A PROJECT on Validation of Sterile Product

8/13/2019 A PROJECT on Validation of Sterile Product

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A PROJECT ON

VALIDATION OF

STERILE PRODUCTS

SUBMITTED BY: NEETI MATHUR



VALIDATION

Preamble:Validation is a key ro!ess "or e""e!ti#e $%ality ass%ran!e&“Validation is establishing documented evidence which provides a highdegree o assurances that a speci ic process or e!uipment will consistentl" produce a product or result meeting its predetermined speci ications and!ualit" attributes#$

The ma%or reasons or validation are&Quality assurance ' (ualit" cannot be assured b" routine !ualit"control testing because o limitation o statistical samples and thelimited acilities o inished product testing# Validation chec)s theaccurac" and reliabilit" o a s"stem or a process to meet the predetermined criteria# A success ul validation provides high degreeo assurance that a consistent level o !ualit" is maintained in eachunit o the inished product rom one batch to another batch#

Economics ' due to success ul validation* there is a decrease insampling and testing procedures and there are less number o productre%ections and retesting# This leads to cost+saving bene its#Compliance ' ,or compliance to current good manu acturing practices* validation is essential#

P'ases o" #alidationDesi(n $%ali"i!ation )D*+ : documented veri ication o the design oe!uipment and manu acturing acilities#Installation $%ali"i!ation )I* -& documented veri ication o thes"stem design and adherence to manu acturer.s recommendations#O erational $%ali"i!ation )O*+: documented veri ication oe!uipment or s"stem per ormance in the target operating range#Pro!ess er"orman!e $%ali"i!ation )P*+: documented veri icationthat e!uipment s"stem operates as e/pected under routine productionconditions# The operation is reproducible* reliable and in a state ocontrol#



Ty e o" Pro!ess Validation

Pros e!ti#e0onducted prior to mar)et the product#

,on!%rrent1ased on in ormation generated during actual implementation othe process# 2Each batch will be released separatel"-#

-etros e!ti#e 2Not re!ommended "or sterile rod%!t+1ased on accumulated historical production* testing and controldata#

3enerall" re!uires data rom 45+65 batches# Use data onl" rom batches made b" the same process#

VALIDATION O. STE-ILE P-ODU,TS

Main ob/e!ti#es:

To build sterilit" into a product#To demonstrate to a certain ma/imum level o probabilit" that the processing and sterili7ation methods have established sterilit" to

all units o a product batch#To provide greater assurance and support to all the results o theend products sterilit" test#

Sterile Prod%!t:The 8roducts which ree o an" viable organisms#

Sterility:Viable microorganisms are absent#

Biob%rden:Total number o viable microorganisms on or in pharmaceutical product prior to sterili7ation#



Terminal Sterili0ation:9peration whereb" the product is sterili7ed separatel" b" autoclave a ter

illed and pac)aged using sterili7ed container and closures in critical processing 7ones#

Ase ti! O eration:9peration whereb" the product is sterili7ed separatel" b" iltering through5#: ; or less ilter then illed and pac)aged using sterili7ed containers andclosures in critical processing 7ones#

Validation Team: 8roduction* (0* (A* Engineer* 8lanner To prepare the validation protocolVeri " the calibration and maintenance status o e!uipment8er orm !uali ication or e!uipments and s"stemVeri " change control<chedule the validation activitiesTraining production operators0onduct validation stud"Monitor the critical steps in manu acturing processAssure that the approved testing standard is being usedEvaluate all test results*8repare the validation report#

Pre1#alidation -e$%irements &8reventive Maintenance or ,acilities and Utilities0alibration o E!uipment0leaning ValidationE!uipment = <"stem (uali icationRaw Materials>0omponents>Test Methods8rocess ?usti ication0hange 0ontrolTraining operators



All must be proven suitable and reliable or the manu acturing process be ore the process can be validated#

Pro!ess 2%sti"i!ation:To identi " critical process steps = process parameter o mi/ing process#To determine the suitable Hold time 8eriodTo con irm the anal"tical tests that will have to be per ormedTo de ine the optimal parameters throughout the overall ampoule

illing process to consistentl" produce the inished products 2 illedampoules- which meet the established speci ications#To assure that the product is sterile a ter sterili7ation process#

Validation Proto!olA document stating how validation will be conducted* including test parameters* product characteristics* production e!uipment to be used anddecision points on what constitutes acceptable test results#

Validation Proto!ol s'o%ld !ontain:Title 8age* Review>Approval 8age8urpose and 9verviewE!uipment @istIngredients and 0omponent @ist(uali ication @ist o E!uipment and <"stem8rocess ,low iagram and escription

E!uipment 0ritical 8rocess 8arameter 8rocess Validation <ampling 8lan>Testing Re!uirementsAcceptance 0riteria<tabilit" Re!uirements8rocess or evaluation o an" deviations occurring duringvalidation0onclusion



E$%i ment ,riti!al Pro!ess Parameter &Mi/ing <peedMi/ing Time

3as lushing timeT"pe and si7e o ilter ,iltering Time and 8ressure used,illing <peedTemperature and uration or Terminal <terili7ation0ritical Manu acturing <tep

issolving <tep pH ad%ustment step,inal mi/ing step

,iltering <tep,illing <tepTerminal <terili7ation <tep@ea) Test <tep

,riti!al Pro!essin( ParameterMi/ing <peedMi/ing Time

,lushing Time pH

,riti!al Pro!essin( Ste s

issolved active ingredientsB

pH ad%ustmentB

,inal mi/ingB

,iltrationB

,illingB



<terili7ation

A!!e tan!e !riteria

issolved active ingredients 0lear solution pH ad%ustment pH within speci ication,inal mi/ing pH* appearance* assa"* content*

bioburden* hold time#,iltration ,ilter integrit"* sterilit"* pH* hold

time#,illing Appearance* 1ioburden* hold time*

o/"gen head space#<terili7ation <terilit"* assa"* pH* endoto/ins etc#@ea) test Number o lea)ed products#Visual inspection Number o de ected products#

Prod%!t Testin(

Validation testing o bul) and ,>3 must be based on testing standardrelease criteria and in+process testing criteria#T"picall" involves non+routine sampling>testing throughout the entire process* with special emphasis on critical process parameters#Routine (0 release testing should be per ormed on a routine sample#These samples should be ta)en separatel" rom the validationsamples#

Validation Bat!':

New product and product trans er* 8rospective validation is re!uiredManu acturing 8rocess* ,ormula* E!uipment and 1atch <i7e have to be i/ed during the validation trials#1atch <i7e should be the same si7e as commercial production batchThe batch si7e must be i/ed or production#

i erent lots but same manu acturer o active ingredients should beused during validation trials#



Validation Bat!': B%lk Sam lin( and Testin(<amples ma" be ta)en b"0ollecting during Trans er

Using a sampling deviceTa)e at least : samples at top* middle and bottomIndividual Testing o sample must be done and the result must meetthe testing standard speci ication

*%ali"i!ation o" Ma3im%m B%lk 4old TimeThe ma/imum period o time which the bul) can be held prior to

ilter* ,ill and>or <terili7ationIt will be counted a ter inished inal mi/ing step until trans er to

ilter* inished ilter until start illing and>or inished illing until starsterili7ation#9ne ull scale batch should be held or most practical ma/imum time period prior to ilter* ill and>or sterili7ationI there is not enough support in ormation > !uali ication done# The period o :C hours will be used#Hold time !uali ication must simulate actual storage condition

.inis' Prod%!t Testin( a"ter Sterili0ation

Uni ormit" o illed volume8er orm testing on illed containers#<terilit"45 samples rom each o the beginning and end o the illing run#<amples must represent all illing no77les#Visual EvaluationAppearance* 0olor o solution9ther TestingAssa"* pH* ensit"* 8"rogen or Endoto/in etc#

Validation -e ortValidation Team must prepare the reportReport must be reviewed and approved b" (A#Dritten Noti ication or either success ul completion or ailure o the process validation must be issued to top management#



In case o ailure* an investigation must be completed anddocumented prior to repeat the validation stud"#

,'an(es and -e#alidation

0hange o an" o the ollowing ma" need revalidation,ormula 0ompositionRaw Material <ourceManu acturing 8rocessManu acturing @ocationE!uipments1atch <i7eTesting <peci ication

,'an(es• Minor: It seems to have no impact on ormulation It is not necessar" to validate

• Intermediate : It could have signi icant impact on ormulation epend on case+b"+case 2A minimum o 4 trial-

• Ma/or : It is li)el" to have signi icant impact on ormulation Revalidation is re!uired 2A minimum o 6 trials-

Minor ,'an(e(ualitative inactive e/cipient change deemed minor b" change controlreview8rocess change deemed minor b" change control reviewManu acturing location change with in same building* samee!uipment* personnel* procedure and utilities are usedE!uipment change but same design* con iguration#

Intermediate ,'an(eActive ingredient source or s"nthesis change deemed intermediate b"change control review

(ualitative inactive e/cipient change deemed intermediate b" changecontrol reviewManu acturing location change to a di erent building on the same siteand same utilities* same e!uipment* personnel* and procedure areused# 8rocess changes* such as mi/ing times or operating speeds orsolutions#



0hange in release speci ication to a tighter limit caused originalvalidation results to be out o speci icationE/tension o the !uali ied in process hold time or intermediate or

inished product prior to pac)agingE!uipment change deemed intermediate b" change control review

Ma/or ,'an(es(uantitative or !ualitative ormulation change deemed ma%or b"change control reviewInactive e/cipient or active ingredient source change deemed ma%or b" change control reviewTrans er product rom on site to another <igni icant change in processE!uipment change to a di erent design* con iguration or operating principle#

,on!l%sionValidation 8rotocol identi ies critical process parameters to beevaluated and predetermined acceptance criteria#8rocess must be continuall" monitored and change control used to

identi " need or process revalidation#8roduction and (A have to review and approve the validation result#8roduct must be held until the validation get approval#

-e1#alidationRegular per ormance o process simulation studies#Monitoring o environment* disin ection procedures* e!uipmentcleaning and sterili7ation 2including containers and closures-#Routine maintenance and re+!uali ication o e!uipment* e#g#autoclaves* ovens* HVA0 2heating* ventilation and air conditioning-s"stems* water s"stems* etc#Regular integrit" testing o product ilters* containers* closures andvent ilters#Re+validation a ter changes#



A& Pro!ess Sim%lations

To ensure the sterilit" o products purporting to be sterile* both sterili7ationand aseptic illing and closing operations must be ade!uatel" validated# Thegoal o even the most e ective sterili7ation processes can be de eated i the

sterili7ed elements o a product 2the drug* the container* and the closure- are brought together under conditions that contaminate an" o those elements#<imilarl"* product sterilit" will be compromised i product elements are notsterile when the" are assembled#

The validation o an aseptic processing operation should include the use o amicrobiological growth nutrient medium in place o the product# This has been termed amedia fill or process simulation & In the normal media illsimulation* the nutrient medium should be e/posed to product contactsur aces o e!uipment* container closure s"stems* critical environments* and process manipulations to closel" simulate the same e/posure that the productitsel will undergo# The sealed containers illed with the media are thenincubated to detect microbial contamination# The results should beinterpreted to determine the potential or a unit o drug product to becomecontaminated during actual operations 2e#g#* start+up* sterile ingredientadditions* and aseptic connections* illing* and closing-# Environmentalmonitoring data rom the process simulation can also provide use ulin ormation or the processing line evaluation#

5& St%dy Desi(n

A recommended media ill program incorporates the contamination ris)actors that occur on a production line* and accuratel" assesses the state o

process control# The media ill program should address applicable issuessuch as&



,actors associated with the longest permitted run on the processing line Number and t"pe o normal interventions* at"picalinterventions* une/pected events 2e#g#* maintenance-*

stoppages* e!uipment ad%ustments or trans ers@"ophili7ation* when applicableAseptic assembl" o e!uipment 2e#g#* at start+up* during processing- Number o personnel and their activities Number o aseptic additions 2e#g#* charging containersand closures as well as sterile ingredients-shi t changes* brea)s* and gown changes 2whenapplicable-

Number and t"pe o aseptic e!uipmentdisconnections>connectionsAseptic sample collections@ine speed and con igurationsManual weight chec)s9perator atigue0ontainer closure s"stems 2e#g#* si7es* t"pe*compatibilit" with e!uipment-<peci ic provisions o aseptic processing related

<tandard 9perating 8rocedures 2e#g#* conditions permitted be ore line clearance is mandated-

A written batch record* documenting production conditions and simulatedactivities* should be prepared or each media ill run# The same vigilanceshould be observed in both media ill and routine production runs# Media

ills should not be used to %usti " an unacceptable practice#

6& .re$%en!y and N%mber o" -%ns

Dhen a processing line is initiall" !uali ied* separate media ills should berepeated enough times to ensure that results are consistent and meaning ul#This approach is important because a single run can be inconclusive* whilemultiple runs with divergent results signal a process that is not in control# Atleast three consecutive separate success ul runs should be per ormed duringinitial line !uali ication# <ubse!uentl"* routine semi+annual !uali icationshould be conducted or each processing line to evaluate the state o control



o the aseptic process# Activities and interventions representative o eachshi t* and shi t changeover* should be incorporated into the design o thesemi+annual !uali ication# ,or e/ample* the evaluation o a shi t shouldaddress its uni!ue time+related and operational eatures# All personnel whoenter the aseptic processing area* including technicians and maintenance personnel* should participate in a media ill at least once a "ear# 8articipationshould be consistent with the nature o each operator s duties during routine production# Each change to a product or line change should be evaluatedusing a written change control s"stem# An" changes or events that have the potential to a ect the abilit" o the aseptic process to e/clude contamination

rom the sterili7ed product should be assessed through additional media ills#,or e/ample* acilit" and e!uipment modi ications* line con igurationchanges* signi icant changes in personnel* anomalies in environmentaltesting results* container closure s"stem changes or* end product sterilit"testing showing contaminated products ma" be cause or revalidation o thes"stem#

Dhere data rom a media ill indicate the process ma" not be in control* acomprehensive documented investigation should be conducted to determinethe origin o the contamination and the scope o the problem# 9ncecorrections are instituted* repeat process simulation runs should be per ormed to con irm that de iciencies in practices and procedures have beencorrected and the process has returned to a state o control# Dhen aninvestigation ails to reach well+supported* substantive conclusions as to thecause o the media ill ailure* three consecutive success ul runs andincreased scrutin" 2e#g#* e/tra supervision* monitoring- o the production process should be implemented#

7& D%ration o" -%ns

The duration o aseptic processing operations is a ma%or consideration indetermining the si7e o the media ill run# Although the most accuratesimulation model would be the ull batch si7e and duration because it most

closel" simulates the actual production run* other appropriate models can be %usti ied# In an" stud" protocol* the duration o the run and the overall stud"design should ade!uatel" mimic worst+case operating conditions and coverall manipulations that are per ormed in the actual processing operation# Inthis regard* interventions that commonl" occur should be routinel"simulated* while those occurring rarel" can be simulated periodicall"#



Dhile conventional manu acturing lines are highl" automated* o ten operateat relativel" high speeds* and are designed to limit operator intervention*there are some processes that include considerable operator involvement#Dhen aseptic processing emplo"s manual illing or closing* or e/tensivemanual manipulations* the duration o the process simulation shouldgenerall" be no less than the length o the actual manu acturing process to best simulate contamination ris)s posed b" operators#

,or lyo 'ili0ation operations* unsealed containers should be e/posed to pressuri7ation and partial evacuation o the chamber in a manner thatsimulates the process# Vials should not be ro7en* as this ma" inhibit thegrowth o microorganisms#

8& Si0e o" -%ns

The simulation run si7es should be ade!uate to mimic commercial production conditions and accuratel" assess the potential or commercial batch contamination# A generall" acceptable starting point or run si7e is inthe range o F*555 to 45*555 units# ,or operations with production si7esunder F*555* the number o media illed units should e!ual the ma/imum batch si7e made on the processing line#

Dhen the possibilit" o contamination is higher based on the process design2e#g#* manuall" intensive illing lines-* a larger number o units* generall" aor approaching the ull production batch si7e* should be used# In contrast* a process conducted in an isolator can have a low ris) o contamination because o the lac) o direct human intervention and can be simulated with alower number o units as a proportion o the overall operation#

<ome batches are produced over multiple shi ts or "ield an unusuall" largenumber o units* and media ill si7e and duration are especiall" importantconsiderations in the media ill protocol# These actors should be care ull"considered when designing the simulation to ade!uatel" encompassconditions and an" potential ris)s associated with the larger operation#

9& Line S eed

The media ill program should ade!uatel" address the range o line speeds2e#g#* b" brac)eting all vial si7es and ill volumes- emplo"ed during production# Each individual media ill run should evaluate a single worst+case line speed* and the speed chosen or each run during a stud" should be



%usti ied# ,or e/ample* use o high line speed is o ten most appropriate in thevaluation o manu acturing processes characteri7ed b" re!uentinterventions or a signi icant degree o manual manipulation# Use o slowline speed is generall" appropriate or evaluating manu acturing processescharacteri7ed b" prolonged e/posure o the sterile drug product andcontainer closures in the aseptic area#

& En#ironmental ,onditions

Media ills should be ade!uatel" representative o the range o conditionsunder which actual manu acturing operations are conducted# An inaccurateassessment 2ma)ing the process appear cleaner than it actuall" is- can result

rom conducting a media ill under e/traordinar" air particulate andmicrobial !ualit"* or under production controls and precautions ta)en in preparation or the media ill# To the e/tent standard operating procedures permit stress ul conditions* it is important that media ills include analogouschallenges to support the validit" o these studies#

;& Media

In general* a microbiological growth medium* such as so"bean casein digestmedium* should be used# Use o anaerobic growth media 2e#g#* luidthiogl"collate medium- would be appropriate in special circumstances# Themedia selected should be demonstrated to promote growth o U<8 G 4indicator microorganisms as well as representative isolates identi ied b"environmental monitoring* personnel monitoring* and positive sterilit" testresults# 8ositive control units should be inoculated with a G455 0,Uchallenge and incubated# ,or those instances in which the growth promotiontesting ails* the origin o an" contamination ound during the simulationshould nonetheless be investigated* and the media ill should be promptl"repeated#

The production process should be accuratel" simulated using media andconditions that optimi7e detection o an" microbiological contamination#Each unit should be illed with an appropriate !uantit" and t"pe o microbialgrowth medium to contact the inner container closure sur aces 2when the



unit is inverted or thoroughl" swirled- and permit visual detection omicrobial growth#

<ome drug manu acturers have e/pressed concern over the possiblecontamination o the acilit" and e!uipment with the nutrient media duringmedia ill runs# However* i the medium is handled properl" and is promptl"

ollowed b" the cleaning* saniti7ing* and* where necessar"* sterili7ation oe!uipment* subse!uentl" processed products are not li)el" to becompromised#

<& In!%bation and E3amination o" Media1.illed Units

Media units should be incubated under conditions ade!uate to detectorganisms that can otherwise be di icult to culture# Incubation conditionsshould be established in accord with the ollowing general guidelines&

Incubation temperature should be suitable or recover" o bioburden and environmental isolates and should at no time beoutside the range o :5+6Fo0# Incubation temperature should bemaintained within :#Fo0 o the target temperature#Incubation time should not be less than 4C da"s# I twotemperatures are used or the incubation o the media illedsamples* the samples should be incubated or at least da"s ateach temperature#

Each media+ illed unit should be e/amined or contamination b" personnelwith appropriate education* training* and e/perience in microbiologicaltechni!ues# There should be direct !ualit" control unit oversight throughoutan" such e/amination# 0lear containers with otherwise identical ph"sical properties should be used as a substitute or amber or other opa!uecontainers to allow visual detection o microbial growth#

Dhen a irm per orms a inal product inspection o units immediatel"ollowing the media ill run* all integral units should proceed to incubation#

Units ound to have de ects not related to integrit" 2e#g#* cosmetic de ect-should be incubatedJ units that lac) integrit" should be re%ected# Erroneousl"re%ected units should be returned promptl" or incubation with the media illlot#



A ter incubation is underwa"* an" unit ound to be damaged should beincluded in the data or the media ill run* because the incubation o the unitssimulates release to the mar)et# An" decision to e/clude such incubatedunits 2i#e#* nonintegral- rom the inal run tall" should be ull" %usti ied anthe deviation e/plained in the media ill report# I a correlation emerges between di icult to detect damage and microbial contamination* a thoroughinvestigation should be conducted to determine its cause 2see <ection VI#1-#

Dritten procedures regarding aseptic interventions should be clear andspeci ic 2e#g#* intervention t"peJ !uantit" o units removed-* providing orconsistent production practices and assessment o these practices duringmedia ills# I written procedures and batch documentation are ade!uate*these intervention units do not need to be incubated during media ills where procedures lac) speci icit"* there would be insu icient %usti ication or

e/clusion o units removed during an intervention rom incubation# In nocase should more units be removed during a media ill intervention thanwould be cleared during a production run#The abilit" o a media ill run todetect potential contamination rom a given simulated activit" should not becompromised b" a large+scale line clearance* which can result in removal oa positive unit caused b" an unrelated event or intervention# I unavoidable*appropriate stud" provisions should be made to compensate in suchinstances#

Appropriate criteria should be established or "ield and accountabilit"#Media ill record reconciliation documentation should include a ullaccounting and description o units re%ected rom a batch#

=& Inter retation o" Test -es%lts

The process simulation run should be observed* and contaminated unitsshould be reconcilable with the appro/imate time and the activit" beingsimulated during the media ill# Video recording o a media ill has been

ound to be use ul in identi "ing personnel practices that could negativel"impact the aseptic process#

An" contaminated unit should be considered as ob%ectionable and ull"investigated# The microorganisms should be identi ied to species level# Inthe case o a media ill ailure* a comprehensive investigation should beconducted* surve"ing all possible causes o the contamination# The e ects



on commercial drugs produced on the line since the last success ul media illshould also be assessed#

Dhenever contamination e/ists in a media ill run* it should be consideredindicative o a potential sterilit" assurance problem* regardless o run si7e#Test results should reliabl" and reproducibl" show that the units produced b" an aseptic processing operation are sterile# Modern aseptic processingoperations in suitabl" designed acilities have demonstrated a capabilit" omeeting contamination levels approaching 7ero and should normall" "ieldno media ill contamination# Recommended criteria or assessing state oaseptic line control are as ollows&

Dhen illing ewer than F555 units* no contaminated unitsshould be detected#Dhen illing rom F*555 to 45*555 units&

++ 4 contaminated unit should result in an investigation*including consideration o a repeat media ill#

++ : contaminated units are considered cause or revalidation*ollowing investigation#

Dhen illing more than 45*555 units&++ 4 contaminated unit should result in an investigation#

++ : contaminated units are considered cause or revalidation*ollowing investigation#

A,,EPTAN,E ,-ITE-IA

,ill must meet the acceptance limits rom the ollowing table&

Ma/imum acceptable contaminatedunits observed in the lot#

Number o good Vials incubated

5 65554 C F5: K6556 K5



C L4K5F 45F:5K 44 F5

464F5

4CCC5L 4F 4545 4KL 544 4 :454: 4LCC5

,or an" run si7e* intermittent incidents o microbial contamination in mediailled runs can be indicative o a persistent low+level contamination problemthat should be investigated# Accordingl"* recurring incidents ocontaminated units in media ills or an individual line* regardless oacceptance criteria* would be a signal o an adverse trend on the aseptic processing line that should lead to problem identi ication* correction* andrevalidation#

B& .iltration E""i!a!y

,iltration is a common method o sterili7ing drug product solutions# Anappropriate sterili7ing grade ilter is one that reproducibl" removes allmicroorganisms rom the process stream* producing a sterile e luent# <uch

ilters usuall" have a rated porosit" o 5#: micron or smaller# Dhatever ilteror combination o ilters is used* validation should include microbiologicalchallenges to simulate worst+case production conditions regarding the si7e omicroorganisms in the material to be iltered and integrit" test results o the

ilters used or the stud"# The microorganisms should be small enough to both challenge the nominal porosit" o the ilter and simulate the smallest

microorganism that ma" occur in production# The microorganism Brevundimonas diminuta 2AT00 4L4CK- when properl" grown* harvestedand used* can be satis actor" in this regard because it is one o the smallest bacteria 25#6 micron mean diameter-# 1ioburden o unsterili7ed bul)solutions should be determined to trend the characteristics o potentiall"contaminating organisms# In certain cases* when %usti ied as e!uivalent as or



better than use o Brevundimonas diminuta * it ma" be appropriate toconduct bacterial retention studies with a bioburden isolate#

The number o microorganisms in the challenge is important because a iltercan contain a number o pores larger than the nominal rating* which has the potential to allow passage o microorganisms# The probabilit" o such passage is considered to increase as the number o organisms 2bioburden- inthe material to be iltered increases# A challenge concentration o at least 45organisms per cm: o e ective iltration area o B. diminuta shouldgenerall" be used# A commercial lot s actual in luent bioburden should notinclude microorganisms o a si7e and>or concentration that would present achallenge be"ond that considered b" the validation stud"#

irect inoculation into the drug ormulation provides an assessment o the

e ect o drug product on the ilter matri/ and on the challenge organism#However* directl" inoculating B. diminuta into products with inherent bactericidal activit" or into oil+based ormulations can lead to erroneousconclusions# Dhen su icientl" %usti ied* the e ects o the product

ormulation on the membrane s integrit" can be assessed using anappropriate alternate method# ,or e/ample* the drug product could be

iltered in a manner in which the worst+case combination o processspeci ications and conditions are simulated# This step could be ollowed b"

iltration o the challenge organism or a signi icant period o time* under thsame conditions* using an appropriatel" modi ied product 2e#g#* lac)ing anantimicrobial preservative or other antimicrobial component- as the vehicle#An" divergence rom a simulation using the actual product and conditions o processing should be %usti ied#

,actors that can a ect ilter per ormance normall" include 24- viscosit" othe material to be iltered* 2:- pH* 26- compatibilit" o the material or

ormulation components with the ilter itsel * 2C- pressures* 2F- low rates*2K- ma/imum use time* 2 - temperature* 2 - osmolalit"* 2L- and the e ectsh"draulic shoc)#

Dhen designing the#alidation roto!ol * it is important to address thee ect o the e/tremes o processing actors on the ilter capabilit" to produce sterile e luent# ,ilter validation should be conducted using theworst+case conditions* such as ma/imum ilter use time and pressure#



,ilter validation e/periments* including microbial challenges* need not beconducted in the actual manu acturing areas# However* it is essential thatlaborator" e/periments simulate actual production conditions# The speci ict"pe o ilter used in commercial production should be evaluated in iltervalidation studies# Dhen the more comple/ ilter validation tests go be"ondthe capabilities o the ilter user* tests are o ten conducted b" outsidelaboratories or b" ilter manu acturers# However* it is the responsibilit" othe ilter user to review the validation data on the e icac" o the ilter in producing a sterile e luent# The data should be applicable to the user s products and conditions o use because ilter per ormance ma" di ersigni icantl" or various conditions and products#

A ter a iltration process is properl" validated or a given product* process*and ilter* it is important to ensure that identical ilter replacements

2membrane or cartridge- used in production runs will per orm in the samemanner# <terili7ing ilters should be routinel" discarded a ter processing o asingle batch# Normall"* integrit" testing o the ilter is per ormed prior to processing* a ter the ilter apparatus has alread" been assembled andsterili7ed# It is important that integrit" testing be conducted a ter iltration todetect an" ilter lea)s or per orations that might have occurred during the

iltration#Forward flow and bubble point tests* when appropriatel"emplo"ed* are two integrit" tests that can be used# A production ilter sintegrit" test speci ication should be consistent with data generated during

iltration e icac" studies#

,& Sterili0ation o" E$%i ment and ,ontainer and ,los%res

To maintain sterilit"* e!uipment sur aces that contact a sterili7ed drug product or sterili7ed container or closure sur aces must be sterile so as not toalter purit" o the drug 2:44#K6 and :44#446-# Those sur aces that are in thevicinit" o sterile product or container closures* but do not directl" contactthe product should also be rendered sterile where reasonable contamination potential e/ists# It is as important in aseptic processing to properl" validate

the processes used to sterili7e such critical e!uipment as it is to validate processes used to sterili7e the drug product and its container and closure#Moist heat and dr" heat sterili7ation are most widel" used#

<terilit" o aseptic processing e!uipment should be maintained b" batch+b"+ batch sterili7ation# ,ollowing sterili7ation o e!uipment* containers* orclosures* transportation or assembl" should be per ormed with adherence to



strict aseptic methods in a manner that protects and sustains the product ssterile state#

5& Sterili0er *%ali"i!ation and Validation

Validation studies should be conducted demonstrating the e icac" o thesterili7ation c"cle# 8re!uali ication studies should also be per ormed on a periodic basis# ,or both the validation studies and routine production* use oa speci ied load con iguration should be documented in the batch records#

The insulating properties o unevacuated air prevent moist heat under pressure rom penetrating or heating up materials and achieving the lethalit"associated with saturated steam# 0onse!uentl"* or such processes* there is a

ar slower thermal energ" trans er and rate o )ill rom the dr" heat in

insulated locations in the load# It is important to remove air rom theautoclave chamber as part o a moist heat under pressure sterili7ation c"cle#

,or the various methods o sterili7ation* special attention should be given tothe nature or t"pe o the materials to be sterili7ed and the placement o biological indicators within the sterili7ation load#

+value o the biological indicator can var" widel" depending on thematerial to be sterili7ed# 8otentiall" di icult to reach locations within thesterili7er load or e!uipment train 2 or <I8 applications- should be evaluated

in initial studies# ,or e/ample* ilter installations in piping can cause asubstantial pressure di erential across the ilter* resulting in a signi icanttemperature drop on the downstream side# 1iological indicators should be placed at appropriate downstream locations o this e!uipment to determine ithe drop in temperature a ects the thermal input at these sites#8re!uali ication and>or revalidation should continue to ocus on the loadareas identi ied as most di icult to penetrate or heat 2e#g#* worst+caselocations o tightl" wrapped or densel" pac)ed supplies* securel" astenedload articles* length" tubing* the sterile ilter apparatus* h"drophobic ilters*stopper load-#

The ormal program providing or regular revalidation should consider theage o the sterili7er and its past per ormance# 0hange control proceduresshould ade!uatel" address issues such as a load con iguration change or amodi ication o the sterili7er#

a# (uali ication& Empt" 0hamber



Temperature distribution studies evaluate numerous locationsthroughout an empt" sterili7ing unit 2e#g#* steam autoclave* dr"heat oven- or e!uipment train 2e#g#* large tan)s* immobile piping-# It is important that these studies assess temperatureuni ormit" at various locations throughout the sterili7er toidenti " potentialcold spots where there can be insu icient heatto attain sterilit"# These heat uni ormit" ortemperaturemapping studies should be conducted b" placing calibratedtemperature measurement devices in numerous locationsthroughout the chamber#

b# Validation& @oaded 0hamber

Heat penetration studies should be per ormed using the

established sterili7er load2s-# Validation o the sterili7ation process with a loaded chamber demonstrates the e ects oloading on thermal input to the items being sterili7ed* and ma"identi "cold spots where there is insu icient heat to attainsterilit"#

The placement o biological indicators 21I- at numerous positions in the load* including the most di icult to sterili7e places* is a direct means o demonstrating the e icac" o an"sterili7ation procedure# In general* the thermocouple 2T0- is placed ad%acent to the 1I so as to assess the correlation betweenmicrobial lethalit" and thermal input# Dhen determining whicharticles are most di icult to sterili7e* special attention should begiven to the sterili7ation o ilters#

Ultimatel"* c"cle speci ications or such sterili7ation methodsare based on the deliver" o ade!uate thermal input to theslowest to heat locations# A sterilit" assurance level o 45+K or better should be demonstrated or a sterili7ation process#

6& E$%i ment ,ontrols and Instr%ment ,alibration

,or both validation and routine process control* the reliabilit" o the datagenerated b" sterili7ation c"cle monitoring devices should be considered to be o the utmost importance# evices that measure c"cle parameters should be routinel" calibrated# Dritten procedures should be established to ensurethat these devices are maintained in a calibrated state# ,or e/ample&



Temperature monitoring devices or heat sterili7ation should becalibrated at suitable intervals* as well as be ore and a tervalidation runs#

evices used to monitor dwell time in the sterili7er should be

periodicall" calibrated#The microbial count and +value o a biological indicatorshould be con irmed be ore a validation stud"#1acterial endoto/in challenges should be appropriatel" prepared and measured b" the laborator"#Instruments used to determine the purit" o steam should becalibrated as appropriate#,or dr" heat dep"rogenation tunnels* devices 2e#g# sensors andtransmitters- used to measure belt speed should be routinel"calibrated#

To ensure robust process control* sterili7ing e!uipment should be properl"designed with attention to eatures such as accessibilit" to sterilant* pipingslope* and proper condensate removal 2as applicable-#

E!uipment control should be ensured through placement o measuringdevices at those ris)+based control points that are most li)el" to rapidl"detect une/pected process variabilit"# Dhere manual manipulations ovalves are re!uired or sterili7er operations* these steps should bedocumented in manu acturing procedures# <terili7ing e!uipment should be properl" maintained to allow or consistentl" satis actor" unction#Evaluation o sterili7er per ormance attributes such as e!uilibrium 2come up-time studies should be help ul in assessing i the unit continues to operate properl"#



ENDOTO>IN ,ONT-OL

:4 0,R :44#K6 states that “E!uipment used in the manu acturing* processing* pac)ing* or holding o a drug product shall be o appropriatedesign* ade!uate si7e* and suitabl" located to acilitate operations or itsintended use and or its cleaning and maintenance#$



:4 0,R :44#KF2a- states that “E!uipment shall be constructed so thatsur aces that contact components* in+process materials* or drug productsshall not be reactive* additive* or absorptive so as to alter the sa et"* identit"*strength* !ualit"* or purit" o the drug product be"ond the o icial or otherestablished re!uirements#$

:4 0,R :44#K 2a- states that “E!uipment and utensils shall be cleaned*maintained* and saniti7ed at appropriate intervals to prevent mal unctions orcontamination that would alter the sa et"* identi "* strength* !ualit"* or purit" o the drug product be"ond the o icial or other establishedre!uirements#$

:4 0,R :44#LC2c- states that “ rug product containers and closures shall beclean and* where indicated b" the nature o the drug* sterili7ed and processed

to remove p"rogenic properties to assure that the" are suitable or theirintended use#$

:4 0,R :44#4K 2a- states that “,or each batch o drug product purporting to be sterile and>or p"rogen+ ree* there shall be appropriate laborator" testing todetermine con ormance to such re!uirements# The test procedures shall bein writing and shall be ollowed#$

Endoto/in contamination o an in%ectable product can occur as a result o poor 03M8 controls# 0ertain patient populations 2e#g#* neonates-* thosereceiving other in%ections concomitantl"* or those administered a parenteralin at"picall" large volumes or doses can be at greater ris) or p"rogenicreaction than anticipated b" the established limits based on bod" weight o anormal health" adult# <uch clinical concerns rein orce the importance oe/ercising appropriate 03M8 controls to prevent generation o endoto/ins#

rug product components* containers* closures* storage time limitations* andmanu acturing e!uipment are among the areas to address in establishingendoto/in control#

Ade!uate cleaning* dr"ing* and storage o e!uipment will control bioburdenand prevent contribution o endoto/in load# E!uipment should be designedto be easil" assembled and disassembled* cleaned* saniti7ed* and>orsterili7ed# I ade!uate procedures are not emplo"ed* endoto/ins can becontributed b" both upstream and downstream processing e!uipment#



Sterilizing-grade filters and moist heat sterilization have notbeen shown to be effective in removing endotoxin.Endotoxin on equipment surfaces can be inactivated by high-temperature dry heat, or removed from equipment surfaces

by cleaning procedures. Some clean-in-place proceduresemploy initial rinses with appropriate high purity waterand/or a cleaning agent e.g., acid, base, surfactant!,followed by final rinses with heated "#$. Equipment shouldbe dried following cleaning, unless the equipment proceedsimmediately to the sterilization step.

Endoto/in 2E# coli 9446&H45-

09NTR9@ <TAN AR EN 9T9 IN 20<E-0ontrol <tandard Endoto/in 20<E- ma" be used to prepare controls or the@imulus Ameboc"te @"sate 2@A@- test or or oven dep"rogenation studies#<tore at :+ o0 be ore reconstitution# irections or use in ovendep"rogenation studies are on the reverse side o this sheet# The vials ma"appear to be empt"* but on close e/amination* a ine web o endoto/in ma" be visible#

MATE-IALS:• 0ontrol <tandard Endoto/in 20<E-* 5#F OPg>vial* 2catalog QE555F-#• @A@ Reagent Dater 2@RD-# Use sterile water or in%ection or

irrigation 2no bacteriostat- or water certi ied as an @RD 2see l"sate pac)age insert-#

• F ml sterile disposable pipette#• 8ara ilm 2American National 0an-#• ilution tubes 2glass tubes dep"rogenated b" dr" heat incubation or

sterile* pol"st"rene disposables-#

P-O,EDU-E:Remove the metal seal rom the vial and asepticall" remove thestopper#



Add @RD to the vial# Recommended reconstitution volume is F ml*however* alternate volumes ma" be used to achieve desiredconcentration o stoc) solution# a# To reconstitute with a pipette* brea) the vacuum b" li ting the stopper %ust enough to allow air toenter* remove the stopper and add @RD# <eal the vial with 8ara ilm#

Vorte/ vigorousl" or one minute* at F+45 minute intervals over a65+K5 minute period at room temperature#

<tore reconstituted 0<E at :+ o0 or not more than our wee)s# onot ree7e 0<E#

Vorte/ the 0<E or at least 65 seconds immediatel" be ore ma)ingthe irst dilution and then ma)e appropriate dilutions to achievedesired concentrations# The dilutions ma" be initiated with threeserial ten old dilutions o the stoc) concentration 2455 ng>ml whenreconstituted with F ml-# <erial two old dilutions ma" then be madeto brac)et the sensitivit" o the @A@ or ma)e dilutions appropriate

or the turbidimetric method# Vorte/ between dilutions#

N9TE& Vials o 0<E appear empt"# Upon close e/amination* "ou ma"see a ver" ine web o endoto/in present in each vial# 0ontactAssociates o 0ape 0od* Inc# i "ou have an" !uestions about the

reconstitution and use o 0ontrol <tandard Endoto/in#

INST-U,TIONS .O- USE IN T4E VALIDATION O.DEPY-O?ENATION:Two methods are recommended or using 0ontrol <tandard Endoto/in20<E-* catalog numbers E555F and E54:F* or monitoring dep"rogenation procedures# These are A- irect 2dr"- method* or

1- Indirect 2reconstituted and dispensed-#

Met'od A



4- Remove the label and closure rom each vial and cover the vials with adouble la"er o aluminum oil#

:- Retain a minimum o two vials or use as positive controls#6- 8lace the challenge vials in the oven load to be used or the validation#C- At the end o the dep"rogenation process* collect the vials or testing#F- Reconstitute processed and control vials o 0<E according to the

procedure on the reverse side o this sheet#K- Test all vials as un)nowns according to the pac)age insert included with

the l"sate#- 0alculate the reduction in endoto/in between the control vials and the processed vials 2mean measured concentration in control vials divided b" the mean measured concentration in process vials-#

I the value is 4555 or greater* then the oven has achieved a 6+log or greaterreduction#

Met'od B

4- Reconstitute a vial according to the procedure on the reverse side othis sheet#

:- Add small ali!uots or dilutions o the 0<E to material to bedep"rogenated# Add an amount su icient to determine at least three logremovals# Ta)e into account an" dilution involved to recover addedendoto/in and an" loss due to non+recoverable adsorption to the vessel#Include at least two vessels as recover" controls#

6- Run material through the dep"rogenation procedure#C- Recover 0<E rom materials using a minimum amount o @A@ reagent

water 2@RD-#F- Test with @A@ as above#K- 0alculate the reduction in endoto/in as indicated in step above#

A PROJECT on Validation of Sterile Product

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Transcript of A PROJECT on Validation of Sterile Product