gro$th can be $ithout a doubt ascribed to9 laboratory error 2as described in the
monograph3.
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/. %dentifcation 5speciation7 of the organism in the sterility test.
%dentifcation of the sterility test isolate5s7 should be to the species level.
(icrobiological monitoring data should be reviewed to determine if the
organism is also found in laboratory and production environments"
personnel" or product bioburden.
:. Cecord of laboratory tests and deviations. Ceview of trends in laboratory
fndings can help to eliminate or implicate the laboratory as the source of
contamination. %f the organism is seldom found in the laboratory
environment" then product contamination is li*ely. %f the organism is
found in laboratory and production environments" it can indicate product
contamination.
The proper handling of deviations is an essential aspect of laboratory
control. Bhen a deviation occurs during sterility testing" it should be
documented" investigated" and remedied. %f any deviation is considered
to have compromised the integrity of the sterility test" the test should be
invalidated immediately without incubation.
Deviation and sterility test positive trends should be evaluated
periodically 5e.g." uarterly" annually7 to provide an overview of
operations. A sterility positive result can be viewed as indicative of
production or laboratory problems and should be investigated globally
since such problems often can e'tend beyond a single batch.
%n order to more accurately monitor potential contamination sources" it is
useful to *eep separate trends by product" container type" flling line" and
personnel. Bhere the degree of sterility test sample manipulation is
similar for a terminally sterilized product and an aseptically processed
product" a higher rate of initial sterility failures for the latter should be
ta*en as indicative of aseptic processing production problems. See
Section %K.A" Process Simulations" which includes similar issues that are
investigated as part of a media fll failure investigation.
(icrobial monitoring of the laboratory environment and personnel over
time can also reveal trends that are informative. .pward trends in the
microbial load in the laboratory should be promptly investigated as to
cause" and corrected. %n some instances" such trends can appear to be
more indicative of laboratory error as a possible source of a sterility test
failure.
Bhere a laboratory has a good trac* record with respect to errors" this
history can help remove the lab as a source of contamination since
chances are higher that the contamination arose from production.
4owever" the converse is not true. Specifcally" where the laboratory has
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a poor trac* record" frms should not assume that the contamination is
automatically more attributable to the error in laboratory and
conseuently overloo* a genuine production problem. Accordingly" all
sterility positives should be thoroughly investigated.
G. (onitoring of production area environment. If particular importance is
trend analysis of microorganisms in the critical and immediately ad$acent
area. Trends are an important tool in investigating the product as the
possible source of a sterility failure. +onsideration of environmental
microbial loads should not be limited to results of monitoring the
production environment for the lot" day" or shift associated with the
suspect lot. -or e'ample" results showing little or no recovery of
microorganisms can be misleading" especially when preceded or followed
by a fnding of an adverse trend or atypically high microbial counts. %t is
therefore important to loo* at both short and long term trend analysis.
;. (onitoring of Personnel. Daily personnel monitoring data and associated
trends should be reviewed and can in some cases strongly indicate a
route of contamination. The adeuacy of personnel practices and training
should also be considered.
E. Product pre#sterilization bioburden. Trends in product bioburden should
be reviewed 5counts and identity7. Adverse bioburden trends occurring
during the time period of the test failure should be considered in the
investigation.
A. Production record review. +omplete batch and production control records
should be reviewed to detect any signs of failures or anomalies which
could have a bearing on product sterility. -or e'ample" the investigation
should evaluate batch and trending data that indicate whether
utilityFsupport systems 5e.g." 4MA+" B-%7 are functioning properly. Cecords
of air uality monitoring for flling lines should show a time at which there
was improper air balance" an unusual high particulate count" etc.
2. (anufacturing history. The manufacturing history of the product or
similar products should be reviewed as part of the investigation. Past
deviations" problems" or changes 5e.g." process" components" euipment7
are among the factors that can provide an indication of the origin of the
problem.
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"II. BATC% RECORD REVIE&' PROCESS CONTROL DOCUMENTATION
Sections ://./66" ://./1A" and ://./11 address documentation of production and control
of a batch" including recording various production and process control activities at the
time of performance. Section ://./66 5b7 reuires a documented record and evaluation of
any deviation from written procedures.
Section ://./0: states that LAll drug product production and control records, including those for
pac.aging and labeling, shall be re!ie$ed and appro!ed by the -uality control unit to determine compliance $ith
all established, appro!ed $ritten procedures before a batch is released or distributed. Any unexplained
discrepancy 2including a percentage of theoretical yield exceeding the maximum or minimum percentages
established in master production and control records3 or the failure of a batch or any of its components to meet
any of its specifications shall be thoroughly in!estigated, $hether or not the batch has already been distributed.
(he in!estigation shall extend to other batches of the same drug product and other drug products that may ha!e
been associated $ith the specific failure or discrepancy. A $ritten record of the in!estigation shall be made and
shall include the conclusions and follo$up.9
(aintaining process and environmental control is a daily necessity for an
aseptic processing operation. The reuirement for review of all batch records
and data for conformance with written procedures" operating parameters"
and product specifcations prior to arriving at the fnal release decision for an
aseptically processed batch calls for an overall review of process and system
performance for that given cycle of manufacture. All in#process data must
be included with the batch record documentation per Section ://./11.
Ceview of environmental monitoring data as well as other data relating to the
acceptability of output from support systems 5e.g." 4)PA F 4MA+" B-%" steam
generator7 and proper functioning of euipment 5e.g." batch alarms report!
integrity of various flters7" should be viewed as essential elements of the
batch release decision.

Bhile interventions andFor stoppages are normally recorded in the batch
record" the manner of documenting these occurrences varies. %n particular"
line stoppages and any unplanned interventions should be su?ciently
documented in batch records with the associated time and duration of the
event. %n general" there is a correlation between product 5or container#
closure7 dwell time in the aseptic processing zone and the probability of
contamination. Sterility failures can be attributed to atypical or e'tensive
interventions that have occurred as a response to an undesirable event
during the aseptic process. Britten procedures describing the need for line
clearances in the event of certain interventions" such as machine
ad$ustments and any repairs" should be established. Such interventions
should be documented with more detail than minor events. %nterventions
that result in substantial activity near e'posed productFcontainer#closures or
that last beyond a reasonable e'posure time should" where appropriate"
result in a local or full line clearance
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Any disruption in power supply" however momentary" during aseptic
processing is a manufacturing deviation and must be included in batch
records 5://./66" ://./0:7.
APPENDI" 1' ASEPTIC PROCESSING ISOLATORS
An emerging aseptic processing technology uses isolation systems to
minimize the e'tent of personnel involvement and to separate the e'ternal
cleanroom environment from the aseptic processing line. A well designed
positive pressure barrier isolator" supported by adeuate procedures for its
maintenance" monitoring" and control" appears to ofer an advantage over
classical aseptic processing" including fewer opportunities for microbial
contamination during processing. 4owever" users should not adopt a <false
sense of security> with these systems. (anufacturers should be also aware
of the need to establish new procedures addressing issues uniue to these
systems.
A( )$inten$nce
1. Genera"
%solator systems have a number of special maintenance reuirements. Bhile
no isolator unit forms an absolute seal" very high integrity can be achieved in
a well#designed unit. 4owever" a lea* in any of certain components of the
system can constitute a signifcant breach of integrity. The integrity of
gloves" half#suits" seams" gas*ets" and seals reuire daily attention and a
comprehensive preventative maintenance program. Ceplacement
freuencies should be established in written procedures that reuire
changing parts before they brea*down or degrade.
2. G"o2e 'negriy
A faulty glove or sleeve 5gauntlet7 assembly represents a route of
contamination and a critical breach of isolator integrity. The choice of
durable glove materials" coupled with a well#$ustifed replacement freuency"
are two aspects of good manufacturing practice that should be addressed.
Bith every use" gloves should be visually evaluated for any macroscopic
physical defect. (echanical integrity tests should also be performed
routinely. This attentive preventative maintenance program is necessary to
prevent use of gloves lac*ing integrity that would place the sterile product at
ris*. Bhen such a breach is discovered" the operation should be terminated.
Due to the potential for microbial migration through microscopic holes in
gloves and the lac* of a highly sensitive glove integrity test" the inner part of
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the installed glove should be sanitized regularly and the operator should also
wear a second pair of thin gloves.
B( Design

1. #ir;o<
The design of an aseptic processing isolator normally employs unidirectional
airJow that sweeps over and away from e'posed sterile materials" avoiding
any turbulence or stagnant airJow in the area of e'posed sterilized
materials" product" and container#closures. %n most sound designs" air
showers over the critical zone once" and then is systematically e'hausted.
Air handling systems should employ 4)PA andFor .9PA flters in series.
2. Maeria"s o( Consr!cion
As in any aseptic processing design" suitable materials should be chosen
based on durability" as well as ease of cleaning and sterilization. -or
e'ample" rigid wall construction incorporating stainless steel and glass
materials is widely used.
3. Press!re +i=erenia"
%solators that include an open e'it portal represent a potential compromise in
achieving complete physical separation from the e'ternal environment. A
positive air pressure diferential adeuate to achieve this full separation
should be employed and supported by ualifcation studies. Positive air
pressure diferentials from the isolator to the surrounding environment have
largely ranged from appro'imately 6.62L to 6.:L water gauge. The
appropriate minimum pressure diferential specifcation established by a frm
will be dependent on the system=s design and" when applicable" its e'it port.
Air balance between the isolator and other direct interfaces 5e.g." dry heat
tunnel7 should also be ualifed.
The positive pressure diferential should be coupled with appropriate
protection at the product egress point5s7 in order to overcome the potential
for ingress of any airborne particles from the
e'ternal environment by induction. %nduction can result from local turbulent
Jow causing air swirls or pressure waves that can push e'traneous particles
into the isolator. 9ocal +lass /66 protection at an opening can provide a
further barrier to induction of outside air into the isolator.
4. C"ean #rea C"assi8caions
The interior of the isolator should" at minimum" meet +lass /66 standards.
The classifcation of the environment surrounding the isolator should be
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based on the design of the product interfaces" such as transfer ports and
discharge points" as well as the number of transfers into and out of the
isolator. A +lass /6"666 or +lass /66"666 bac*ground is appropriate
depending on isolator design and manufacturing situations. The area
surrounding the isolator should be $ustifed. An isolator should not be located
in an unclassifed room.
C( Tr$ns*er o* )$teri$ls,Supplies
The ability to maintain integrity and sterility of an isolator is impacted by the
design of transfer ports. Marious adaptations" of difering capabilities" allow
for the transfer of supplies into and out of the isolator.

1. 'nrod!cion>
(ultiple material transfers are generally made during the processing of
a batch. -reuently" transfers are performed via direct interface with a
decontaminating transfer isolator or dry heat depyrogenation tunnel
with balanced airJow. Such provisions" if well designed" help ensure
that microbiological ingress does not result from the introduction of
supplies. Properly operated CTPs 5rapid transfer ports7 are also
generally considered to be an efective transfer mechanism. The
number of transfers should be *ept to a minimum because the ris* of
ingress of contaminants increases with each successive material
transfer.
Some transfer ports can have signifcant limitations" including marginal
decontaminating capability 5e.g." ultraviolet7 or a design that would
compromise isolation by allowing ingress of air from the surrounding
room. %n the latter case" localized 4)PA#fltered laminar airJow cover
in the area of such a port should be implemented.

2. +ischarge>
%solators often include a LmouseholeL or other e'it port through which
product is discharged" opening the isolator to the outside environment.
The mousehole represents a potential route of contamination.
Su?cient overpressure should be supplied and monitored on a
continuous basis at this location to ensure that isolation is maintained.
D( Decont$+in$tion
1. *!r(ace E3pos!re
Britten procedures for decontamination of the isolator should be
established. The decontamination process should provide full e'posure
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of all isolator surfaces to the chemical agent. -or e'ample" in order to
facilitate contact with the sterilant" the glove apparatus should be fully
e'tended with glove fngers separated during the decontamination
cycle.
2. Efcacy
A decontamination method should be developed which renders the
inner surfaces of the isolator free of viable microorganisms.
Decontamination can be accomplished using a number of vaporized
agents" although these agents possess limited capability to penetrate
obstructed or covered surfaces. Process development and validation
studies should include a thorough determination of cycle capability.
The characteristics of these agents generally preclude the reliable use
of statistical methods 5e.g." fraction negative7 to determine process
lethality. An appropriate" uantifed &% challenge should be placed on
various materials and in many locations throughout the isolator"
including di?cult to reach areas. +ycles should be developed with an
appropriate margin of e'tra *ill to provide confdence in robustness of
the decontamination processes. -or most production applications"
demonstration of a si'#log reduction of the challenge &% is
recommended.
The uniform distribution of the defned concentration of
decontaminating agent should also be evaluated concurrent with these
studies. +hemical indicators may also be useful as a ualitative tool to
show that the decontaminating agent reached a given location.
3. -re.!ency
Bhile isolators vary widely in design" their interior and content should
be designed to be freuently decontaminated. %f an isolator is to be
used for multiple days between decontamination cycles" the freuency
adopted should include a built#in safety margin and be well $ustifed.
This freuency" established during validation studies" should be
reevaluated and increased if production data indicate any deterioration
of the microbiological uality of the isolator environment.
A breach of isolator integrity 5e.g." power failure" gloveFseam tear"
other air lea*s" valve failure" out of specifcation pressure7 should lead
to a decontamination cycle. &reaches of integrity should be
investigated and any product that may have been impacted by the
breach re$ected.
#( "illing !ine Sterili0$tion
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%n order to ensure sterility of product contact surfaces from the start of each
operation" the entire path of the sterile liuid stream should be sterilized. %n
addition" loose materials or euipment to be used within the isolator should
be chosen based on their ability to withstand steam sterilization 5or
euivalent method7. %t is e'pected that any materials that can be sub$ected
to a steam sterilization cycle will" in fact" be autoclaved.
"( #n3iron+ent$l )onitoring
An appropriate environmental monitoring program should be established
which routinely ensures acceptable microbiological uality of air" surfaces"
and gloves 5or half#suits7 as well as particulate levels" within the isolator. Air
uality should be monitored periodically during each shift. As an e'ample"
the e'it port should be monitored for particulates to detect any unusual
results.
G( Personnel
Bhile cleanroom apparel reuirements are generally reduced" the
contribution of human factor to contamination should not be overloo*ed.
%solation processes generally include periodic or even freuent use of one or
more gloves for aseptic manipulations and handling of component transfers
into and out of the isolator. +ontaminated gloves can lead to product non#
sterility. This concern is heightened because locations on gloves" sleeves" or
half suits can be among the more di?cult to reach places during surface
sterilization. (eticulous aseptic techniue standards must be observed
5://.//G7.
APPENDI" 2' BLO&(FILL( SEAL TEC%NOLOG#
&low#fll#seal 5&-S7 technology is an automated process by which containers
are formed" flled" and sealed in a continuous operation. This manufacturing
technology includes economies in container#closure processing and reduced
human intervention" and is often used for flling and pac*aging of
ophthalmics and" less freuently" for in$ectables. This section discusses
some of the critical control points of this technology. )'cept where otherwise
noted below" the aseptic processing standards discussed elsewhere in this
document should be applied to &low -ill Seal technology.
A( #1uip+ent Design $nd Air .u$lity
A &-S machine operates by /7 heating a plastic polymer resin! :7 e'truding it
to form a parison 5a tubular form of the hot resin7! G7 cutting the parison with
a high temperature *nife! ;7 moving the parison under the blow#fll needle
5mandrel7! E7 inJating it to the shape of the mold walls! E7 flling the formed
container with the liuid product! A7 removing the mandrel! 27 sealing.
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Throughout this operation sterile#air is used" for e'ample" to form the parison
and inJate it prior to flling. %n most operations" the three steps which pose
greatest potential for e'posure to particle contamination andFor surrounding
air are those in which3 the parison is cut! the parison is moved under the
blow#fll mandrel! and the mandrel is removed 5$ust prior to sealing7.
&-S machinery and its surrounding barriers should be designed to prevent
potential for e'traneous contamination. As with any aseptic processing
operation" it is critical that contact surfaces be sterile. A validated steam#in#
place cycle should be used to sterilize the euipment path through which the
product is conveyed. %n addition" any other surface 5e.g." above or nearby7
that has potential to contaminate the sterile product needs to be sterile.
The classifed environment surrounding &-S machinery should generally
meet +lass /6"666 standards" but special design provisions 5e.g." isolation
technology7 can $ustify an alternate classifcation. 4)PA#fltered or sterile air
provided by membrane flters is necessary in the critical zone in which sterile
product or materials are e'posed 5e.g." parison formation" container
moldingFflling steps7. Air in the critical zone should meet +lass /66
microbiological standards. A well#designed &-S system should also normally
achieve +lass /66 particulate levels.
)uipment design should incorporate specialized measures to reduce
particulate levels. %n contrast to non#pharmaceutical applications using &-S
machinery" control of air uality 5i.e." particulates7 is critical for sterile drug
product manufacture. Particles generated during the plastic e'trusion"
cutting" and sealing processes provide a potential means of transport for
microorganisms into open containers prior to sealing. Provisions for carefully
controlled airJow could protect the product by forcing generated particles
outward while preventing any ingress from the ad$acent environment.
-urthermore" designs separating the flling zone from the surrounding
environment are important in ensuring product protection. &arriers" pressure
vacuums" microenvironments" and appropriately directed high velocities of
sterile air have been found useful in preventing contamination 5Cef. /G7.
Smo*e studies and multi#location particulate data are vital when performing
ualifcation studies to assess whether proper particulate control dynamics
have been achieved throughout the critical area.
%n addition to suitable design" an adeuate preventative maintenance
program should be established. -or e'ample" because of its potential to
contaminate the sterile drug product" the integrity of the boiling system
5e.g." mold plates" gas*ets7 should be carefully monitored and maintained.
B( $lid$tion,.u$li4c$tion
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Advantages of &-S processing are *nown to include rapid containerFclosure
processing and minimized interventions. 4owever" a properly functioning
process is necessary to realize these advantages. )uipment
ualifcationFreualifcation and personnel practices should be given special
attention. )uipment sterilization" media flls" polymer sterilization"
endoto'in removal" product#plastic compatibility" formingFsealing integrity"
and unit weight variation are among the *ey issues that should be covered
by validationFualifcation studies.
Appropriate data should ensure that &-S containers are sterile and non#
pyrogenic. This can generally be achieved by validating that time#
temperature conditions of the e'trusion process destroy the worst#case
endoto'in load on the polymeric material.
The plastic polymer material chosen should be pharmaceutical grade" safe"
pure" and pass .SP criteria for plastics. Polymer suppliers should be
ualifed and monitored for raw material uality.
C( B$tc6 )onitoring $nd Control
%n#process monitoring should include various control parameters 5e.g."
container weight variation" fll weight" lea*ers" air pressure" etc.7 to ensure
ongoing process control. )nvironmental monitoring is particularly
important. Samples should be ta*en during each shift at specifed locations
under dynamic conditions. Due to the generation of high levels of particles
near the e'posed drug product" continuous monitoring of particles can
provide valuable data relative to the control of a blow#fll#seal operation.
+ontainer#closure defects can be a ma$or problem in control of a &-S
operation. %t is necessary for the operation to be designed and set#up to
uniformly manufacture lea*#proof units. As a fnal measure" inspection of
each unit of a batch should employ a reliable" sensitive fnal product
e'amination capable of detecting a defective unit 5e.g." <lea*ers>7.
Signifcant defects due to heat or mechanical problems" such as mold
thic*ness" containerFclosure interface defciencies" poorly formed closure" or
other deviations should be investigated in accord with Sections ://./66 and
://./0:.
APPENDI" $' PROCESSING PRIOR TO FILLING*SEALING OPERATIONS
The purpose of this appendi' is to supplement the guidance provided in this
document with information on products regulated by +&)C or +D)C that are
sub$ect to aseptic processing from early in the manufacturing process" or
that reuire aseptic processing through the entire manufacturing process"
due to their inability to be sterilized. The scope of this appendi' includes
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aseptic processing activities that ta*e place prior to the flling and sealing of
the fnished drug product. Special considerations include those for3
A( Aseptic processing *ro+ e$rly +$nu*$cturing steps
Due to their nature" some products undergo aseptic processing at some or all
manufacturing steps preceding the fnal product closing step. There is a
point in the process after which a product can no longer be rendered sterile
by fltration" and the product is handled aseptically in all subseuent steps.
Some products are formulated aseptically because the formulated product
cannot be sterilized by fltration. -or e'ample" products containing
aluminum ad$uvant are formulated aseptically because once they are alum
adsorbed" they cannot be sterile fltered.
Bhen a product is processed aseptically from early steps" the product and all
components or other additions are rendered sterile prior to entering the
manufacturing process. %t is critical that all transfers" transports" and storage
stages are carefully controlled at each step of the process to maintain
sterility of the product.
Procedures that e'pose the product or product contact euipment surfaces
to the environment" such as aseptic connections" should be performed under
unidirectional airJow in a +lass /66 environment. The environment of the
room surrounding the +lass /66 environment should be class /6"666 or
better. (icrobiological and particulate monitoring should be performed
during operations. (icrobial surface monitoring should be performed at the
end of operations" but prior to cleaning. Personnel monitoring should be
performed in association with operations.
Process simulation studies should be designed to incorporate all conditions"
product manipulations" and interventions that could impact on the sterility of
the product during manufacturing. The process simulation" from early
process steps" should demonstrate that controls over the process are
adeuate to protect the product during manufacturing. These studies should
incorporate all product manipulations" additions" and procedures involving
e'posure of product contact surfaces to the environment. The studies should
include worst#case conditions such as ma'imum duration of open operations
and ma'imum number of participating operators. 4owever" process
simulations do not need to mimic total manufacturing time if the
manipulations that occur during manufacturing are adeuately represented.
%t is also important that process simulations incorporate storage of product or
transport to other manufacturing areas. -or instance" there should be
assurance of bul* vessel integrity for specifed holding times. The transport
of bul* tan*s or other containers should be simulated as part of the media
fll. Please refer to Section %K.A for more guidance on media simulation
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studies. Process simulation studies for the formulation stage should be
performed at least twice per year.
B( Aseptic processing o* cell5b$sed t6er$py products %or o* products
intended *or use $s cell b$sed t6er$pies(
+ell#based therapy products represent a subset of the products for which
aseptic manipulations are used throughout the process. Bhere possible"
closed systems should be used during production. +ell#based therapy
products often have short processing times at each manufacturing stage"
even for the fnal product. Iften" it is appropriate for these products to be
administered to patients before fnal product sterility testing results are
available. %n situations where results of fnal sterility testing are not available
before the product is administered" additional controls and testing should be
considered. -or e'ample" additional sterility tests can be performed at
intermediate stages of manufacture" especially after the last manipulation of
the product prior to administration. Ither tests that may indicate microbial
contamination" such as microscopic e'amination" gram stains" and endoto'in
testing should be performed prior to product release.
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REFERENCES
l. %SI /;A;;#/3 +leanrooms and Associated +ontrolled )nvironments"
+lassifcation of Air +leanliness.
:. Technical Irder 66#:E#:6G" +ontamination +ontrol of Aerospace -acilities"
..S. Air -orce" December l" l02:.
. *0ung-!ist, ?., and @einmuller, ?., Clean @oom Design7 Ainimi5ing Contamination (hrough
+roper DesignB Interpharm +ress, 1""8.
'. CASA Standard for Clean @oom and Dor. Stations for Aicrobially Controlled En!ironment,
+ublication C&? ,'#.2 2August l"683
E. (orbidity and (ortality Bee*ly Ceport" +linical Sepsis and Death in a
8ewborn 8ursery Associated with +ontaminated (edications T &razil" /00A">
+enters for Disease +ontrol and Prevention" Uuly" /001! ;25:07!A/6#:.
A. ,randics" Peter" <Pyrogens in Parenteral Pharmaceuticals"> Pharmaceutical
Technology" April :666.
2. 9ord" A. and Uohn B. 9evchu*" LPersonnel %ssues in Aseptic Processing"L
&iopharm" /010.
1. Technical Ceport 8o. GA" <+urrent Practices in the Malidation of Aseptic
Processing"L Parenteral Drug Association" %nc." :66:.
0. 9eahy" Timothy U. and (ary U. Sullivan <Malidation of &acterial # Cetention
+apabilities of (embrane -ilters"L Pharmaceutical Technology" 8ov. l021.
/6. Pall" David &. and )rwin A. Pirnbauer" et al" LParticulate Cetention by
&acteria Cetentive (embrane -ilters"L Pall +orporation +olloids and Surfaces"
l 5l0167 :GE#:EA" )lsevier Scientifc Publishing +ompany" Amsterdam.
//. Technical Ceport 8o. :A" LSterilizing -iltration of 9iuids"L Parenteral Drug
Association" %nc." /001.
/:. Pharmacopoeial -orum" Uuly#August l016" p. GE;" L+ommentary on the
Sterility Tests and Sterilization +hapters of the ..S. Pharmacopoeia"L Aubrey
S. Iutschoorn" Sr. Scientist" ..S.P. Drug Standards Division.
/G. Price" Uef" <&low#-ill#Seal Technology3 Part %" A Design for Particulate
+ontrol"> Pharmaceutical Technology" -ebruary" /001.
/;. .nited States Pharmacopoeia
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R#!#ANT GUIDANC# DOCU)#NTS
Some relevant -DA guidances include3
,uidance for the Submission of Documentation for Sterilization Process
Malidation in Applications for 4uman and Meterinary Drug Product" /00;
,uideline for Malidation of 9imulus Amebocyte 9ysate Test as an )nd
Product )ndoto'in Test for 4uman and Animal Parenteral Drugs" &iological
Products" and (edical Devices" /012
,uide to %nspections of 9yophilization of Parenterals" /00G
,uide to %nspections of 4igh Purity Bater Systems" /00G
,uide To %nspections of (icrobiological Pharmaceutical Ouality +ontrol
9aboratories" /00G
,uide To %nspections of Sterile Drug Substance (anufacturers" /00;
Pyrogens3 Still a Danger! /020 5%nspection Technical ,uide7
&acterial )ndoto'insFPyrogens! /01E 5%nspection Technical ,uide7
4eat )'changers to Avoid +ontamination! /020 5%nspection Technical
,uide7
-or more in(ormaion on -+# g!idanceA see o!r <ebsie a www.fda.gov.
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DRA"T G!OSSAR2
Air loc*# A small room with interloc*ed doors" constructed to maintain air
pressure control between ad$oining rooms 5generally with diferent air
cleanliness standards7. The intent of an aseptic processing airloc* is to
preclude ingress of particulate matter and microorganism contamination
from a lesser controlled area.
Alert 9imit# An established microbial or particulate level giving early warning
of potential drift from normal operating conditions and which trigger
appropriate scrutiny and follow#up to address the potential problem. Alert
9imits are always lower than Action 9imits.
Action 9imit# An established microbial or particulate level which when
e'ceeded should trigger appropriate investigation and corrective action
based on the investigation.
Aseptic Processing -acility# &uilding containing cleanrooms in which air
supply" materials" and euipment are regulated to control microbial and
particulate contamination.
Aseptic Processing Coom# A room in which one or more aseptic activities or
processes is performed.
Asepsis# State of control attained by using an aseptic wor* area and
performing activities in a manner that precludes microbiological
contamination of the e'posed sterile product.
&ioburden# Total number of microorganisms associated with a specifc item
prior to sterilization.
&arrier# Physical partition that afords aseptic manufacturing zone protection
by partially separating it from the surrounding area.
&iological %ndicator 5&%7# A population of microorganisms inoculated onto a
suitable medium 5e.g." solution" containerFclosure7 and placed within
appropriate sterilizer load locations to determine the sterilization cycle
e?cacy of a physical or chemical process. The challenge microorganism is
selected based upon its resistance to the given process. %ncoming lot D#
value and microbiological count defne the uality of the &%.
+lean Area# An area with defned particulate and microbiological cleanliness
standards 5e.g." +lass /66" +lass /6"666 or +lass /66"6667.
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+leanroom# A room designed" maintained" and controlled to prevent
particulate and microbiological contamination of drug products. Such a room
is assigned and reproducibly meets an appropriate air cleanliness
classifcation.
+lean Vone# See +lean Area.
+omponent# Any ingredient intended for use in the manufacture of a drug
product" including those that may not appear in the fnal drug product.
+olony -orming .nit 5+-.7# A microbiological term which describes the
formation of a single macroscopic colony after the introduction of one 5or
more7 microorganism5s7 to microbiological growth media. Ine colony
forming unit is e'pressed as / +-..
+ritical areas # Areas designed to maintain sterility of sterile materials.
Sterilized product" containerFclosures" and euipment may be e'posed in
critical areas.
+ritical surfaces # Surfaces which may come into contact with or directly
impact on sterilized product or containersFclosures. +ritical surfaces are
rendered sterile prior to the start of the manufacturing operation and sterility
is maintained throughout processing.
Decontamination# A process which eliminates viable bioburden via use of
sporicidal chemical agents.
Depyrogenation# A process used to destroy or remove pyrogens 5e.g."
endoto'in7.
D value # The time 5in minutes7 of e'posure to a given temperature that
causes a one#log or 06Q reduction in the population of a specifc
microorganism.
Dynamic# +onditions relating to clean area classifcation under conditions of
normal production.
)ndoto'in# A pyrogenic product 5e.g." lipopolysaccharide7 present in the
bacterial cell wall. )ndoto'in can lead to reactions in patients receiving
in$ections ranging from fever to death.
,owning Oualifcation# Program which establishes" both initially and on a
periodic basis" the capability of an individual to don the complete sterile
gown in an aseptic manner.
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4)PA flter# 4igh )?ciency Particulate Air flter with minimum 6.G micron
particle retaining e?ciency of 00.02Q.
4MA+# 4eating" Mentilation" and Air +onditioning.
%ntervention# An aseptic manipulation or activity that occurs at the critical
zone.
%solator # A decontaminated unit" supplied with 4)PA or .9PA fltered air"
which provides uncompromised" continuous isolation of its interior from the
e'ternal environment 5e.g." surrounding clean room air and personnel7.
9aminarity# .nidirectional air Jow at a velocity su?cient to uniformly sweep
particulate matter away from a critical processing or testing area.
Iperator# Any individual participating in the aseptic processing operation"
including line set#up" fller" maintenance" or other personnel associated with
aseptic line activities.
Iver*ill sterilization process # A process that is su?cient to provide at least a
/: log reduction of microorganisms having a minimum D value of / minute.
Pyrogen# Substance which induces a febrile reaction in a patient.
Sterilizing grade flter# A flter which" when appropriately validated" will
remove all microorganisms from a Juid stream" producing a sterile eSuent.
Terminal sterilization# The application of a lethal agent to sealed" fnished
drug products for the purpose of achieving a predetermined sterility
assurance level 5SA97 of usually less than /6
#A
5i.e." a probability of a non#
sterile unit of greater than one in a million7.
.9PA flter# .ltra#9ow Penetration Air flter with minimum 6.G micron particle
retaining e?ciency of 00.000 Q.
Malidation# )stablishing documented evidence which provides a high degree
of assurance that a specifc process will consistently produce a product
meeting its predetermined specifcations and uality attributes.
Borst case# A set of conditions encompassing upper and lower processing
limits and circumstances" including those within standard operating
procedures" which pose the greatest chance of process or product failure
5when compared to ideal conditions7. Such conditions do not necessarily
induce product or process failure.
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