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Aseptic Processing
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Aseptic Processing - Overview
Certain pharmaceutical products must besterile
injections, ophthalmic preparations, irrigations
solutions, haemodialysis solutions
Two categories of sterile products
those that can be sterilized in final container
terminally sterilized!
those that cannot be terminally sterilized andmust be aseptically prepared
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Aseptic Processing - Overview
Aseptic processing
Objective is to maintain the sterility of a product,
assembled from sterile components
Operating conditions so as to prevent microbial
contamination
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Aseptic Processing - Overview
Objective
To review specific issues relating to the
manufacture of aseptically prepared products"
#anufacturing environment
Clean areas
Personnel
Preparation and filtration of solutions
Pre-filtration bioburden
$ilter integrity%validation
&'uipment%container preparation and sterilization $illing Process
(alidation of aseptic processes
)pecific issues relating to *solators, +$) and +ul
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#anufacturing &nvironment
Classification of Clean Areas Comparison of classifications
Table
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#anufacturing &nvironment
Classification of Clean Areas
Classified in terms of airborne particles Table .!
/At rest0 - production e'uipment installed and operating
/*n operation0 - *nstalled e'uipment functioning in defined
operating mode and specified number of personnel present
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#anufacturing &nvironment
$our grades of clean areas" 1rade 2 e'uivalent to Class 33,333, *)O 4!"
Clean area for carrying out less critical stages in
manufacture of aseptically prepared products eg5
handling of components after washing5 1rade C e'uivalent to Class 3,333, *)O 6!"
Clean area for carrying out less critical stages in
manufacture of aseptically prepared products eg5
preparation of solutions to be filtered5
1rade + e'uivalent to Class 33, *)O 7!"
+acground environment for 1rade A zone, eg5
cleanroom in which laminar flow worstation is housed5
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#anufacturing &nvironment
1rade A e'uivalent to Class 33 8) $ederal)tandard .39&!, *)O 7 *)O :;::-!"
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#anufacturing &nvironment
These are average values Individual settle plates may be exposed for less than 4 hours
Values are for guidance only - not intended to represent specifications
Levels (limits of detection of microbiological contamination should be
established for alert and action purposes and for monitoring trends of
air !uality in the facility
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#anufacturing &nvironment
&nvironmental #onitoring
Physical
Particulate matter
2ifferential pressures
Air changes, airflow patterns Clean up time%recovery
Temperature and relative humidity
Airflow velocity
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#anufacturing &nvironment
&nvironmental #onitoring - Physical
Particulate matter
Particles significant because they can contaminate and
also carry organisms
Critical environment should be measured not more than
>3cm from worsite, within airflow and duringfilling%closing operations
Preferably a remote probe that monitors continuously
2ifficulties when process itself generates particles e5g5
powder filling!
Appropriate alert and action limits should be set and
corrective actions defined if limits e?ceeded
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#anufacturing &nvironment
&nvironmental #onitoring - Physical
2ifferential pressures
Positive pressure differential of 3-7 Pascals should be
maintained between adjacent rooms of different
classification with door closed!
#ost critical area should have the highest pressure
Pressures should be continuously monitored and
fre'uently recorded5
Alarmsshould sound if pressures deviate
Any deviations should be investigated and effect onenvironmental 'uality determined
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#anufacturing &nvironment
&nvironmental #onitoring - Physical Air Changes%Airflow patterns
Air flow over critical areas should be uni-directional
laminar flow! at a velocity sufficient to sweep particles
away from filling%closing area
for +, C and 2 rooms at least .3 changes per hour areususally re'uired
Clean up time%recovery
Particulate levels for the 1rade A /at rest0 state should
be achieved after a short /clean-up0 period of .3 minutesafter completion of operations guidance value!
Particle counts for 1rade A /in operation0 state should
be maintained whenever product or open container is
e?posed
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#anufacturing &nvironment
&nvironmental #onitoring - Physical
Temperature and @elative umidity
Ambient temperature and humidity should not be
uncomfortably high could cause operators to
generate particles! 4BC!
Airflow velocity
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#anufacturing &nvironment
Personnel
#inimum number of personnel in clean areas
especially during aseptic processing
*nspections and controls from outside
Training to all including cleaning and maintenancestaff
initial and regular
manufacturing, hygiene, microbiology
should be formally validated and authorized to enter
aseptic area )pecial cases
supervision in case of outside staff
decontamination procedures e5g5 staff who wored withanimal tissue materials!
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#anufacturing &nvironment
Personnel.! igh standards of hygiene and cleanliness
should not enter clean rooms if ill or with open
wounds
Periodic health checs
=o shedding of particles, movement slow andcontrolled
=o introduction of microbiological hazards
=o outdoor clothing brought into clean areas, should
be clad in factory clothing Changing and washing procedure
=o watches, jewellery and cosmetics
&ye checs if involved in visual inspection
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#anufacturing &nvironment
Personnel >! Clothing of appropriate 'uality"
1rade 2 hair, beard, moustache covered protective clothing and shoes
1rade C hair, beard, moustache covered single or .-piece suit covering wrists, high nec!,
shoes%overshoes no fibres%particles to be shed
1rade A and + headgear, beard and moustache covered, mass,gloves
not shedding fibres, and retain particles shed byoperators
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#anufacturing &nvironment
Personnel :! Outdoor clothing not in change rooms leading to
1rade + and C rooms Change at every woring session, or once a day if
supportive data! Change gloves and mass at every woring session $re'uent disinfection of gloves during operations Eashing of garments F separate laundry facility
=o damage, and according to validated procedures
washing and sterilization!
@egular microbiological monitoring of operators
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Aseptic Processing
*n aseptic processing, each component is
individually sterilised, or several components arecombined with the resulting mi?ture sterilized5
#ost common is preparation of a solution which is
filtered through a sterilizing filter then filled into sterile
containers e5g active and e?cipients dissolved in Eater
for *njection!
#ay involve aseptic compounding of previously sterilized
components which is filled into sterile containers
#ay involve filling of previously sterilized powder
sterilized by dry heat%irradiation
produced from a sterile filtered solution which is then
aseptically crystallized and precipitated
re'uires more handling and manipulation with higher potential
for contamination during processing
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Aseptic Processing
Preparation and $iltration of )olutions )olutions to be sterile filtered prepared in a 1rade C
environment
*f not to be filtered, preparation should be prepared in
a 1rade A environment with 1rade + bacground e5g5
ointments, creams, suspensions and emulsions! Prepared solutions filtered through a sterile 35..Gm or
less! membrane filter into a previously sterilized
container
filters remove bacteria and moulds
do not remove all viruses or mycoplasmas
filtration should be carried out under positive pressure
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Aseptic Processing
Preparation and $iltration of )olutions .! consideration should be given to complementingfiltration process with some form of heat treatment
2ouble filter or second filter at point of fill advisable
$itlers should not shed particles, asbestos containingfilters should not be used
)ame filter should not be used for more than one day
unless validated
*f bul product is stored in sealed vessels, pressure
release outlets should have hydrophobic microbialretentive air filters
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Aseptic Processing
Preparation and $iltration of )olutions >! Time limits should be established for each phase of
processing, e5g5
ma?imum period between start of bul product
compounding and sterilization filtration!
ma?imum permitted holding time of bul if held afterfiltration prior to filling
product e?posure on processing line
storage of sterilized containers%components
total time for product filtration to prevent organisms
from penetrating filter
ma?imum time for upstream filters used for clarification
or particle removal can support microbial attachment!
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Aseptic Processing
Preparation and $iltration of )olutions :! $illing of solution may be followed by lyophilization
freeze drying!
stoppers partially seated, product transferred to
lyophilizer 1rade A%+ conditions!
@elease of air%nitrogen into lyophilizer chamber atcompletion of process should be through sterilizing
filter
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Aseptic Processing
Prefiltration +ioburden natural microbial load!
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Aseptic Processing
Prefiltation +ioburden .! =o defined /ma?imum0 limit but the limit should not
e?ceed the validated retention capability of the filter
+ioburden controls should also be included in /in-
process0 controls particularly when product supports microbial growth
and%or manufacturing process involves use of culture
media
&?cessive bioburden can have adverse effect on the
'uality of the product and cause e?cessive levels ofendoto?ins%pyrogens
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Aseptic Processing
$ilter integrity
$ilters of 35..Gm or less should be used for filtrationof li'uids and gasses if applicable!
filters for gasses that may be used for purging or
overlaying of filled containers or to release vacuum in
lyphilization chamber filter intergrity shoud be verified before filtration and
confirmed after filtration
bubble point
pressure hold
forward flow
methods are defined by filter manufacturers and limits
determined during filter validation
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Aseptic Processing
$ilter (alidaton $ilter must be validated to demonstrate ability toremove bacteria
most common method is to show that filter can retain a
microbiological challenge of 36C$8 of Brevundimonas
diminutaper cm.of the filter surface
a bioburden isolate may be more appropriate for filter
retention studies than Brevundimonas diminuta
Challenge concentration is intended to provide a margin
of safety well beyond what would be e?pected in
production
preferably the microbial challenge is added to the fully
formulated product which is then passed through the
filter
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Aseptic Processing
$ilter validation .! if the product is bactericidal, product should be passedthrough the filter first followed by modified product
containing the microbial challenge after removing any
bactericidal activity remaining on the filter!
filter validation should be carried out under worst caseconditions e5g5 ma?imum allowed filtration time and
ma?imum pressure
integrity testing specification for routine filtration
should correlate with that identified during filter
validation
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Aseptic Processing
&'uipment%container preparation and
sterilization All e'uipment including lyophilizers! and product
containers%closures should be sterilized using
validated cycles
same re'uirements apply for e'uipment sterilization thatapply to terminally sterilized product
particular attention to stoppers - should not be tightly
paced as may clump together and affect air removal
during vacuum stage of sterilization process
e'uipment wrapped and loaded to facilitate air removal
particular attention to filters, housings and tubing
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Aseptic Processing
&'uipment%container preparation andsterilization .!
C*P%)*P processes
particular attention to deadlegs - different orientation
re'uirements for C*P and )*P
heat tunnels often used for
sterilization%depyrogenation of glass vials%bottles
usually high temperature for short period of time
need to consider speed of conveyor validation of depyrogenation > logs endoto?in units!
worst case locations
tunnel supplied with &PA filtered air
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Aseptic Processing
&'uipment%container preparation and
sterilization .! e'uipment should be designed to be easily assembled and
disassembled, cleaned, sanitised and%or sterilized
e'uipment should be appropriately cleaned - O-rings and
gasets should be removed to prevent build up of dirt orresidues
rinse water should be E$* grade
e'uipment should be left dry unless sterilized immediately
after cleaning to prevent build up of pyrogens!
washing of glass containers and rubber stoppers should bevalidated for endoto?in removal
should be defined storage period between sterilization and
use period should be justified!
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Aseptic Processing
Process (alidation
=ot possible to define a sterility assurance level
for aseptic processing
Process is validated by simulating the
manufacturing process using microbiological
growth medium media fill!
Process simulation includes formulation compounding!,
filtration and filling with suitable media using the same
processes involved in manufacture of the product
modifications must be made for different dosage formatse5g5 lyophilized products, ointments, sterile buls, eye
drops filled into semi-transparent%opa'ue containers,
biological products
A i P i
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Aseptic Processing
Process (alidation .!
#edia fill program should include worst case
activities
$actors associated with longest permitted run e5g5
operator fatigue!
@epresentative number, type, and comple?ity of
normal interventions, non-routine interventions
and events e5g5 maintenance, stoppages, etc!
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Aseptic Processing
Process (alidation >!
Eorst case activities cont!
=o of personnel and their activities, shift changes,
breas, gown changes
@epresentative number of aseptic additions e5g5
charging containers, closures, sterile ingredients!
or transfers
Aseptic e'uipment connections%disconnections
Aseptic sample collections
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Aseptic Processing
Process (alidation :!
Eorst case activities cont!
Eeight checs
Container closure systems
)pecific provisions in processing instructions
Eritten batch record documenting conditions and
activities
)hould not be used to justify risy practices
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Aseptic Processing
Process (alidation 7!2uration
2epends on type of operation
+$), *solator processes - sufficient time to include
manipulations and interventions $or conventional operations should include the total
filling time
)ize
7333 - 3333 generally acceptable or batch size if H7333 $or manually intensive processes larger numbers
should be filled
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Aseptic Processing
Process (alidation ;!
$re'uency and =umber
Three initial, consecutive per shift
)ubse'uently semi-annual per shift and process
All personnel should participate at least annually,consistent with routine duties
Changes should be assessed and revalidation
carried out as re'uired
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Aseptic Processing
Process (alidation 6! &nvironmental conditions
@epresentative of actual production conditions no5 of
personnel, activity levels etc! - no special precautions not
including adjustment of (AC!
if nitrogen used for overlaying%purging need to substitute with
air
#edia
Anaerobic media should be considered under certain
circumstances
)hould be tested for growth promoting properties including
factory isolates!
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Aseptic Processing
Process (alidation 4! *ncubation, &?amination
*n the range .3->7IC5
*f two temperatures are used, lower temperature first
*nspection by 'ualified personnel5
All integral units should be incubated5 )hould be
justification for any units not incubated5
8nits removed and not incubated! should be
consistent with routine practices although incubationwould give information regarding ris of intervention!
+atch reconciliation
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Aseptic Processing
Process (alidation 9!
*nterpretation of @esults Ehen filling fewer than 7333 units"
no contaminated units should be detected
One ! contaminated unit is considered cause for
revalidation, following an investigation
Ehen filling from 7333-3333 units
One ! contaminated unit should result in an investigation,
including consideration of a repeat media fill
Two .! contaminated units are considered cause for
revalidation, following investigation
Ehen filling more than 3333 units One ! contaminated unit should result in an investigation
Two .! contaminated units are considered cause for
revalidation, following investigation
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Aseptic Processing
Process (alidation 3! *nterpretation of @esults
#edia fills should be observed by JC andcontaminated units reconcilable with time andactivity being simulated (ideo may help!
*deally - no contamination5 Any contaminationshould be investigated5
Any organisms isolated should be identified tospecies level genotypic identification!
*nvalidation of a media fill run should be rare
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Aseptic Processing
Process (alidation ! +atch @ecord @eview
Process and environmental control activities
should be included in batch records and reviewed
as part of batch release *n-process and laboratory control results
&nvironmental and personnel monitoring data
Output from support systems&PA%(AC, E$*, steam
generator!
&'uipment function batch alarm reports, filter integrity! *nterventions, 2eviations, )toppages - duration and
associated time
Eritten instructions regarding need for line clearances
2isruptions to power supply
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Aseptic Processing
Additional issues specific to *solator and
+$) Technologies
*solators
2econtamination process re'uires a :-; log
reduction of appropriate +iological *ndicator +*!
#inimum ; log reduction of +* if surface is to be
free of viable organisms
)ignificant focus on glove integrity - daily checs,
second pair of gloves inside isolator glove
Traditional aseptic vigilance should be maintained
Aseptic Processing
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Aseptic Processing
+low-$ill-)eal +$)!
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Aseptic Processing
*ssues relating to Aseptic +ul Processing
Applies to products which can not be filtered at point offill and re'uire aseptic processing throughout entire
manufacturing process5
&ntire aseptic process should be subject to process
simulation studies under worst case conditions
ma?imum duration of KopenK operations, ma?imum noof operators!
Process simulations should incorporate storage and
transport of bul5
#ultiple uses of the same bul with storage in between
should also be included in process simulations Assurance of bul vessel integrity for specified holding
times5
Aseptic Processing
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Aseptic Processing
+ul Processing .!
Process simulation for formulation stage should beperformed at least twice per year5
Cellular therapies, cell derived products etc
products released before results of sterility tests
nown also TP=s, radioactive preps, cytoto?ics! should be manufactured in a closed system
Additional testing
sterility testing of intermediates
microscopic e?amination e5g5 gram stain!
endoto?in testing
8seful Publications
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8seful Publications
P*C%) @ecommendation on the (alidation of Aseptic
Processes $2A 1uidance for *ndustry- )terile 2rug Products Produced
by Aseptic Processing - Current 1ood #anufacturing
Process
*)O >:34Aseptic Processing of Health Care Products
Part 1: General Requirements
Part 2: Filtration
Part : !"ophili#ation
Part $: Clean%&n%Place 'echnologies
Part (: )terili#ation%&n%Place
Part *: &solator )"stems