可刪除復(fù)制PSCCV清潔驗(yàn)證

Cleaning

Validation清潔驗(yàn)證Charles

M.

Heldebrant,

Ph.D.PSC

AsiaFDA

Requires

Cleaning

ValidationFDA要求清潔驗(yàn)證21USC351(a)(2)(B)...adrug......shallbe

deemed

adulterated...21

USC

351(a)(2)(B)…一個(gè)藥物…應(yīng)被認(rèn)為是劣藥…21

CFR

211.67

Equipment

cleaning

andmaintenance.21

CFR

211.67設(shè)備清潔和維修Equipmentandutensilsshallbecleaned,maintained,and,asappropriateforthenatureofthedrug,sanitizedand/orsterilizedatappropriaintervalstopreventmalfunctionsorcontaminatiothatwouldalterthesafety,identity,strength,qorpurityofthedrugproductbeyondtheofficialootherestablishedrequirements.設(shè)備和器具應(yīng)在合時(shí)的時(shí)間間隔內(nèi)已清潔、維修、和（若適宜藥物性質(zhì)）消毒和/或滅菌,以預(yù)防功能錯(cuò)誤或污染（否則那將改變藥品的安全、成分特性、規(guī)格、質(zhì)量或純度,超出官方或其它已建立的要求）。21CFR

211.67(a)Writtenproceduresshallbeestablishedandfollowedforcleaningandmaintenanceofequipment,includingutensils,usedinthemanufacture,processing,packing,orholdingofadrugproduct.Theseproceduresshallinclude,butarenotnecessarilylimitedto,thefollowing:應(yīng)建和遵循（用于生產(chǎn)、加工、包裝、或置存藥品的）設(shè)備（包括器具）的清潔和維修書面規(guī)程。這些規(guī)程應(yīng)包括但不限于以下:21CFR

211.67(b)Assignmentofresponsibilityforcleaningandmaintainingequipment;Maintenanceandcleaningschedules,includingwhereappropriate,sanitizingschedules;清潔和維修設(shè)備的職責(zé)分配；維修和清潔計(jì)劃,包括（若合適）消毒計(jì)劃；21CFR

211.67(b)(1)-(2)(3)Adescriptioninsufficientdetailofthemethoequipment,andmaterialsusedincleaningandmaintenanceoperations,andthemethodsofdisassemblingandreassemblingequipmentasnecessarytoassurepropercleaningandmaintenance;（3）以足夠細(xì)節(jié)描述用于清潔和維修操作的方法、設(shè)備、和物品,以及（必要的）拆卸和重裝設(shè)備的方法,以確保合適清潔和維修。21CFR

211.67(b)(3)Removalorobliterationofpreviousbatchidentification;Protectionofcleanequipmentfromcontaminationpriortouse;Inspectionofequipmentforcleanlinessimmediatelybeforeuse.除去或消除上批生產(chǎn)識(shí)別；保護(hù)清潔設(shè)備,在使用前免受污染；在馬上使用設(shè)備前,檢查設(shè)備的清潔情況。21CFR

211.67(b)(4)-(6)Recordsshallbekeptofmaintenance,cleaning,sanitizing,andinspectionasspecifiedin211.18and211.182.記錄應(yīng)保留維修、清潔、消毒、和檢查內(nèi)容,如211.180和211.182所述。21CFR

211.67(c)Guide

to

Evaluation

of

Sterile

Process

Inspecti評(píng)價(jià)無菌工藝檢查指南FDAProgram7356.002AFacilityCleaning/Disinfection設(shè)施清潔/消毒Aretherewrittenproceduresdescribingthecleanup,sanitizing/sterilizationofdrugproductionequipmentandutensils?是否有書面規(guī)程，描述清潔、消毒/滅菌藥品生產(chǎn)設(shè)備和器具？Weretheseproceduresfollowedfortheequipmentandutensilsusedtomanufacturetheselecteddrugproduct?是否遵循設(shè)備和器具規(guī)程(規(guī)程用于生產(chǎn)所選擇的藥品)？Cleaning

Validation

Master

Plan清潔驗(yàn)證主計(jì)劃Scope范圍Definitions定義

Responsibilities職責(zé)

Validation

Approach驗(yàn)證方法Cleaning

Validation

Master

Plan清潔驗(yàn)證主計(jì)劃Test

Methods測(cè)試方法Classification

of

Formulations

and

Equipment制劑和設(shè)備的分類Validation

Plan驗(yàn)證計(jì)劃Scope范圍ThisValidationMasterPlanincludesallcleaningproceduresforallequipmentusedforthemanufactureofanyformulationatthe.....facility.此驗(yàn)證主計(jì)劃包括（用于在…廠施生產(chǎn)任何制劑）的所有設(shè)備的所有清潔規(guī)程。Definitions定義What

do

you

mean

by

the

words:下列單詞的意義:Soil臟物

Clean清潔Sanitized已消毒

Sterile無菌

Residue

Free無殘留Maximum

Allowable

Residue最大可允許殘留Soil臟物Anyproduct,ingredientorexcipient任何產(chǎn)品、活性成分或輔料Clean清潔Freefromthepreviousproduct,anycleaningagentorsurfacechangesthatcouldaffecttheproductanywhereintheequipment,evenwhereyoucan’tsee!在設(shè)備上的任何地方，沒有（可影響產(chǎn)品的）先前的產(chǎn)品、任何清潔劑或表面改變，即使您看不見！Sanitized/Sterile已消毒/無菌Not

More

Than

X/No

Viable

Organisms不超過X(一些數(shù)目)/No(沒有)可見微生物Residue-Free無殘留Free

from

any

residue沒有任何殘留Pyrogen-Free無熱原Free

from

any

pyrogen沒有任何熱原Maximum

Allowable

Residue最大可允許殘留Alimitforthemaximumamountofresidueallowedinasampletakenfromthecleanequipment.為一個(gè)限度,指在清潔設(shè)備上一個(gè)取樣樣品中,允許的最大量殘留Thevalueiscalculatedfromavailabletoxicitydatsamplesize,drugdoseandequipmentsurfacearea該值從可獲得的毒性資料、取樣大小、用藥劑量和設(shè)備表面積中計(jì)算MAR

SpreadsheetMAR計(jì)算表Maximum

Allowable

Residue最大可允許殘留IftheMARcalculatedfromtoxicityistoohigh,usanarbitraryvalue,suchas10ppmperswab.如果從毒性數(shù)據(jù)算出的MAR過大,使用一個(gè)主觀的值,如每次擦拭10ppm。JustifyyourMARselectionineachCleaningValidationProtocol在每個(gè)清潔驗(yàn)證方案中,針對(duì)您選擇的MAR,說明理由Responsibilities職責(zé)Trained

Operations

PersonnelPrepare

Protocols,

Execute

Studies,

Prepare

Report已培訓(xùn)的操作人員準(zhǔn)備方案、執(zhí)行試驗(yàn)、準(zhǔn)備報(bào)告Trained

Quality

PersonnelReview

and

Approval

of

Protocols

and

Reports已培訓(xùn)的質(zhì)量人員審核和批準(zhǔn)方案和報(bào)告Responsibilities職責(zé)ManagementProvide

Resources

and

Oversight管理層提供資源和監(jiān)管Validation

Approach驗(yàn)證方法Validation

of

Cleaning

at

Worst-Case

Conditions在最壞條件下清潔驗(yàn)證Maximum

Soil

Level最大臟物水平

Maximum

Dirty

Hold

Time最大臟物保持時(shí)間

Maximum

Clean

Hold

Time最大清潔保持時(shí)間Validation

Approach驗(yàn)證方法Validation

of

Cleaning

at

Worst-Case

Conditions在最壞條件下清潔驗(yàn)證Minimum

Cleaning

Cycles最小清潔周期

Minimum

Sanitization

Cycle最小滅菌周期Validation

Approach驗(yàn)證方法HowManyRuns?(3ConsecutivePassingRuns)作多少次？（連續(xù)3次通過）ReleaseofEquipmentAfterCleaningValidation清潔驗(yàn)證后放行設(shè)備Validation

Approach驗(yàn)證方法Cleaning

Validation

of

a

New

Formulation新制劑的清潔驗(yàn)證Cleaning

Validation

of

New

Equipment新設(shè)備的清潔驗(yàn)證Shelf-Life

of

Clean

Equipment清潔設(shè)備的生命周期Validation

Approach驗(yàn)證方法DeviationorCAPAEvaluationofCleaning偏差或CAPA評(píng)估WhattoDoAfterFailureofCleaningValidationRuns?出現(xiàn)清潔驗(yàn)證不合格次后怎么辦？Validation

Approach驗(yàn)證方法Single

Use

Materials單次使用的物料Periodic

Revalidation周期性再驗(yàn)證

Review審核Test

Methods測(cè)試方法Doyouclaimthatcleanedequipmentis您是否聲稱已清潔的設(shè)備是Sanitized?已消毒？Sterile?無菌？Pyrogen-free?無熱原？Test

Methods測(cè)試方法Visual/MachineInspection視覺/機(jī)器檢查Visual/InstrumentInspectionofCleanedEquipment,e.g.,Surfacereflectance視覺/儀器檢查已清潔的設(shè)備,如表面折射SwabSamples擦拭樣品Takenfromthecleanedsurfacewithawipe,e.g.,ChemicalresidueorMicrobialresidue用抹布從已清潔的設(shè)備上取樣,如化學(xué)殘留或微生物殘留Test

Methods測(cè)試方法RinseSamples淋洗樣品Rinsecollectedfromthecleanedequipment,e.g.,TotalOrganicCarbon,Conductivity,pH,ChemicalorMicrobialResidue從已清潔的設(shè)備的淋洗收集,如總有機(jī)碳、電導(dǎo)率、pH、化學(xué)或微生物殘留Test

Methods測(cè)試方法Write

SOPs編寫SOPQualify

Specialized

Equipment確認(rèn)專門設(shè)備Train

Personnel培訓(xùn)人員Test

Methods測(cè)試方法Validate

analytical

methods

to

ICH

standards“...suitable

for

their

intended

use.”根據(jù)IC標(biāo)準(zhǔn),驗(yàn)證分析方法-“…適合于預(yù)期的用途”Validate

Recovery

for

All

Sampling

Methods對(duì)于所有取樣方法,驗(yàn)證回收率Classification

of

Formulations制劑分類Classify

similar

formulations

into

classes將類似制劑分成同類Validate

one

member

of

the

class

to

represent

allmembers,

or

validate

several

members

of

the

class

toprovide

at

least

3

consecutive

passing

runs.驗(yàn)證同類中的一個(gè)成員以代表所有成員,或驗(yàn)證同類中的幾個(gè)成員,并提供至少連續(xù)3個(gè)合格次數(shù)試驗(yàn)Classification

of

Equipment設(shè)備分類Classify

similar

equipment

into

classes將類似設(shè)備分成同類Validate

one

member

of

the

class

to

represent

allmembers,

or

validate

several

members

of

the

class

toprovide

at

least

3

consecutive

passing

runs.驗(yàn)證同類中的一個(gè)成員以代表所有成員,或驗(yàn)證同類中的幾個(gè)成員,并提供至少連續(xù)3個(gè)合格次數(shù)試驗(yàn)Classify

equipment

used

and

cleaned

together

intoa

single

class分類一起使用和清潔的設(shè)備為一個(gè)單類Validate

the

entire

class

comprised

of

all

thevarious

pieces

of

equipment

at

one

time.一次驗(yàn)證包含所有不同設(shè)備的整個(gè)類別Classification

of

Equipment設(shè)備分類Validation

Plan驗(yàn)證計(jì)劃Develop

Cleaning

Processes開發(fā)清潔流程Clean-in-Place

(CIP)在線清潔Clean-out-of-Place

(COP)離線清潔Facility

(Walls,Floor,Ceiling,Ducts,etc.)設(shè)施(墻,地,天花板,管道等)Develop

Cleaning

Processes開發(fā)清潔流程Identify

what

to

clean識(shí)別清潔什么What

equipment

to

use

for

cleaning用什么設(shè)備清潔What

materials

to

use

to

clean

and

rinse用什么物品清潔和淋洗Develop

Cleaning

Processes開發(fā)清潔流程N(yùn)ooks

and

Crannies小而隱秘的地方Forward-flow

and

Retrograde-flow正流和反流Can

the

Cleaning

Agent

Get

to

the

Dirt?清潔試劑會(huì)觸及臟物嗎?Cleaning

Process

Design

Data清潔流程設(shè)計(jì)數(shù)據(jù)Lower

Limit下限Upper

Limit上限If

there

is

no

cleaning

process

design

data,

evaluate

theprocess

at

the

lower

and

upper

process

limits

for

the

keysteps

in

the

cleaning

process.如果沒有清潔流程設(shè)計(jì)數(shù)據(jù),針對(duì)清潔流程的關(guān)鍵步驟,在上下流程限度評(píng)價(jià)流程Set

cleaning

process

ranges

based

on

theprocess

requirements

and

on

the

capability

ofequipment

to

achieve

and

maintain

processcontrol基于流程要求和設(shè)備性能產(chǎn)能和保持流程控制的能力,設(shè)清潔流程范圍Do

not

set

tight

cleaning

process

rangesunless

absolutely

necessary除非絕對(duì)必要,不要設(shè)置太緊的清潔流程范圍Cleaning

Process

Ranges清潔流程范圍Specifications標(biāo)準(zhǔn)Establish

specifications

for

the

cleaningprocess

and

clean

equipment為清潔流程和清潔設(shè)備,建立標(biāo)準(zhǔn)The

specification

is

how

you

prove

that

theequipment

meets

your

definition

of

clean標(biāo)準(zhǔn)是您如何證明設(shè)備符合您定義的清潔Specifications標(biāo)準(zhǔn)

Make

Specifications

SMART建立標(biāo)準(zhǔn)SMARTSpecific具體Measurable可測(cè)量Attainable可達(dá)到Reasonable合理Timely及時(shí)Specifications標(biāo)準(zhǔn)Do

not

create

unnecessary

specifications不要建立不必要的標(biāo)準(zhǔn)Specifications

become

the

acceptancecriteriainthecleaningvalidationprotocol!清潔驗(yàn)證方案中，標(biāo)準(zhǔn)變成接收標(biāo)準(zhǔn)??！SOPsThe

SOPs

provide

the

instructions

to

operatethecleaningequipmentandcleantheequipment.SOP提供指令,以操作清潔設(shè)備、和清潔設(shè)備All

SOPs

should

be

in

final

form

for

thecleaningvalidation用于驗(yàn)證時(shí),所有SOP應(yīng)是最終版Cleaning

Validation

Plan清潔驗(yàn)證計(jì)劃Equipment

List設(shè)備清單Timeline時(shí)間表Resources資源Cleaning

Validation

Protocol清潔驗(yàn)證計(jì)劃The

written,

approved

documentdescribinghowtodothecleaningvalidationstudy書面、批準(zhǔn)的文件,描述如何做清潔驗(yàn)證試驗(yàn)A

controlled

document一個(gè)控制文件Cleaning

Validation

Protocol清潔驗(yàn)證方案SamplingPlan取樣計(jì)劃Wheretotakethesamples?在哪里取樣？Whattosamples?取什么樣？Whentotakethesamples?何時(shí)取樣？Howtotakethesamples?如何取樣？Whowilltakethesamples?誰取樣？Cleaning

Validation

Protocol清潔驗(yàn)證方案Acceptance

Criteria

for

Each

CleaningValidation

Run每次清潔驗(yàn)證的接收標(biāo)準(zhǔn)Acceptance

Criteria

to

Validate

theCleaningProcess(e.g.,3consecutivepassingvalidationruns)驗(yàn)證清潔流程的接收標(biāo)準(zhǔn)（如,連續(xù)三次驗(yàn)證通過）Cleaning

Validation

Protocol清潔驗(yàn)證方案The

protocol

and

any

amendments

totheprotocolarereviewedandapprovedby方案和方案增補(bǔ)由以下部門審核和批準(zhǔn):Operations生產(chǎn)運(yùn)營Other

key

departments其它關(guān)鍵部門Quality

Assurance質(zhì)量保證Cleaning

Validation

Protocol清潔驗(yàn)證方案Use

a

standard

format使用標(biāo)準(zhǔn)格式Keep

the

original

approved

document

indocument

control保持原先批準(zhǔn)的文件在文件控制狀態(tài)Issue

an

execution

copy

for

eachvalidationrun對(duì)于每次驗(yàn)證,發(fā)行執(zhí)行版Execute

the

Study試驗(yàn)執(zhí)行Schedule

the

runs計(jì)劃驗(yàn)證次數(shù)Perform

the

study

according

to

theapprovedprotocol根據(jù)批準(zhǔn)的方案,執(zhí)行試驗(yàn)Document

any

deviations記錄任何偏差Record

any

comments記錄任何評(píng)論Execute

the

Study執(zhí)行試驗(yàn)Collect

and

maintain

all

raw

data收集和保留所有原始數(shù)據(jù)Follow

good

documentation

practices遵循GDPPromptly

investigate

and

resolve

anydeviations快速調(diào)查和解決任何偏差Cleaning

Validation

Report清潔驗(yàn)證報(bào)告Collect

the

raw

data收集原始數(shù)據(jù)Tabulate

the

raw

data制表整理原始數(shù)據(jù)Analyze

the

data分析數(shù)據(jù)Verify

that

all

runs

meet

all

acceptancecriteria證實(shí)所有次數(shù)符合所有接收標(biāo)準(zhǔn)Cleaning

Validation

Report清潔驗(yàn)證報(bào)告Prepare

the

validation

report

presenting

thedataandconclusions準(zhǔn)備驗(yàn)證報(bào)告,報(bào)告展示數(shù)據(jù)和結(jié)論數(shù)據(jù)或打印件的復(fù)制件Use

a

standard

format使用標(biāo)準(zhǔn)格式Attach

copies

of

raw

data

or

printouts附上原始Discuss

and

resolve

any

“circumstancesaffecting

the

quality

or

integrity

of

the

data”討論和解決任何“影響質(zhì)量或數(shù)據(jù)完整性的情況”Cleaning

Validation

Report清潔驗(yàn)證報(bào)告The

report

or

any

amendment

to

thereport

are

reviewed

and

approved

by報(bào)告或任何報(bào)告增補(bǔ)由以下部門審核和批準(zhǔn)Operations生產(chǎn)運(yùn)營Other

key

departments其它關(guān)鍵部門Quality

Assurance質(zhì)量保證The

approved

report

or

any

amendmentis

a

controlled

document批準(zhǔn)的報(bào)告或任何增補(bǔ)是控制文件Cleaning

Validation

Report清潔驗(yàn)證報(bào)告Keep

the

original

approved

document

andassociated

raw

data

in

document

control

orarchives保持原先批準(zhǔn)的文件和相關(guān)原始數(shù)據(jù)在文件控制或文件檔案中The

cleaning

validation

report

is

the

writtenproof

that

the

cleaning

process

is

validated.清潔驗(yàn)證報(bào)告是清潔流程已驗(yàn)證的書面證明Update

the

cleaning

validation

master

plan更新清潔驗(yàn)證主計(jì)劃Cleaning

Process

Revalidation清潔流程再驗(yàn)證Consider

during

the

change

contr