1-2 sterilisationvalidationqualification (1)

7/26/2019 1-2 SterilisationValidationQualification (1)

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Manufacture of sterile medicines Advanced workshop for SFDA GMPinspectors - Nanjin! Novem"er #$$%1

Sterilization - validation,

qualification requirements

Mrs Robyn Isaacson


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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"ersterilization #rocesses


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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


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"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 eonential fas"ion


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Definition of Sterile

MI(RO!I23 I52()I62)IO5

5t7 5oe

-4t

0

200

400

600

800

1000

1200

)ime

5oofsurvivin$or$anisms

-2.00

-1.50

-1.00

-0.50

0.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50

No remaining

Log No remaining

No remaining 1000 368 135 50 18 7 2 1 0 0 0

Log No remaining 3.00 2.57 2.13 1.70 1.26 0.83 0.39 -0.04 -0.47 -0.91 -1.34

0 1 2 3 4 5 6 7 8 9 10


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D-value - )ime *or dose+ required to reduce t"e#o#ulation of or$anisms by / lo$ *or 809+

D-Value

Resistance of an or$anism is referred as its D-value


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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"ena##ly a safety factor t"at will deliver an

e&tra 1 lo$ reduction


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:&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 D-

value *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 andan S23 of /0-1+ *'oint >+


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(ommonly used met"ods of sterilization Moist %eat

Dry %eat

?as *:t"ylene o&ide+

Radiation *?amma or :lectron+

.iltration

Ot"ers - @6, Steam and formalde"yde,

"ydro$en #ero&ide


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Moist %eat Saturated steam

(ommon cyclesA /;/B( for /C minutes

/EB( for minutes

Ot"er cycles of lower tem#erature and lon$ertime may be used *e=$= //CB( for 0 minutes+

@sed for sterilization ofA

terminal sterilization of aqueous injections,

o#"t"almic #re#arations, irri$ation F"aemodialysis solutions, equi#ment used in

ase#tic #rocessin$


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Moist %eat

not suitable for non-aqueousGdry

#re#arations

#referred met"od of sterilization


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Dry %eat

3et"ality due to o&idative #rocesses %i$"er tem#eratures and lon$er eosure

times required

)y#ical cyclesA

/10B( for /;0 minutes

/H0B( for 10 minutes

/


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Dry %eat

@sed forA

$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*

;C0B(+

*'yro$ens - substances found in cell wall of

some bacteria w"ic" can cause fever w"en

introduced into t"e body+


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: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 cyclesA

/-;E"ours

;C-/;00 m$G3 $as

;C-1CB( 0-


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:t"ylene O&ide @sed forA

"eat labile #roduct containers

surface sterilization of #owders

2dequate aeration to reduce to&ic

residues


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Radiation

?amma rays $enerated by (obalt 10 or (aesium/H radionuclides or

2ccelerated electrons from an electron $enerator

;C 4ilo$rays *4?y+ usual dose

dose de#endent on bioburden *resistance of or$anismsnot #redictable+

#rocess must be #ro#erly validated

used forA

dry #"armaceutical #roducts "eat labile #roduct containers

can cause unacce#table c"an$es


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.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 ventfilters


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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

containerGclosure inte$rity must be establis"ed

items bein$ sterilised must contain water *if

sealed+ or material must allow for removal ofair and #enetration of steam for steam *moist

"eat+ sterilization


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6alidation - 'rotocol

Requirements for Moist %eat SterilizationOt"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,containerGclosure 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


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6alidation - 'rotocol

Moist %eat continuedA

#erformance c"aracteristics of all equi#ment e=$=

#ressure $au$es, valves, alarm systems, timers,

steam flow ratesG#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 finalevaluation *s"ould "ave eerience and

necessary trainin$ and be aut"orized+


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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=$=

tem#erature recorders and sensors t"ermocou#les

#ressure sensors for jac4et and c"amber

timers

conductivity monitors for coolin$ water

flow metres for waterGsteam 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$


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6alidation - (alibration Indicators s"ould be calibrated

#"ysical and c"emcial indicators s"ould be testedto demonstrate acce#table res#onse to time and

tem#erature

biolo$ical indicators s"ould be tested for count and

timeGtem#erature eosure res#onse

for commercial indicators - test certificate wit" countand D-value and eosure res#onse s"ould be

available= Results acce#table if verified in "ouse

#eriodically=

In "ouse indicators must be fully c"aracterized *D-

value, identification+ and a##ro#riate for sterilization#rocess

2ll indicators s"ould be a##ro#riately stored and

wit"in eiry


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6alidation - (ycle Develo#ment

(once#t of .o

3et"ality factor equivalent to time at /;/B( / minute at /;/B( is equivalent to .o of /=

3et"ality can accumulate durin$ "eat u# and cooldown #"ases

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

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


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.o is calculated usin$ t"e followin$

equationA

.o7 JtK/0*)-/;/G>+

w"ereA

Jt is t"e time interval between measurements oftem#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$anism by / lo$


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)"e minimum .o required by a sterilzation

#rocess is related to t"e resistance of t"e

bioburden *D-value+

.o7 D/;/*3o$2 - 3o$ !+

w"ereA D/;/ is equal to t"e time at /;/B( 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+


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)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 .oof at least /;

)"is will ac"ieve a /; lo$ reduction of microor$anisms

wit" a D-value of / minute

*2ssumin$ eac" #roduct unit contains /01or$anisms a /; lo$reduction will result in /0-1or$anisms #er unit or #robability

of survival *S23+ of / in a million+

*5ormal bioburden is usually muc" lower and t"e or$anisms

normally muc" less resistant t"an t"is+


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6alidation - (ycle Develo#ment!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 tosterilization


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6alidation - (ycle Develo#mentS#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 offibrous #a#er im#re$nated wit"

t"e s#ore sus#ension

S#ore Sus#ensions- #ure s#oresus#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#leGconvenient to

use+


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6alidation - (ycle Develo#ment '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 L+, wit" a

minimum safety factor of anadditional si&-lo$ reduction

*'oint >+

Determination of t"e

minimum .o

required is based

on t"e bioburden and its "eat

resistance

"at .owould be required for a bioburden of /0;*/00+ if D-value was /


30/49


6alidation of Sterilization

!asic 'rinci#les

Installation ualification *I+

:nsurin$ equi#ment is installed as #er

manufacturerNs s#ecification

O#eration ualification *O+ :nsurin$ equi#ment, critical control equi#mentand instrumentation are ca#able of o#eratin$

wit"in required #arameters

'erformance ualifcation *'+ Demonstratin$ t"at sterilizin$ conditions are

ac"ieved in all #arts of sterilization load

'"ysical and microbiolo$ical


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6alidation - :qui#ment

Installation ualification

:nsurin$ equi#ment is installed as #er

manufacturerNs 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


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6alidation - :qui#ment

O#erational ualification

: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

6 lid i ' f


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6alidation - 'erformance

'erformance ualification

Demonstratin$ t"at sterilizin$ conditions are

ac"ieved in all #arts of sterilization load

'"ysicaland 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

6 lid ti ' f


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'erformance ualification - '"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 "eatGcold 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

6 lid ti ' f


35/49



'erformance ualification - '"ysical *+

%eat #enetration studies to detect t"e ma&imumand 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

6 lid ti ' f


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'erformance ualification - '"ysical *E+

%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

6 lid ti ' f


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'erformance ualification - 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 /;/B( for /C minutes

*e&ce#t @S and 2ustralia+

biolo$ical indicators *!I+ containin$ s#ores of Geobacillusstearothermophilusare 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

6 lid ti ' f


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6alidation re#ort must demonstrate requirements

in 6alidation #rotocol "ave been met, anydeviations 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 containerGclosure

systems or cycle #arameters require full validation

R ti ' d ti


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Routine 'roduction

Issues considered for routine #roduction

Manufacturin$ environment s"ould be controlled

'rocedures in #lace to minimize t"e #re-

sterilization 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 containerGclosure system s"ould be

#eriodically verified 'eriodic lea4 testin$ of c"amber *if vacuum is #art

of cycle+

R ti ' d ti


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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

containerGclosure system

uality of steam s"ould be defined and

#eriodically tested for contaminants

R ti ' d ti


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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" St ili ti '


42/49


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+

I, O, '

Requirements for routine monitorin$ andcontrol

Ot" St ili ti '


43/49



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

Ot"er Sterili ation 'rocesses


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Radiation

@sually #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///H



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Radiaton *;+

(orrect dose of radiation *P;C 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 non-

irradiated materials

6ariation in density of #ac4a$in$ s"ould be

addressed durin$ validation



46/49



?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 *calledconditionnin$+

need to ta4e into account validation #erformed in

summer or winter



47/49

Manufacture of sterile medicines Advanced workshop for SFDA GMP

inspectors - Nanjin! Novem"er #$$%47


?asses and .umi$ants *;+

)em#erature distribution is acce#table

(oncentration of sterilant $as is sufficient

@se 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

@seful 'ublications


48/49


inspectors - Nanjin! Novem"er #$$%48

@seful 'ublications

ISOG:5 /H11C - Sterilization of health care

products - Moist Heat *'arts / and ;+

ISOG:5 ///C - Sterilization of health care

products - Ethylene Oxide *'arts / and ;+

ISOG:5 ///H - Sterilization of health care

products - Radiation *'arts /,; and +

alidation of Moist Heat Sterilization !rocesses"

#ycle $esi%n& $e'elopment& (ualification and

on%oin% #ontrol)'D2 )ec"nical Re#ort 5o= /

Revised ;00H


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1-2 sterilisationvalidationqualification (1)

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