process simulation test- islamabad

7/26/2019 Process Simulation Test- Islamabad

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ROCESS SIMULATION TEST

IN INJECTABLE

VALIDATION

(MEDIA FILL)

DR. AJMAL NASIRDirector Technical

BF Biosciences ltd

LAHORE


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INJECTABLES

Injections must be sterile and as per definition shall be Free

from Organisms,

Sterility is One of the most examined areas of pharmaceutical

and medical device manufacturing .

he favored method to assure sterility is erminal Sterili!ation" #utoclaving or Irradiation etc$.

%aterials sensitive to heat can not be terminally sterili!ed.

&ence ASEPTIC PROCESS andASEPTIC FILLING .


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ASEPTIC PROCESSING?

The Production Of Sterile Drug Products By Bringing

Together The Product, Container & Closure sterilized

through different Sterilization Methods Separately, And

Assemled !n An"#tremely $igh %uality "nironment

By S'illed Personnel (sing The )ight "*uipment And

Techni*ues+


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ASEPTIC FILLING

#septic filling is an #septic 'rocessthat re(uires the close coordinationand complex interaction bet)een *

Personnel,

Sterilized Product,

The ill-inish "*uipment System, Cleanroom - Support acilities,

Sterilized illing Components+


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HISTORICAL BACKGROUND

S+'+%+- //0* #fter 12 years F3# replaced older guidelines In September

//0,)ith an updated document,

Guidance for Industry - Sterile Drug ProductsProduced by Aseptic Processing - Current GoodManufacturing Practices.

+urope made some changes to the *

'EC Guide to Good Manufacturing Practice Anne!I Manufacture of Sterile Medicinal Products"

hese documents initiated a thought process at various

forums. %ore focus on sterility #ssurance

#septic 'rocess Simulations faced significant

changes as compared to other parts .


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ASEPTIC FILLING

#septic processing is a process being operated in a controlled 4

but NOT STERILE ENVIRONMENT .

'robability of non5sterility cannot be calculated.

Involves a great deal of process control, )ith sensitive handling

of components until they are sealed )ithin their final

containers.

#ll efforts are made to minimize the ris o! contamination"

he industry )or6s to a recogni!ed, accepted contamination

levels, 'robability of viable contamination is recogni!ed and calculated


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To "nsure The Sterility Of ProductsPurporting To Be Sterile, Sterilization,

Aseptic illing And Closing Operations Must

Be Ade*uately .alidated /0 122+2234+

he goal of even the most effective

sterili!ation processes can be defeated if the

sterili!ed elements of a product "the drugformulation, the container, and the closure$

are brought together under conditions that

contaminate any of those elements.


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STERILITY ASSURANCE CHALLENGE

7ontamination Is #n +ver5'resent hreat .

%aterials , surfaces and inefficiencies in air filtration may

carry organisms.

'otential viable contamination comes from o#erators

running the process.

Sterility testing Sample numbers are too small to detect

lo$ le%el contamination.

Only GROSS contamination is li6ely to be detected.

Sterility #ssurance need another ool to 8uarantee .

Process Sim&lations 'Me(ia Fills) supported byenvironmental monitoring and other related processes

demonstrates control of the process to the industry

standard for allo)able contamination levels.


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STERILITY TEST VERSUS MEDIA FILL

Sterility est %edia Fill

8uidance3ocuments

F3# 8uidance for Industry7ode of Federal

-egulations%ultiple 'harmacopeia

F3# 8uidance for Industry+9 8uide to 8ood

%anufacturing 'ractice-evision to #nnex 1

Sample si!e:;ot %aximum / #ll

%edia Soybean57asein 3igest%edium "S$Fluid hioglycollate %edium"F%$

ryptic Soya roth"Soybean57asein 3igest %edium "S$$"F% in case anaerobesdetected in sterility Failure$

Incubationconditions

S 10 days < /5=>7F% 10 days < ?/5?=>7

S 2 days < /5=>7S 2 days < ?/5?=>7

8ro)th promotion @es @es

est method 3estructive*Sample contents transferred

Aon5destructive*Integral container

Sensitivity False positives3etects high level sterility

failure

Ao false positives3etects single vial failure


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PROCESS SIMULATION

7ommonly Bno)n as *MEDIA FILL+"

7arried out to demonstrate that the process is capableand robust enough to produce products )ith highest

degree of Sterilit, Ass&rance"

%edia fills utili!e culture media in place of product to

evaluate contamination levels and validate #septic

'rocessing .

%edia Fill 'rogram 'rovides +valuation Of %ultiple

Systems.

he media fill should be designed to mimic, as closely as

possible to the aseptic processes used in practice.

'rocess Simulation is ONE element in the

validation of an aseptic process.


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DEFINITION

he C%edia FillC, or Croth FillC, techni(ue, is one

in )hich a li-&i( micro.iolo/ical n&trient /ro$th

me(i&mis prepared and filled in a simulation of a

normal manufacturing operation. he nutrient

medium processed and handled in a manner )hich

sim&lates the 0normal0 man&!act&rin/ #rocess as

closely as possible )ith the same exposure topossible contamination '!rom o#erators1

en%ironment1 e-&i#ment an( s&r!aces) as )ould

occur during routine manufacture. he sealed

containers of medium thus produced are thenincubated &n(er #rescri.e( con(itions and

examined for evidence of microbial gro)th, and

thus of an indication of the level of contaminated

units produced. Health Canada


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PROCESS SIMULATION TEST

est shall be designed to accurately represent the

aseptic process.Follo)ing 'arameters shall be addressed in est

3esign*

S93@ 3+SI8A

%+3I# FI;; 3O79%+A F-+D9+A7@

%+3I# FI;; -9A SIE+ S'++3

+AGI-OA%+A#; 7OA-O;

%+3I# D9#;I@

IA79#IOA FI;;+3 9AIS #A#;@SIS

-+S9;S IA+-'-+#IOA


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PRE - REQUISITES

Galidated manufacturing process.

Galidated e(uipment.

Galidated sterili!ation cycles.

rained and (ualified 'ersonnel.

#ll materials suitable for sterile manufacturing :

processing.


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STUDY DESIGN

Shall cover all possible contamination -is6s.

Shall closely simulate process.

Horst case scenarios incorporated .

Shall contain*

;ongest possible runs

Aormal and non routine interventions.

;yophili!ation "if applicable$. #ssembling of e(uipment " start up and during processing$

Aumber of )or6ers : activities

#septic additions " container , closure 7harging, transfers$

8o)n changes, shift 7hanges,

#septic sampling

;ine speed

Height chec6s

7ontainer closure systems


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MEDIA FILL DOCUMENT

# )ritten approved atch -ecord.

Same vigilance as In -outine -un.

7lear 3efinition of -ationales.

# separate 3ocument approval for each -un.

3etailed instructions for the test .

7omplete list of planned interventions


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LIST OF PERMITTED INTERVENTIONS

DURING FILLING

#djustment of )eight in the dosing )heel.#djustment of Stopper holding spring.

ransfer of li(uid from container to hopper.

ransfer of stoppers from bag to hopper.

'ic6ing un stoppered vials from the out feed bac6 to conveyor for

stoppering.

#djustment of separator.

'ic6ing up of fallen vials from turn table.

7leaning of machine )ith vacuum cleaner.

#djustment of stoppering channel height.

#djustment of stoppering pressure rollers.


DURING FILLINGLIST OF PERMITTED INTERVENTIONS

DURING FILLING


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DURING FILLING

-eplacing of a piston from the )heel.

#djustment of turn table over load sensor.

;ifting and closing of the ;#F cabinet door.

7hec6ing the )eight in balance.

#djustment of dosing air.

7leaning of vacuum pot.

'ushing stopper in the channel by forceps.

'o)er interruption "samples should be mar6ed$

Aumber of personnel in sterile filling area " persons$.

%ultiple dosing of the li(uid. -unning the machine at a slo)er speed than actual production

run.

7overing the )or6ing shift usually 1 hours and shift 7hange

over

+ntry of maintenance person for repairing of %:7

LIST OF PERMITTED

INTERVENTIONS DURING FILLING


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FREQUENCY

Initially at least ? consec&ti%e1 se#arate1 s&ccess!&l, runs on

each line.

-outine semi Ann&al Dualification for each ;ine .

#ll authori!ed personnel for aseptic processing including

technicians an( maintenance #ersonnel, should participate in a

media fill at least once a year.

'articipation should be consistent )ith the nature of each

operatorJs duties during routine production.

+ach 7hange shall be controlled through )ritten 7hangecontrol.

7hanges and events )ith potential to effect sterility should be

assessed through a((itional%edia Fill.


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FREQUENCY (Cont!"

7#9S+S OF FO- -+G#;I3#IOA OF &+

S@S+%*

Facility and e(uipment modifications,

;ine configuration changes,

Significant changes in personnel,

#nomalies in environmental testing results,

7ontainer closure system changes,

+xtended shutdo)ns,

+nd product sterility testing sho)ing contaminated

products.


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MEDIA FILL RUN SI#E $ SPEED

-un si!e should be sufficient to provide a high probability of detecting a lo$inci(ence of microbial contamination.

# generally acceptable starting point for run si!e is in the range of =,/// to

1/,/// units.

For operations )ith production si!es under =,///, the number of media

filled units should at least e(ual the maximum batch si!e made on the

processing line. he media fill program should ade(uately address the range of line

speeds employed during production.

+ach media fill run should evaluate a single line speed, and the speed

chosen should be justified.

For example, use of high line speed is often most appropriate in theevaluation of manufacturing processes characteri!ed by fre(uent

interventions or a significant degree of manual manipulation.

9se of slo) line speed is generally appropriate for evaluating

manufacturing processes )ith prolonged exposure of the sterile

drug product and containers:closures in the aseptic area.


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ENVIRONMENTAL CONTROL

%edia fills should be ade(uately representative of #ctual

'rocess 7onditions

Stressful conditions 'ermitted as per SO's shall be

simulated."e.g., maximum number of personnel present

and elevated activity level$, .

7hallenges shall be supportive to the study design.

Stressful conditions do not include artificially created

environmental extremes, such as reconfiguration of &G#7

systems to operate at )orst5case limits .


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MEDIA QUALITY 8enerally soybean casein digest medium, is used.

#naerobic gro)th media "e.g., fluid thioglycollate medium$should be considered in special circumstances.

%edia must 'romote promote gro)th of gram5positive, gram5

negative bacteria, yeast and mold "e.g., 9S' indicator

organisms$.

+nvironmental monitorin/ an( sterilit, test isolates can besubstituted "as appropriate$ or added to the gro)th promotion

challenge.

8ro)th promotion units should be inoculated )ith a K1// 7F9

challenge.

In case of failure of 8ro)th 'romotion test the origin of any

contamination found during the simulation should nonetheless

be investigated and the media fill promptly repeated.

+ach unit should be filled )ith enough (uantity and type of

microbial gro)th medium to contact the inner container closure

surfaces ")hen the unit is inverted or thoroughly s)irled$ and

permit visual detection of microbial gro)th.


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INCUBATION $ FILLED UNITS ANALYSIS

Incubation temperature should be at no time be

outside the range of /5?=o7.

Incubation temperature should be maintained

)ithin L.=o7 of the target temperature.

Incubation time should not be less than 10 days.

If t)o temperatures are used for the incubation

of the media filled units, the units should be

incubated for at least 2 days at each temperature

"starting )ith the lo)er temperature$.

S 2 days < /5=>7

S 2 days < ?/5?=>7


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INCUBATION $ FILLED UNITS ANALYSIS

Filled units to be inspected by Traine( sta!! onl,

under supervision of Dualified %icrobiologist.

+ach 'ositive unit must be brought in notice of

D7 %icrobiologist

Only integral units shall be incubated.

#ll intervention units must be recorded in the

%edia fill document separately .


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RESULTS $ INTERPRETATION

Hhen filling fe)er than =/// units, no contaminate(

&nits sho&l( .e (etecte(.

One "1$ contaminated unit is considered cause for

revalidation, follo)ing an investigation.

Hhen filling from =,/// to 1/,/// units*

One "1$ contaminated unit should result in an investigation,including consideration of a repeat media fill.

)o "$ contaminated units are considered cause for

revalidation, follo)ing investigation.

Hhen filling more than 1/,/// units*

One "1$ contaminated unit should result in an investigation. )o "$ contaminated units are considered cause for

revalidation, follo)ing investigation.

For any run si!e, intermittent incidents of microbial contamination in

media filled runs can be indicative of a persistent lo)5level

contamination problem and that should be investigated.


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G#-I#IOAS FO-

3IFF+-+A 3OS#8+

FO-%S


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STERILE PO%DERS

)o possible procedures* Fill the chosen inert po)der into the containers "e.g.

ampoules:vials$ )hich are already filled )ith sterile li(uid

medium. Fill the inert po)der first, and then add the sterile li(uid

medium.

7ommonly sterile '+8 /// is used as po)der .

In both these variations, a po)der fill is simulated, but an

additional, non5routine step "i.e. the filling of the li(uid

gro)th medium$ is involved.


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SUSPENSION PRODUCTS&

Simulate the entire normal process as closely

as possible,

9se sterile inert po)der in place of the

normal po)der product.%icroni!e etc. "if part of the normal process$

and form suspension.

9se sterile li(uid gro)th medium in place of

the normal li(uid phase of the suspensionproduct.

Fill as normal and incubate.


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FREE#E-DRIED PRODUCT&

Simulate the entire normal process i.e.

preparation of bulk solution,

filling of solution,

loading of freeze-dryer, running of freeze-drying cycle,

sealing/closing of containers,

inspection.

#ctual free!e5drying of the medium solution isnot practicable, but exposure, holding times in

the free!e dryer should be as normal.

.


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SEMI-SOLID PRODUCTS('!! )t'*+,' o+nt'nt) .n /*'.)"&

Simulate the normal process cycle as

closely as possible,Fill a sterile li(uid gro)th medium made

to similar consistency as the normal

product by the addition of agar

"approximately 0 g. per liter$ orcarboxymethylcellulose


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DO) AND DON0T)

Galidate %aximum number of )or6ers in the area.

-un line at slo)er speed to give maximum exposure to

open containers.

3o planned interventions

Galidate all si!es of containers specially )ith large mouth

si!e.

;oading of containers and stoppers shall be an essential

part of study.

3on not use inert gases to in the media fill run. Insteaduse filtered air.


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I '#@S IA &+ ;OA8 -9A

%O-+ 7OAFI3+A7+

-+89;#O-@ #''-OG#;S

AO -+M+7IOA.


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process simulation test- islamabad

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