WHO Ppt on Aseptic Processing

7/24/2019 WHO Ppt on Aseptic Processing

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Aseptic Processing


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Manufacture of sterile medicines Advanced workshop for SFDA GMP

inspectors - Nanjin! Novem"er #$$%2

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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Manufacture of sterile medicines Advanced workshop for SFDA GMPinspectors - Nanjin! Novem"er #$$%

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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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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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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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$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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1rade A e'uivalent to Class 33 8) $ederal)tandard .39&!, *)O 7 *)O :;::-!"


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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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&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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&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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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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&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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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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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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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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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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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

A ti P i


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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!

A ti P i


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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

A ti P i


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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

A ti P i


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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

A ti P i


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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

A ti P i


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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

WHO Ppt on Aseptic Processing

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