1-2 SterilisationValidationQualification

Sterilization - validation, qualification requirements
Mrs Robyn Isaacson
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors - Nanjin ! Novem"er #$$%
Sterilization - Overview
Objectives
Discuss definition of Sterile !riefly describe sterilization met"ods Describe a##roac"es to be used for t"e validation of a sterilization #rocess usin$ Moist %eat as an e&am#le Describe requirements for routine monitorin$ and control of sterilization Review issues t"at are s#ecific to ot"er sterilization #rocesses
Sterile 'roducts - Overview

(ertain #"armaceutical #roducts must be sterile
injections, o#"t"almic #re#arations, irri$ations solutions, "aemodialysis solutions
)wo cate$ories of sterile #roducts

t"ose t"at can be sterilised in final container *terminally sterilised+ t"ose t"at cannot be terminally sterilised and must be ase#tically #re#ared
,"at is t"e definition of sterile .ree from microor$anisms
In #ractice no suc" absolute statement re$ardin$ absence of microor$anisms can be #roven
Defined as t"e #robability of / in a million of a container bein$ contaminated */0-1+ )"is referred to as t"e Sterility 2ssurance 3evel *S23+
Or$anisms are 4illed in an e&#onential fas"ion

4 Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors - Nanjin ! Novem"er #$$%
Definition of Sterile
MI(RO!I23 I52()I62)IO5 -4t 5 t 7 5o e
1200 3.50 3.00 1000 2.50 2.00 5o of survivin$ or$anisms 800 1.50 1.00 600 0.50 0.00 -0.50 200 -1.00 -1.50 0 -2.00
No remaining Log No remaining
400
0 1000 3.00
1 368 2.57
2 135 2.13
3 50 1.70
4 18 1.26
5 7 0.83
)ime
6 2 0.39
7 1 -0.04
8 0 -0.47
9 0 -0.91
10 0 -1.34
No remaining Log No remaining
Resistance of an or$anism is referred as its D-value
Microbial Inactivation
4 3 2 1 0 1 -1 -2 -3 )ime 2 3 4 5 6
D-Value
D-value - )ime *or dose+ required to reduce t"e #o#ulation of or$anisms by / lo$ *or 809+
3o$ 5o of Survivin$ Or$anisms
2 sterilization #rocess must deliver a Sterility 2ssurance 3evel *S23+ of / in a million */0-1+ It is not #ossible to measure /0-1 )"e required S23 can be ac"ieved by a##lyin$ a #rocess t"at will reduce t"e number of or$anisms to zero and t"en a##ly a safety factor t"at will deliver an e&tra 1 lo$ reduction
:&am#le .or an initial bioburden of /0; t"e sterilization #rocess will need to ac"ieve an < lo$ reduction in viable or$anisms )"is will require < times t"e Dvalue *e=$= if t"e or$anism "as a D value of ; minutes t"en < & ; 7 /1 minutes will be required to ac"ieve an < lo$ reduction and an S23 of /0-1+ *'oint >+
3o$ 5o of Survivors
Microbial Deat" (urve

2
-1
-2
-3
-4
> ?
-5
-6
-7 0 1 2 3 4 )ime 5 6 7 8
(ommonly used met"ods of sterilization
Moist %eat Dry %eat @as *:t"ylene o&ide+ Radiation *@amma or :lectron+ .iltration Ot"ers - A6, Steam and formalde"yde, "ydro$en #ero&ide
Moist %eat
Saturated steam (ommon cyclesB
/;/C( for /D minutes /EFC( for E minutes Ot"er cycles of lower tem#erature and lon$er time may be used *e=$= //DC( for E0 minutes+
Ased for sterilization ofB

terminal sterilization of aqueous injections, o#"t"almic #re#arations, irri$ation G "aemodialysis solutions, equi#ment used in ase#tic #rocessin$
10
Moist %eat
not suitable for non-aqueousHdry #re#arations #referred met"od of sterilization
11
Dry %eat
3et"ality due to o&idative #rocesses %i$"er tem#eratures and lon$er e&#osure times required )y#ical cyclesB
/10C( for /;0 minutes /I0C( for 10 minutes /<0C( for E0 minutes tunnels used for t"e sterilisation of $lass vials may use muc" "i$"er tem#eratures *E00C+ for a muc" s"orter #eriod
12
Dry %eat
Ased forB
$lassware and #roduct containers used in ase#tic manufacture, non aqueous t"ermostable #owders and liquids *oils+
also used for de#yro$enation of $lassware * ;D0C(+

*'yro$ens - substances found in cell wall of some bacteria w"ic" can cause fever w"en introduced into t"e body+
13
:t"ylene O&ide @as

:it"er #ure or in mi&tures wit" ot"er inert $ases Requires #resence of moisture (om#le& #rocess )y#ical cyclesB
/-;F"ours ;D-/;00 m$H3 $as ;D-1DC( E0-<D9 relative "umidity
14
:t"ylene O&ide
Ased forB
"eat labile #roduct containers surface sterilization of #owders
2dequate aeration to reduce to&ic residues
15
Radiation
@amma rays $enerated by (obalt 10 or (aesium /EI radionuclidesJ or 2ccelerated electrons from an electron $enerator ;D 4ilo$rays *4@y+ usual dose
dose de#endent on bioburden *resistance of or$anisms not #redictable+
#rocess must be #ro#erly validated used forB

dry #"armaceutical #roducts "eat labile #roduct containers
can cause unacce#table c"an$es

.iltration
Removes or$anisms from liquids and $asses 0=; - 0=;; micron for sterilization com#osed of cellulose esters or ot"er #olymeric materials filter material must be com#atible wit" liquid bein$ filtered used for bul4 liquids, $asses and vent filters
17
6alidation - Overview
Selection of sterilzation #rocess must be a##ro#riate for #roduct
terminal sterilization is t"e met"od of c"oice moist "eat *autoclavin$+ is t"e most common #rocess used for terminal sterilization #roduct must not be affected by "eat containerHclosure inte$rity must be establis"ed items bein$ sterilised must contain water *if sealed+ or material must allow for removal of air and #enetration of steam for steam *moist "eat+ sterilization
6alidation - 'rotocol
Requirements for Moist %eat Sterilization
Ot"er #rocesses follow similar requirements
6alidation #rotocol s"ould include t"e followin$ details for eac" sterilization #rocess
#rocess objectives in terms of #roduct ty#e, containerHclosure system, S23 required s#ecifications for time, tem#erature, #ressure and loadin$ #attern descri#tion of all equi#ment and su##ort systems in terms of ty#e, model, ca#acity and o#eratin$ ran$e
6alidation - 'rotocol
Moist %eat continuedB
#erformance c"aracteristics of all equi#ment e=$= #ressure $au$es, valves, alarm systems, timers, steam flow ratesH#ressures, coolin$ water flow rates, cycle controller functions, door closure $as4etin$ and air brea4 systems and filters met"odolo$y for monitorin$ #erformance of equi#ment and t"e #rocess and labatory testin$ met"odolo$y #ersonnel res#onsible for all sta$es and final evaluation *s"ould "ave e&#erience and necessary trainin$ and be aut"orized+
6alidation - (alibration
3aboratory testin$ s"ould be #erformed by a com#etent laboratory, met"odolo$y s"ould be documented 2ll instruments must be calibrated e=$=

21
tem#erature recorders and sensors t"ermocou#les #ressure sensors for jac4et and c"amber timers conductivity monitors for coolin$ water flow metres for waterHsteam water level indicators w"en coolin$ water is used t"ermometers includin$ t"ose for t"ermocou#le reference, c"amber monitorin$ and laboratory testin$
6alidation - (alibration
Indicators s"ould be calibrated
#"ysical and c"emcial indicators s"ould be tested to demonstrate acce#table res#onse to time and tem#erature biolo$ical indicators s"ould be tested for count and timeHtem#erature e&#osure res#onse
for commercial indicators - test certificate wit" count and D-value and e&#osure res#onse s"ould be available= Results acce#table if verified in "ouse #eriodically= In "ouse indicators must be fully c"aracterized *Dvalue, identification+ and a##ro#riate for sterilization #rocess
2ll indicators s"ould be a##ro#riately stored and wit"in e&#iry

6alidation - (ycle Develo#ment

(once#t of .o
3et"ality factor equivalent to time at /;/C(
/ minute at /;/C( is equivalent to .o of /= 3et"ality can accumulate durin$ "eat u# and cool down #"ases
Typical temperat re pro!ile o! a "eat #terili$ation proce##
%"at &o l' (e t"e )o o! a cycle at 121*+ !or 15 min te#,
23

.o is calculated usin$ t"e followin$ equationB
.o 7 KtL/0*)-/;/H>+ w"ereB
Kt is t"e time interval between measurements of tem#erature *)+ ) is t"e tem#erature of sterilised #roduct at time *t+ > is a tem#erature coefficient w"ic" measures t"e number of de$rees required to c"an$e t"e D-value of an or$anism by / lo$
24

)"e minimum .o required by a sterilzation #rocess is related to t"e resistance of t"e bioburden *D-value+
.o 7 D/;/ *3o$2 - 3o$ !+ w"ereB
D/;/ is equal to t"e time at /;/C( to reduce t"e #o#ulation of t"e most resistant or$anism in eac" #roduct container by 809 *or / lo$+ 2 is t"e number of microo$anisms #er container ! is t"e ma&imum acce#table #robability of survival *Sterility 2ssurance 3evel , /0-1+
25

)wo a##roac"es to sterilization
Over4ill 'robability of survival
Over4ill a##roac" used w"en t"e #roduct can wit"stand e&cessive "eat treatment wit"out adverse effects
(ycle s"ould deliver an .o of at least /;
)"is will ac"ieve a /; lo$ reduction of microor$anisms wit" a D-value of / minute *2ssumin$ eac" #roduct unit contains /01 or$anisms a /; lo$
reduction will result in /0-1 or$anisms #er unit or #robability of survival *S23+ of / in a million +
26
*5ormal bioburden is usually muc" lower and t"e or$anisms normally muc" less resistant t"an t"is+ Manufacture of sterile medicines Advanced workshop for SFDA GMP
inspectors - Nanjin ! Novem"er #$$%

!iolo$ical Indicators device consistin$ of a 4nown number of microor$anisms, of a 4nown resistance to a #articular sterilization #rocess in or on a carrier and enclosed in a #rotective #ac4a$e=
Or$anisms are in t"e form of endos#ores *not ve$etative state+ as t"ese are most resistant to sterilization
Or$anism D-6alue / - ;=< 0=E 0=< M /=F 0=D Geobacillus stearothermophilus *most common+ Bacillus coagulans Clostridium sporogenes Bacillus atropheus
27

S#ore Stri#s - a narrow stri# of
fibrous #a#er im#re$nated wit" a bacterial s#ore sus#ension contained in a $lassine envelo#e
S#ore Dots - (ircular #ieces of

fibrous #a#er im#re$nated wit" t"e s#ore sus#ension
S#ore Sus#ensions - #ure s#ore

sus#ension of t"e desired c"allen$e or$anism w"ic" can be inocluated onto t"e surface of a material Self contained units containin$ s#ore stri#s or sus#ensions and t"e media in w"ic" t"ey are to be incubated *sim#leHconvenient to use+

'robability of Survival a##roac" used used for "eat labile #roducts
)"e #rocess is validated to ac"ieve a destruction of t"e #resterilization bioburden to a level of /00 *'oint ?+, wit" a minimum safety factor of an additional si&-lo$ reduction *'oint >+ Determination of t"e minimum .o required is based on t"e bioburden and its "eat resistance
,"at .o would be required for a bioburden of /0; */00+ if D-value was /29 Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors - Nanjin ! Novem"er #$$%
6alidation of Sterilization
!asic 'rinci#les Installation Nualification *IN+
:nsurin$ equi#ment is installed as #er manufacturerOs s#ecification
O#eration Nualification *ON+

:nsurin$ equi#ment, critical control equi#ment and instrumentation are ca#able of o#eratin$ wit"in required #arameters
'erformance Nualifcation *'N+

Demonstratin$ t"at sterilizin$ conditions are ac"ieved in all #arts of sterilization load '"ysical and microbiolo$ical Manufacture of sterile medicines Advanced workshop for SFDA GMP
inspectors - Nanjin ! Novem"er #$$%
30
6alidation - :qui#ment
Installation Nualification :nsurin$ equi#ment is installed as #er manufacturerOs s#ecification
considerations for new and e&istin$ equi#ment s#ecifications for t"e ty#e of autoclave, construction materials, #ower su##lies and su##ort services, alarm and monitorin$ systems wit" tolerances and accuracy requirements for e&istin$ equi#ment documented evidence t"at t"e equi#ment can meet #rocess s#ecifications
6alidation - :qui#ment
O#erational Nualification :nsurin$ equi#ment, critical control equi#ment and instrumentation are ca#able of o#eratin$ wit"in required #arameters )"ree or more test runs w"ic" demonstrate
controls, alarms, monitorin$ devices and o#eration indicators function c"amber #ressure inte$rity is maintained c"amber vacuum is maintained *if a##licable+ written #rocedures accurately reflect equi#ment o#eration #re-set o#eration #arameters are attained for eac" run
32
6alidation - 'erformance
'erformance Nualification
Demonstratin$ t"at sterilizin$ conditions are ac"ieved in all #arts of sterilization load '"ysical and microbiolo$ical
'"ysical
%eat distribution studies on em#ty c"amber
ma&imum and minimum cycle times and tem#eratures to identify "eat distribution #atterns includin$ slowest "eatin$ #oints mulit#le tem#erature sensin$ devices s"ould be used *t"ermocou#les+ location of devices s"ould be documented and ensure t"at "eat distribution is uniform
'erformance Nualification - '"ysical *;+
%eat distribution of ma&imum and minimum c"amber load confi$urations
multi#le t"ermocou#les t"rou$"out c"amber *not inside #roduct containers+ to determine effect of load confi$uration on tem#erature distribution tem#erature distribution for all loads usin$ all container sizes used in #roduction s"ould be tested #osition of t"ermocou#les s"ould be documented Slowest to "eatHcold s#ots in eac" run s"ould be documented, inlcudin$ t"e drain re#eat runs s"ould be #erformed to c"ec4 variability tem#erature distribution #rofile for eac" c"amber load confi$uration s"ould be documented
'erformance Nualification - '"ysical *E+
%eat #enetration studies to detect t"e ma&imum and minimum tem#erature wit"in all loads
all #arts of eac" load must be on contact wit" steam need to determine lowest and "i$"est tem#erature locations and slowest and fastest to "eat locations *measured inside #roduct containers+ need to consider all variables suc" as container size, desi$n, material, viscosity of solution and fill volume= (ontainer wit" ma&imum fill volume and slowest to "eat solution s"ould be used ma&imum and minimum load confi$urations for eac" sterilization cycle usin$ routine cycle #arameters
35
'erformance Nualification - '"ysical *F+ %eat #enetration *;+
May be necessary for container ma##in$ for lar$er volumes - cold s#ot t"en used for #enetration studies 5eed to consider effects of #ac4a$in$ e=$= overwra##in$ )"ree runs #erformed once cold s#ots "ave been identified to demonstrate re#roducibility
36
'erformance Nualification - Microbiolo$ical !iolo$ical c"allen$e studies
used w"en 'robability of Survival a##roac" is used may not be necessary w"en cycle is P /;/C( for /D minutes *e&ce#t AS and 2ustralia+ biolo$ical indicators *!I+ containin$ s#ores of Geobacillus stearothermophilus are most commonly used *considered worst case += !Is containin$ ot"er or$anisms may be used #erformance studies based on #roduct bioburden require a considerable amount of wor4 indicators s"ould be #laced t"rou$"out t"e load, adjacent to t"ermocou#les, at cold s#ots and slowest to "eat locations *identified durin$ "eat #enetration studies+ any $rowt" is unacce#table unless #rocessin$ errors demonsrated
6alidation re#ort must demonstrate requirements in 6alidation #rotocol "ave been met, any deviations must be justified Requalification must be re#eated on an annual basis *usually one run is acce#table+ 2ny c"an$es or modifications must be evaluated
may just require requalification any c"an$es to loadin$ #atterns, new containerHclosure systems or cycle #arameters require full validation
38
Routine 'roduction
Issues considered for routine #roduction
Manufacturin$ environment s"ould be controlled 'rocedures in #lace to minimize t"e #resterilization bioburden
bioburden limits s#ecified *alt"ou$" not so im#ortant w"en over4ill cycle used+
)ime between fillin$ and sterilization s"ould be s#ecified Inte$rity of containerHclosure system s"ould be #eriodically verified 'eriodic lea4 testin$ of c"amber *if vacuum is #art of cycle+
Routine 'roduction
(oolin$ water s"ould be sterile Differentiation between sterilized and not-yet sterilized #roduct '"ysical se#aration *double ended autoclave+ 3abellin$ and use of visual indicators *e=$ autoclave ta#e+ 'eriodic testin$ of containers to verify inte$rity of containerHclosure system Nuality of steam s"ould be defined and #eriodically tested for contaminants
40
Routine 'roduction
:ac" sterilization cycle must be monitored
tem#erature, time and #ressure recorded tem#erature recorder inde#endent from cycle controller second inde#endent tem#erature recorder drain tem#erature s"ould be recorded c"emical and biolol$ical indicators *if a##licable+
Sterilisation cycle records s"ould form #art of batc" records

Ot"er Sterilization 'rocesses

Sterilization usin$ ot"er #rocesses s"ould follow a similar a##roac" as t"at described for moist "eat
6alidation #rotocol :qui#ment calibration Determinin$ t"e #rocess t"at will deliver t"e desired S23 */0-1+ IN, ON, 'N Requirements for routine monitorin$ and control
42

Dry %eat
S"ould "ave air circulation in t"e c"amber 'ositive #ressure in t"e c"amber to #revent entry of non-sterile air %:'2 filtered air su##lied !iolo$ical indicators containin$ Bacillus atropheus *if used+
removal of endoto&in is usually sufficient
,"en removin$ #yro$ens need to validate #rocess usin$ c"allen$e tests
43

Radiation
Asually #erformed by contractin$ service *need to ensure validation status, res#onsibilities+ !ased on bioburden of #roduct bein$ sterilised
!iolo$ical indicators may be used as additional control but may not be as resistant as naturally occurin$ bioburden
Met"od defined in International Standard ISO ///EI
44

Radiaton *;+
(orrect dose of radiation *Q;D 4@y+ received by all #roducts *measured wit" dosimeters+
quantitative measurement number, location, wit"in calibration time-limit
Radiation sensitive colour discs a##lied to #ac4a$in$ #rocedures to distin$uis" irradiated and nonirradiated materials 6ariation in density of #ac4a$in$ s"ould be addressed durin$ validation
45

@asses and .umi$ants
e=$= et"ylene o&ide, "ydro$en #ero&ide va#our Only w"en no ot"er met"od is suitable Must demonstrate t"at #rocess does not adversely affect #roduct 'ac4a$in$ must be able to #ermit in$ress of $as and "umidity :nsure #roduct load is adequately "eated and "umidified #rior to sterilization *called conditionnin$ +
need to ta4e into account validation #erformed in summer or winter

@asses and .umi$ants *;+
)em#erature distribution is acce#table (oncentration of sterilant $as is sufficient Ase of biolo$ical indicators is im#ortant *Bacillus atropheus+ %alf cycles
If cycle of "alf normal time destroys biolo$ical indicators */01 or$anisms+, double time will ac"ieve S23 of /0-1
2eration
6entilated conditions Defined limits of residuals 'rocess included in validation
Safety and to&icity issues considered

Aseful 'ublications
ISOH:5 /I11D - Sterilization of health care products - Moist Heat *'arts / and ;+ ISOH:5 ///ED - Sterilization of health care products - Ethylene Oxide *'arts / and ;+ ISOH:5 ///EI - Sterilization of health care products - adiation *'arts /,; and E+ !"alidation of Moist Heat Sterilization #rocesses$ Cycle %esign& %e'elopment& (ualification and ongoing Control) 'D2 )ec"nical Re#ort 5o= / Revised ;00I
48
Nuestions-
49

1-2 SterilisationValidationQualification

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1-2 SterilisationValidationQualification

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Sterilization - validation, qualification requirements

Mrs Robyn Isaacson

Sterile 'roducts - Overview

)wo cate$ories of sterile #roducts

Or$anisms are 4illed in an e&#onential fas"ion

No remaining Log No remaining

No remaining Log No remaining

3o$ 5o of Survivin$ Or$anisms

Microbial Deat" (urve

Ased for sterilization ofB

also used for de#yro$enation of $lassware * ;D0C(+

:t"ylene O&ide @as

2dequate aeration to reduce to&ic residues

#rocess must be #ro#erly validated used forB

can cause unacce#table c"an$es

2ll indicators s"ould be a##ro#riately stored and wit"in e&#iry

6alidation - (ycle Develo#ment

Typical temperat re pro!ile o! a "eat #terili$ation proce##

%"at &o l' (e t"e )o o! a cycle at 121*+ !or 15 min te#,

6alidation - (ycle Develo#ment

6alidation - (ycle Develo#ment

6alidation - (ycle Develo#ment

6alidation - (ycle Develo#ment

6alidation - (ycle Develo#ment

S#ore Dots - (ircular #ieces of

S#ore Sus#ensions - #ure s#ore

6alidation - (ycle Develo#ment

O#eration Nualification *ON+

'erformance Nualifcation *'N+

Sterilisation cycle records s"ould form #art of batc" records

Ot"er Sterilization 'rocesses

Ot"er Sterilization 'rocesses

,"en removin$ #yro$ens need to validate #rocess usin$ c"allen$e tests

Ot"er Sterilization 'rocesses

Met"od defined in International Standard ISO ///EI

Ot"er Sterilization 'rocesses

Ot"er Sterilization 'rocesses

Ot"er Sterilization 'rocesses

Safety and to&icity issues considered

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