中國食品藥品檢定研究院8. 無菌藥品生產與微生物監(jiān)控

Sterility

AssuranceofInjectionsand

In-ProcessControl

and

MonitoringofMicrobialContamination注射劑的無菌保證與微生物過程監(jiān)控潘友文2019年11月8日Agenda?

Sterility

assuranceofterminallysterilizedproducts?

Sterility

assuranceofaseptically

filled

products?

Biologicsprocessing?

Rapid

crobiologicaltest

methodsAgenda?

Sterility

assuranceofterminallysterilizedproducts?

Sterility

assuranceofaseptically

filled

products?

Biologicsprocessing?

Rapid

crobiologicaltest

methodsSterility

Assurance

of

Terminally

SterilizedProducts?

Probability

ofasingleviablemicroorganismcurring

on

anitem

aftersterilization

islessthan10

Thatistheprobability

ofnon-sterile

unit(PNSU)islessth10-6.Figure

3.1–1

MicroSurvivor

Curve

Acc

ding

tothe

Semilogarithmic

ModelPDA

TR#1.Process

flow

of

terminally

sterilized

liquidproductsPDA

TR#30Parametric

Release

of

Terminally

SterilizedProductsLoad

processingconfirmationBulkformulationBioburdente

tReview

critical

andkey

parametersin

thesterilization

cycleFilterFillReleaseYesNoparametersmeet?BioburdentestSterilizeLoadLoadreleasedto

marketredAgenda?

Sterility

assuranceofterminallysterilizedproducts?

Sterility

assuranceofaseptically

filled

products?

Biologicsprocessing?

Rapid

crobiologicaltest

methodsSterility

Assurance

of

Aseptically

FilledProducts?

Key

factors?

Sterile

environment

whe

esterile

productisexposed?

Sterility

and

integrityofcontainerandclosures?

Sterility

and

integrityofsterile

fil

ers?

Sterility

assuranceisensuredby?

Highqualityofraw

materials?

Consistently

controlledsterile

environment?

Validated

processesEvolution

of

Sterile

Environment

forAseptically

Filled

ProductsConventionalA+BsettingSterilityassurance

issigni

antlyincreasedRestricted

AccessBarrierIsolatorwithglovesIsolatorwithoutglovesIsolator

without

GlovesIsolator

without

GlovesIsolator

without

GlovesAgenda?

Sterility

assuranceofterminallysterilizedproducts?

Sterility

assuranceofaseptically

filled

products?

Biologicsprocessing?

Rapid

crobiologicaltest

methods由CHO細胞表達的生物原料生產流程上游育種培養(yǎng)生產培養(yǎng)轉種培養(yǎng)收獲超濾和透析過濾層

多步)稀釋和定性下游除菌過濾至貯罐除病毒過濾冷凍/貯存/運輸細胞培養(yǎng)流程及微生物檢測轉種培養(yǎng)育種培養(yǎng)生產培養(yǎng)細胞種子冷凍管10mL收獲10mL10L20L80L400L2000L12000L無菌病毒含菌量病毒細胞生長速度和細胞活性支原體支原體生產培養(yǎng)收

獲:

離心和粗濾離心收獲/澄清收獲后的細胞培養(yǎng)液深層濾器生物反應器過濾后采樣點過濾前采樣點離心機層析（多步）集液罐過濾器HCCF和緩沖液層析柱過濾后采樣點過濾前采樣點除病毒過濾(常規(guī)流)過濾后采樣點進料罐除病毒過預過濾器濾器集液罐過濾前采樣點超濾/滲濾進料和緩沖液集液罐循環(huán)罐切向流超濾/滲濾系統(tǒng)過濾后采樣點過濾前采樣點微生物控制策略?

生產系統(tǒng)的清潔、消毒/滅菌?

封閉管路系統(tǒng)?

控制性生產環(huán)境?

微生物和內毒素檢測?

兩級

控?

警戒限度/糾偏限度?

糾偏限度/合格標準?

風險管理?

風險評估風險評估?

生產設施的設計（人流、物流和廢物流）?

設備

（清潔消毒設計、組裝、清潔、消毒規(guī)程）?

工藝（開放還是封閉、微生物促生長條件評估、貯存時間評估）?

物料（原料、重復用樹脂和滲濾膜的保存）?

公用系統(tǒng)（空

、環(huán)境監(jiān)控、水系統(tǒng)、氣體系統(tǒng)等）?

工作人員（進出、衛(wèi)生和更衣規(guī)范）Agenda?

Sterility

assuranceofterminallysterilizedproducts?

Sterility

assuranceofaseptically

filled

products?

Biologicsprocessing?

Rapid

crobiologicaltest

methodsPrinciples

of

RMM/AMM

TechnologiesMetabolites(CO

,acids)Presenceofnucleicacids(PCR,sequencing,

hybridization

etc)2(pH,

CO

colorindicator)2Particularproteins,peptidesOuter

membraneInnermem

raneEnzyme

presenceivity(Flu

ogenicsubstratese.g.

CFDA)&CO2,H+RNADNAHousekeepingenzymese.g.esteraseATPLipidsCellular

energy(Bioluminescence)Autofluorescentsubstance(Riboflavin,NADHetc)Membintegrity(Impermeant/permeant

DNAorlipidsfluorescent

stains)25Rapid

Technology

Used

in

SterilityGrowthDirectBact/ALERTCelsis

Advance?SystemM

hodGrowthbased1-5days~30/daySmall

volumeTime

toresultThroughputSample

size/typeLOD~30/day120/hourRandomFilterabl

samples1CF

aftergrowth1CFU

afterenrichmentLowsample

volume,hard

todetect

slowgrowerBig,supplies

areexpensiveLimitationHardtodetectmoldRapid

Technology

Used

in

BioburdenGrowthDirectScanRDI?SystemM

hodGrowthbased1-5daysTime

toresultThroughputSample

size/typeLOD~50/day30/dayFilterable

samples

(smallmembrane)1cellFilte

ble

samples1CFU

aftergrowthFalse

positive/negative,

Destructive,highcapital

investmentLimitationBig,supplies

are

exp

nsiveRapid

Technology

Used

in

IDMicroSeq?MALDIBiotyperSystemProbes16S

rDNAProtein,peptidesMALDI-TOFmassspectrometryTechniquePCR

SequencingTime

toresultThroughput4-5hours80/day2-3min30-60/hourCellsfromcolony

orliquidsampleSample

typeFeaturesCellsfromacolonyEasy

torate,costFast,butlimiteddatabase28effectiveRapid

Technology

Used

in

BETEndosafe?nexgen-MCS?Endosafe?nexgen-PTS?SystemProbesBuiltinstandardTechniqueKineticchromo15

minTime

tores

tThroughput20/day100/daySample

typeFeaturesLiquidsy

tooperate,fast,morecostRapid

Technology

Used

in

EMViableairborne

particulates

–Automaticfluorescence?

Realtimemonitoring

ofairborneviableandnonviableparticulates?

Limitation–

Difficultyinvalidation–

Highpotentialoffalse

positivesdue

to

nonviable

autofluoresentparticulatesinairReferences??FDAGuidanceforIndustry:Submission

ofDocumentation

ofApplicationsfor

Parametric

Re

aseofHumanandVeterinaryDrugProductsTerm

allySterilizedbyMoist

HeatProcesses(2010)

/regulatory-information/search-fda-guidance-documents/submisson-documentation-applicat

ns-parametric-release-human-and-veter

ary-drug-productsFDACompliance

Policy

Guide:

Sec.490.200

Param

tric

Release-ParenteralDrugProducts

TerminallySterilizedbyMoist

Heat(2012).

h

ps:///regulatory-information/search-parenteral-drug-products-terminally-sterilized-moist-heatguidance-documents/cpg-sec-490200-parametric-release-??echnicalReportNo.30.Revsed2012.

Parametric

releaseofpharmaceuticalandmedicaldeviceproduc

s

terminallysterilizedoistheat.

ParenteralDrug

soci

tion.

MD.USA.MarlaStevens-Riley.2015.

Parame

ic

Release:ARegulatoryPerspectiv

.AmericanPharmaceut