aseptic processing operation
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Seminar on
Aseptic Processing operation
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Schedule (contents)
Introduction to aseptic processing,
Aseptic Processing vs. Terminal Sterilization
contamination:
Sources and control,
Microbial environmental monitoring
Microbiological testing o air and !ater
"haracterization o aseptic process,
Media and incubation conditions.
"onclusion
#eerences
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Aseptic Processing
Aseptic Processing is the processing o
drug components ( drug product,
containers, e$cipients, etc.) in a manner
that ma%es impossibleo microbiological
contamination o the inal sealed product.
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Progression o S&mptoms
'ever
ecreased lood Pressure
#apid reathing and *eart #ate
S%in +esions
Spontaneous lood "lotting
rgan 'ailure
eath
Sepsisis a serious medical condition characterized b& a
!hole-bod& inflammatorystate caused b& infection.
http://en.wikipedia.org/wiki/Inflammationhttp://en.wikipedia.org/wiki/Infectionhttp://en.wikipedia.org/wiki/Infectionhttp://en.wikipedia.org/wiki/Inflammation -
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"auses o sepsis
Sterile drug manuacturers should have a %een
a!areness o the public health implications odistributing a non-sterile product. Poor cMP
conditionsat a manuacturing acilit& can
ultimatel& pose a lie-threatening health ris% to a
patient.
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Asepsisis the practice to reduce or eliminate
contaminants (such asbacteria, viruses, ungi, and
parasites) rom entering the ield to prevent inection.
Ideall&, a ield is /sterile/ 0 ree o contaminants 0 a
situation that is diicult to attain. *o!ever, the goal iselimination o inection.
http://en.wikipedia.org/wiki/Bacteriahttp://en.wikipedia.org/wiki/Virushttp://en.wikipedia.org/wiki/Fungihttp://en.wikipedia.org/wiki/Parasiteshttp://en.wikipedia.org/wiki/Infectionhttp://en.wikipedia.org/wiki/Infectionhttp://en.wikipedia.org/wiki/Parasiteshttp://en.wikipedia.org/wiki/Fungihttp://en.wikipedia.org/wiki/Virushttp://en.wikipedia.org/wiki/Bacteria -
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Producing drug products b&
Terminal sterilization
Product containers are illed and
sealed under high-1ualit&
environmental conditions designed tominimize contamination, but not to
guarantee sterilit&.
Product in its inal container is
sub2ect to a sterilization process such
as heat or irradiation.
Aseptic processing
rug product, container, and
closure are sub2ect to sterilization
separatel&, and then broughttogether.
ecause there is no process to
sterilize the product in its inal
container, it is critical that
containers be illed and sealed in an
e$tremel& high 31ualit&environment.
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Terminal Sterilization
DrugProduct
Container/ Closure
Excipiants
SterilizationProcess Sterile Drug Product !
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Aseptic ProcessingDrug
Product
Sterilization
Process
Container
Closure
Excipient
Sterilization
Process
Sterilization
Process
Sterilization
Process
Sterile
Closure
Sterile
Excipient
Aseptic
Processin
g
Sterile
DrugProduct
SterileContaine
r
Sterile
Final
Product
Can use multiple sterilization processes each optimized for the individual compon
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acteria, virus, ungi and other viable microbes cause a
serious contamination.
acterial spores and endoto$ins
4on viable Particles li%e dust, ibers, or other material are
suspended in the air and ma& contaminate product.
"ontaminating agents
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*umans and bacteria
ver 566 dierent species o bacteria are ound
associated !ith humans.
acteria are ound in the intestines, e&es, nares, mouth,
hair and s%in.
r& s%in can have 76668s o microbes 9 mm5
Staphylococcus epidermidis
Scanning ;M. "".
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Sources of Contamination:
Personnel born contaminants
Poor or improper Sanitization:Procedures deicient, or poorl&e$ecuted
Air born contaminants. Inadequate HEPA seal(over ariable velocities bet!een
ilters. Inade1uate laminar lo! resulted. +o! or undetectablevelocit& at !or% surace.
!echanical failure o illing tan%? main pump ailure? coolings&stem lea%s at 2oints.
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"ontrol
"ststep # eliminating the source of
contamination$ndStep % &educe the &is' of
contamination through:Sterile barriers
Surace monitoringAseptic techni1ue
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o!ning (sterile barrier)
I people are a ma2or source
o contamination !e avoidcontaminating the product
!hile !e process it.
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Surace Monitoring
Touch or Contact plates
- RDAC Plates
(#eplicate rganismetection
and "ounting)
Sa"s
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Aseptic Techni1ue (s%ill)
Contact sterile materials only (ith sterile instruments:
perators should not contact sterile products, containers,
closures, or critical suraces !ith an& part o their go!n or
gloves
@eep the entire bod& out o the path o unidirectional airlo!
Approach a necessar& manipulation in a manner that does not
compromise sterilit& o the product
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#hat$s rong ith this picture%
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CORRECT
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&orizontal air'lo (ertical air'lo
.ors.od.nih.go)/ds/pu"s/"sc/graphics/'ig*.gi'
)nidirectional airflo(
The operator should
never come between the
air source and the
product.
pressure dierential b9ncritical area rom e$ternal environment
(7.B-B6 Pa)
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*isinfectants
IS+P&+P,- A-C+H+- ./012 Po!erul disinectant
;ectivel& %ills bacteria and ungi
Mode o action: denatures proteins, dissolves lipidsand can lead to cell membrane disintegration.
ut does not inactivate spores
e.g., phenols, Alcohols, Aldeh&des etc.,
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Sporicidal agents
lutaraldeh&de
'ormaldeh&de
sodium h&pochlorite
Iodine and iodophors
Pero$&gens
;th&lene o$ide
P- Propiolactone
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Isolators
Ad3antage:
4o direct contact
bet!een operator C
product.
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Microbial identiication should
e$tend to the species level.
#outine traditional techni1ues
phenot&pic and
biochemical. enot&pic techni1ues are
suggested or ailure
investigations.
Microbial ;nvironmental Monitoring:
Identiication
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Phenotypic technique
4ram Stain
Identi&ing Microbes
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Staphylococcus xylosus
&eduction of
5etrazolium Violet
iochemical Assa&s
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enot&pic Methods
Dse 4A se1uence (oten ribosomal #4A genes
r4A) to identi& organism
'aster, and more accurate then traditional
biochemical and phenot&pic techni1ues
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QC Micro: +denti',ing icro"es
enot,pe ased Assa,0PCR0 Pol,1erase Chain Reaction
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;$tremel& heat stable 3 recommended conditions or
inactivation are 7E66
" or F hours.
Endotoxin: a p,rogenic 2'e)er inducing3 su"stance 2e.g. lipopol,saccharide3
present in the "acterial cell all. Endotoxin reactions range 'ro1 'e)er to death.
;ndoto$in Testing
+A+ Assa&(+imulus amoeboc&te l&sate)
E6*+5+7I6 -I!I5 +& WFIIS08$9 E)ml
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Microbiological testing o !ater Dniversal solvent ,Dsed as >ehicle and used to rince and cleaning o
apparatus
Gater should also be tested or presence o coliorms and9or
pseudomonads i appropriate (ma& cause bioilm)
Gater should be tested using #5A agar (lo! nutrient or the recover&o !ater borne organisms) incubated or at least B da&s at F6-FBH"
Sampling procedures should ollo! those used in production
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Microbiological testing o air
Co1pressed Air/4itrogen/C5 Air sampling should be done and tested or the presence
o non-viables and viables b& e$posure to the environment.
Pressure control oriices should be used to provide astead& stream o air.
'all out plate
Slit sampler
(slit-to-agar sa1pler3
Slit Sampler
.6e( ;runs(ic' Scientifics !odel S5A%$
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"haracterization o aseptic process
The our pillars o a robust aseptic process
Personnel training C monitoring
;nvironmental monitoring 'acilities design
Media ills
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Personnel Training C Monitoring
Avoiding contamination means %no!ing the potential sources
o contamination Personnel
;1uipment
Air9li1uids rug product
"ontainers9closures
utside environment
An&thing rought in contact !ith, or in the vicinit& o, the product
is a potential source o contamination
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;nvironmental Monitoring
The goal o the environmental monitoring program is to
provide meaningul inormation on the 1ualit& o the
aseptic processing environment during production as
!ell as environmental trends.
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6.
5.
*.7.
8.
9.:.
;.
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'acilities: eneral "lean room esign
*;PA9D+PA ilters on ceiling
;$haust vents on loor
Airloc%s and interloc%ing doors to control air balance
Seamless and rounded loor to !all 2unctions
#eadil& accessible corners
'loors, !alls, and ceilings constructed o smooth hardsuraces that can be easil& cleaned
+imited e1uipment, i$tures and personnel
+a&out o e1uipment to optimize comort and movemento operators
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'acilities: "lean room "lassiication
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Class 6=>=== clean roo1
http0//.a1ericancleanroo1s.co1/a1/photogaller,?=;.ht1l
Class 6== clean roo1
acilities:"lean room "lassiication
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'acilities: *;PA 'ilters
http0//people.deas.har)ard.edu/@ones/la"?arch/nano?'acilities/hepa.gi'
*igh ;icienc& Particulate Air ilters
Minimum particle collection eicienc&:
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Media 'ill test
Dsed to validate the aseptic process
Dse microbial gro!th media instead o drug
product-an& contamination !ill result in
microbial gro!th.
It doesn8t provide a direct relation or sterilit&
but gives an ade1uate evaluation or operationalprocessing steps.
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Media and Incubation conditions
So&bean casein digest medium (S")
'luid thiogl&collate medium ('TM) or anerobes
Inoculated !ith K 766 cu challenge At least 7L da&s incubation F6-FBH" or S", 56-5BH" or 'TM temperatures should be monitored product produces suspension, locculation or deposit in
media, suitable portions (5-B=) should be transerred toresh media, ater 7L da&s, and incubated or a uther da&s
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Theoretical ;valuation
Gh&te mathematical model
contamination is due to air borne microbes
d e1uivalent particle diameter
A area o container opening (cm5)
t time (sec)
"ont rate (c) 6.66F5.d5.A.t
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PostScript (conclusion)
The challenge in aseptic processing is ala,s
personnel0
B As a source o' 1icro"ial and
Particle conta1ination.BAs a "rae on the i1ple1entation o'
+1pro)ed technolog,.
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#;';#;4";S
;nc&clopedia o pharm.technolog&
#DSS;++ A. .. acterial Spores and "hemical Sporicidal Agents.clinical microbiology reviews. F(5):
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ThanQ
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