質(zhì)量控制和保證中英版

7

QualityAssuranceandControl質(zhì)量包管和質(zhì)量控制

MICHAELC.VANDERZWAN

PharmaceuticalTechnical,RochePharmaceuticals,Basel,Switzerland

I.Introduction介紹235

ILDefiningandAssuringtheQualityoftheActivePharmaceuticalIngredient

原料藥質(zhì)量的界說和包管240

III.TheRegulationsforQuality質(zhì)量羈系245

IV.TheQualityControlandQualityAssuranceDepartment

質(zhì)量控制和質(zhì)量包管273

AppendixA附錄280

目錄

I.INTRODUCTION介紹4

A.TheProduct產(chǎn)物4

B.TheProcess工藝5

C.TheFacilities設(shè)備5

D.ThePeople人員6

E.TheQualityManagementDepartment質(zhì)量治理部分6

F.TheRegulatoryAuthorities羈系機(jī)構(gòu)7

G.TheRegulations規(guī)矩8

II.DEFININGANDASSURINGTHEQUALITYOFTHEACTIVE

PHARMACEUTICALINGREDIENT原料藥質(zhì)量的界說和質(zhì)量包管9

A.DefiningtheAPIQuality原料藥質(zhì)量的界定10

B.TestingtheAPIforItsDefinedAttributes原料藥界說的屬性測(cè)試11

C.DesigningQualityintotheProcess工藝中的質(zhì)量設(shè)計(jì)12

D.ValidationoftheProcess工藝驗(yàn)證13

E.Reality實(shí)際15

III.THEREGULATIONSFORQUALITY質(zhì)量規(guī)矩錯(cuò)誤!未定義書簽。

Introduction:TheEmergenceofSpecificRegulationsforAPIs導(dǎo)言：API具體規(guī)

矩的出現(xiàn)錯(cuò)誤!未定義書簽。

1.ICHQ7ASectionI:"Introduction”第一部分：簡(jiǎn)介...錯(cuò)誤!未定義書簽。

2.ICHQ7ASection2:"QualityManagemen亡第二部分質(zhì)量治理.錯(cuò)誤!未定義

書簽。

3.ICHQ7ASection3:"Personnel”第三部分人員錯(cuò)誤!未定義書簽。

4.ICHQ7ASection4:"BuildingsandFacilities”第四部分廠房和設(shè)施錯(cuò)誤!未定

義書簽。

5.ICHQ7ASection5:"ProcessEquipmen亡第五部分工藝設(shè)備錯(cuò)誤!未定義書

簽。

6.ICHQ7ASection6:"DocumentsandRecords”第六部分文件和記錄..錯(cuò)誤!

未定義書簽。

7.ICHQ7ASection7:"MaterialsManagemen亡第7部分物料治理33

8.ICHQ7ASection8:"ProductionandIn-ProcessControls”第8部分產(chǎn)物和歷

程控制36

9.ICHQ7ASection9:"PackagingandIdentificationLabelingofAPIsand

Intermediates^第9部分原料藥和中間體的包裝和標(biāo)識(shí)標(biāo)簽39

10.ICHQ7ASection10:"StorageandDistribution”儲(chǔ)存和發(fā)運(yùn)41

11.ICHQ7ASection11:"LaboratoryControls^^第11部分實(shí)驗(yàn)室控制…42

12.ICHQ7ASection12:“Validation”42

13.ICHQ7ASection13:“ChangeControl”第13部分變動(dòng)控制47

14.ICHQ7ASection14:44RejectionandRe-UseofMaterials”第14部分物料

的拒收和再用49

15.ICHQ7ASection15:“ComplaintsandRecalls”第15部分投訴與召回.52

16.ICHQ7ASection16“ContractManufacturers(IncludingLaboratories)”

第16部分協(xié)議制造商（包羅實(shí)驗(yàn)室）54

IV.THEQUALITYCONTROLANDQUALITYASSURANCE

DEPARTMENT質(zhì)量控制和質(zhì)量包管部54

I.INTRODUCTION介紹

Thequalityofactivepharmaceuticalingredients(APIs)isdefinedasmeetingthe

appropriatespecificationsfbrtheAPIandbeingproducedinafacilitycompliantwith

ICHguidelines"Q7A''andFDA'scurrentgoodmanufacturingpractices(cGMPs)

regulations.MostcountriesregulatethemanufactureofAPIs.Theseregulations

requireatotalsystemsapproachtoassuringanAPIhastheappropriatelevelof

quality.Allcomponentsinthissystemmustbeproperlydesigned,validated,

maintained,andoperatedtoallowthemanufacturertoassuretheAPIconsistently

meetsqualityrequirements.Thegeneralcomponentsofthesystemaretheprocess,

facilities,andthepeople.Thischapterconcernsthesecomponents,aswellasthe

productqualityitself,theregulations,andthequalitymanagement(QM)department.

活性藥物身分(APIs)的質(zhì)量應(yīng)被界說為切合相應(yīng)的API范例，并且正在建立中

的設(shè)施應(yīng)切合ICH指南Q7A，和FDA現(xiàn)行的動(dòng)態(tài)藥品生產(chǎn)治理范例(cGMP)的規(guī)

定。大多數(shù)國(guó)度對(duì)原料藥的生產(chǎn)制造都有規(guī)定。這些規(guī)矩要求有一個(gè)總的系統(tǒng)要

領(lǐng)來包管API的質(zhì)量在適當(dāng)水平。這個(gè)系統(tǒng)中的所有組件必須經(jīng)過正確的設(shè)計(jì)，

驗(yàn)證，維護(hù)和操縱，以包管束造商的API始終切合質(zhì)量要求。該系統(tǒng)中普遍的組

件包羅工藝歷程、設(shè)施和人員。本章內(nèi)容包羅這些組件，以及產(chǎn)物質(zhì)量自己，規(guī)

矩條例和質(zhì)量治理部(QM)。

A.TheProduct產(chǎn)物

ThequalityofanAPIisdeterminedbytwofactors:itsconformanceto

pre-establishedspecificationsandwhetheritisproducedaccordingtoadocumented

validatedprocessinacGMPcompliantfacility.TheAPImustpossessappropriate

chemicalandphysicalattributestoassurethatitdeliverstheintended

pharmacologicaleffect.Thechemicalattributesdescribetheappropriatepurityand

impuritylimits.Impurityspecificationsareestablishedfromclinicaltoxicological

studiesandarealsobasedonreasonableminimumsexpectedfromregulatory

authoritiesandconsumers.Thephysicalattributesdescribethenecessary

characteristicsforreliablepharmaceuticalprocessingintofinaldosageforms.These

attributesaredeterminedbyempiricalevidencefromformulationtrialstoproduce

uniformandstabledosageformsofadequatebioavailability.

API的質(zhì)量是由兩個(gè)因素決定:是否與預(yù)先創(chuàng)建的標(biāo)準(zhǔn)相一致，是否在切合cGMP

要求的設(shè)施內(nèi)并且憑據(jù)成文的經(jīng)驗(yàn)證的工藝歷程生產(chǎn)出來的。API必須具有適當(dāng)

的化學(xué)和物理屬性，以確保它提供預(yù)期的藥理學(xué)作用?；瘜W(xué)屬性描述了適當(dāng)?shù)募?/p>

度和雜質(zhì)限度。雜質(zhì)范例憑據(jù)臨床毒理學(xué)研究創(chuàng)建，同時(shí)基于從羈系部分和消費(fèi)

者那里得到預(yù)期的公道最低值。物理屬性描述了可靠藥物加工成最終劑型的須要

特征。這些屬性由配方試驗(yàn)的經(jīng)驗(yàn)證據(jù)確定，以生產(chǎn)具有足夠生物利用度、均勻

且穩(wěn)定的劑型。

B.TheProcess工藝

ThequalityoftheAPIisdesignedintothemoleculethroughthedevelopmentofthe

fullmanufacturingprocess,fromthelaboratoryscalesyntheticprocessthroughtoend

product.

API的質(zhì)量通過全面的制造工藝的生長(zhǎng)被設(shè)計(jì)身分子，從實(shí)驗(yàn)室范圍的合成歷程

通向最終產(chǎn)物。

Thesyntheticprocessmustbedesignedtominimizeimpurities,especiallythosethat

provedifficulttoremoveinthelaststep.Thus,througheffectiveprocessdevelopment,

yieldsaremaximized,wasteisminimized,andimpuritiesarenotformed,eliminated,

orcertainlyminimized.Thespecificcontrolsusedbythedevelopmentalchemistto

producethehigh-yield,high-qualityproductmustbedocumented;thisdocumentation

formsthebasisfortheproofofconceptandfbrthevalidationreport.Innearlyall

countriestoday,regulatoryauthoritiesrequiretheAPItobeproducedfroma

documentedprocessthatreliablymeetsallappropriatespecifications.Thiswas

strengthenedbytheissuanceandadoptionoftheInternationalConferenceon

HarmonizationTripartiteGuidelineofQ7A"GoodManufacturingPracticeGuidefor

APIs."TheEuropeanUnion,theJapaneseMinistryofHealthandtheUnitedStates

Food&DrugAdministrationadoptedtheguide.

合成要領(lǐng)必須被設(shè)計(jì)成最小化的雜質(zhì)，尤其是那些證明在最后一個(gè)步調(diào)難以撤除

的。因此，通過有效的工藝開發(fā)、產(chǎn)量最大化、廢棄物最小化、不形成、消除或

最小化雜質(zhì)。所采取的生長(zhǎng)化學(xué)家的具體控制來產(chǎn)生高收益、高品質(zhì)的產(chǎn)物必須

被記錄;本文檔組成了看法證明和驗(yàn)證陳訴的底子。在今天險(xiǎn)些所有的國(guó)度、羈

系部分要求API應(yīng)在切合所有相應(yīng)范例、有記錄的工藝歷程來生產(chǎn)。這方面因?yàn)?/p>

國(guó)際聚會(huì)會(huì)議的三方協(xié)調(diào)指南Q7A“良好生產(chǎn)實(shí)踐指南的API”的刊行和通過得到

了增強(qiáng)。歐盟，日本羈系部分和美國(guó)食品藥品監(jiān)督治理局通過了這個(gè)指南。

C.TheFacilities設(shè)施

ThefacilitiesinwhichAPIsareproducedarealsoaddressedinthischapterbecausea

componentofqualityofanAPIisthatitbeproducedincGMP-compliantfacilities.

ThosecomponentsofthefacilitygovernedbycGMParethereforepartofthischapter.

TheessenceofcGMPforfacilitiesor,forthatmatter,anyaspectofAPImanufacture

isthatthefacilityperformsasdesignedtoassurethequalityoftheproduct.

生產(chǎn)API的設(shè)施在本章節(jié)也進(jìn)行討論，因?yàn)锳PI的質(zhì)量的組成部分是通過cGMP的

標(biāo)準(zhǔn)設(shè)施來生產(chǎn)的。因此，由cGMP統(tǒng)領(lǐng)的設(shè)施的組成部分是本章節(jié)的一部分。

對(duì)付這個(gè)問題，cGMP的設(shè)施或API制造的任何方面的的本質(zhì)是設(shè)施執(zhí)行的設(shè)計(jì),

以包管產(chǎn)物的質(zhì)量。

Further,theperformancecharacteristicmustbedocumented,andmanagementmust

demonstratethefacilitycontinuallyperformsasdesigned.Performancecontrol

monitoring,preventativemaintenance,andcarefullycontrolledandapprovedrepairs

orchangestofacilitycomponentsareallconsideredpartofassuringqualityofAPIs.

別的，性能特點(diǎn)必須記錄，治理必須證明該設(shè)施連續(xù)按設(shè)計(jì)執(zhí)行。性能控制監(jiān)控、

預(yù)防性維護(hù)、精密控制和批準(zhǔn)的設(shè)備部件的維修或變動(dòng)都被認(rèn)為是包管API質(zhì)量

的一部分。

D.ThePeople人員

ThepeoplewhoproducetheAPIareconsideredacriticalpartofthesystemand,as

such,becomepartoftherequirementsforqualityofAPIs.Todotheirjobseffectively

andtoassurequalityoftheAPI,theymustbeproperlytrainedandequipped.

Qualifiedpersonnelmustconductthetraining;theequipmentmustbeofproper

designandfunction.ThesupervisorsofpeoplemanufacturingAPIsmustalsobe

properlytrainedtodotheirjobs.Finally,theremustbeanadequatenumberofpeople

toallowsufficienttimetoperformtheseresponsibilitiesinasatisfactorymanner.

生產(chǎn)API的人員是該系統(tǒng)的一個(gè)重要組成部分，因此，成為API的質(zhì)量要求的

一部分。為了有效地做好本職事情，以確保API的質(zhì)量，就必須進(jìn)行適當(dāng)?shù)呐?/p>

訓(xùn)和裝備。合格人員必須進(jìn)行培訓(xùn);設(shè)備必須有適當(dāng)?shù)脑O(shè)計(jì)和成果。人造API的

羈系人員也必須進(jìn)行適當(dāng)?shù)呐嘤?xùn)來做好本職事情。最后，必須有適當(dāng)?shù)娜藬?shù)，以

便有富裕的時(shí)間、以令人滿意的方法執(zhí)行這些職責(zé)。

E.TheQualityManagementDepartment質(zhì)量治理部分

Asinmostanyothermanufacturingenterprise,thereisaqualitycontrolandora

qualityassurancedepartment.Today,thesedepartmentsareusuallycombinedintoa

QMdepartment.

因?yàn)樵诖蠖鄶?shù)的任何其他制造企業(yè)，有一個(gè)質(zhì)量控制部和/或質(zhì)量包管部。如今，

這些部分通常被歸并成一個(gè)質(zhì)量治理部分。

TheroleoftheQMdepartmenthasalsoadvancedfrom6'check-test-decide99

responsibilitytobeinganequalpartnerwithmanufacturingandengineeringto

manageandimprovethequalityoftheentireprocessandsystem.

質(zhì)量治理部分的腳色也從“查抄、測(cè)試、決定'的職責(zé)變?yōu)榕c制造和工程平等的參

加者來提高全歷程和系統(tǒng)的質(zhì)量。

ForAPIsanddrugproducts,theQMdepartment,throughitsqualityassurancearm,

stillhastheresponsibilityvestedinitbyregulationstoreleaseallproductsforuseand

eventuallytothemarket.AsacomponentofthesystemtoproduceAPIs,theactivities

andresponsibilitiesoftheQMdepartmentarealsoacomponentofproductquality.

MostcGMPsrequirethattheQMdepartmentisresponsibletoreviewandapprove

productionprocedures,andanychangestothem,mostreports,procedures,and

controls,deemednecessarytoassurethequalityoftheprocessandproduct.

對(duì)付原料藥和藥物產(chǎn)物，質(zhì)量治理部分，通過其質(zhì)量包管的手臂，另有賦予的責(zé)

任，通過規(guī)矩來釋放所有產(chǎn)物中使用，并最終推向市場(chǎng)。作為該系統(tǒng)的一個(gè)組成

部分來生產(chǎn)原料藥，運(yùn)動(dòng)和QM部分的職責(zé)是也產(chǎn)物質(zhì)量的一個(gè)組成部分。大多

數(shù)的cGMP要求質(zhì)量治理部分賣力審查和批準(zhǔn)生產(chǎn)的步伐，并且對(duì)它們的變動(dòng)，

大多數(shù)陳訴，步伐和控制，認(rèn)為有須要確保歷程和產(chǎn)物的質(zhì)量。

Finally,theQMdepartmentmusthaveadequatelaboratoryfacilitiesandproperly

trainedandexperiencedpeopletoeffectivelycarryouttheirresponsibilities.

最后，質(zhì)量治理部分必須有足夠的實(shí)驗(yàn)室設(shè)施和適當(dāng)?shù)呐嘤?xùn)，經(jīng)驗(yàn)富厚的人來有

效地履行其職責(zé)。

F.TheRegulatoryAuthorities羈系機(jī)構(gòu)

Healthauthoritiesineverycountryregulatedrugproducts.Inmostcountries,these

regulationsalsoincludeAPIs.ThesecGMPregulationsrequirethatadrugmustmeet

allpredefinedqualityspecificationsandbeproducedfromadocumentedvalidated

process.Further,ifthedrug,orAPI,isnotproducedandcontrolledaccordingtothe

establishedprocess,thenthedrugisconsideredadulterated,andthereforenotfitfor

useorsale.Theregulationsaddresseveryaspectofdrugproductmanufacture,and

essentiallyrequirethattheproducerhasdocumentedevidenceofproofofcontrolover

anyaspectthatmightaffectproductquality.Theregulatorsweredeliberateintheir

useoftheword"current''whenthecGMPswerepromulgated.Thisqualifierenables

theagenciestocontinuouslyrequirethatmanufacturersmaintaintheirfacilitiesand

processesatthestateoftheart,therebyalwaysassuringthepublicthatdrugproducts

areassafeandeffectiveaspossible.

每一個(gè)國(guó)度由衛(wèi)生主管部分管束藥品。在大多數(shù)國(guó)度，這些規(guī)矩還包羅原料藥。

這些的cGMP規(guī)矩要求藥品必須切合所有預(yù)定的質(zhì)量標(biāo)準(zhǔn)，并從記錄驗(yàn)證歷程

中產(chǎn)生的。別的，沒有按已創(chuàng)建的要領(lǐng)制備并控制的藥物或API,則該藥物被認(rèn)

為是摻假，因此不適合使用或出售。該規(guī)矩涉及藥品生產(chǎn)每一個(gè)環(huán)節(jié)，并且根本

上要求生產(chǎn)者記錄控制證明可能影響產(chǎn)物質(zhì)量的任何方面。羈系機(jī)構(gòu)頒布的規(guī)矩

即cGMP,不絕要求制造商維持其設(shè)備和工藝的狀態(tài)，從而包管始終如一的生產(chǎn)

寧靜有效的藥品。

G.TheRegulations規(guī)矩

TheproductionofAPIsisregulatedinmostcountries.TheICH-harmonizedtripartite

guidelineQ7AentitledasGoodManufacturingPracticeGuideforAPIswas

recommendedforadoptionatStep4oftheICHprocessonthe10thofNovember

2000.Thisdocumentwasadoptedbythefollowingagenciesdenotingitswidespread

acceptance:

原料藥的生產(chǎn)在大多數(shù)國(guó)度是受羈系的。良好生產(chǎn)實(shí)踐指南APIICH-三方協(xié)調(diào)指

導(dǎo)Q7A(2000年11月10日)被發(fā)起使用。下列機(jī)構(gòu)體現(xiàn)普遍擔(dān)當(dāng)：

_EuropeanUnion(EU)adoptedbyCPMP,November2000,issuedas

CPMP/ICH/19354)0歐盟采取CPMP,2000年11月，以CPMP/ICH/1935Q0刊行

_JapaneseMHLWadoptedNovember2nd,2001MSBnotificationNO.1200

日本MHLW采取2001年11月2日的MSB通知，第1200期

_UnitedStatesFDApublishedintheFederalRegister,Vol.66,No186,September

25th,2001,pages49028-49029.

美國(guó)FDA頒發(fā)在聯(lián)邦注冊(cè)，第66卷第186期，2001年9月25日，2001年，第

49028-49029頁

Theproductionprocessandalltestsandcontrolsmustbeapprovedbytheregulating

governmentinwhichAPIswillbeused,andthefacilitiesandsystemsinwhichthey

areproducedmustmeetthemanufacturingstandardssetdownbythegoverningbody.

Thus,thequalityofAPIsisbasedontwocomponents:meetingfinalquality

specificationsandbeingproducedaccordingtotheregulated,approvedprocessina

facilitycompliantwiththeappropriatemanufacturingstandards.Itisimportantto

notethatbothcriteriamustbemet:finalspecificationsandcomplianceto

manufacturingstandards.Thesetwocomponentswillbedealtwithseparatelyinthis

chapter.Itisalsoimportanttonotethattheapproachtowardqualitydescribedinthis

chaptershouldapplytoanyAPIregardlessofthecountryinwhichitwillbeusedor

sold,orwhetherornotitwillbearegulateditem.

生產(chǎn)歷程中，所有的測(cè)試和控制必須由政府羈系包羅API,設(shè)施和系統(tǒng)，生產(chǎn)必

須滿足的制造標(biāo)準(zhǔn)。因此，原料藥的質(zhì)量是基于兩部分組成:切合最終質(zhì)量范例，

按規(guī)定的已批準(zhǔn)的工藝在適合的設(shè)施中生產(chǎn)。注意，兩個(gè)標(biāo)準(zhǔn)都必須滿足。這兩

部分將在本章中另行論述。同樣重要的是要注意，在本章中描述的API質(zhì)量適用

于原料藥將在其中使用或出售，不管這個(gè)國(guó)度是否受規(guī)矩管束。

Theapproachtoquality,describedinthischapter,isbasedonsoundscientific

principles,goodQMprinciples,andappliestoanyAPI.Infact,theseprinciplesapply

tothemanufactureofanychemicalthatrequiresahighassuranceofquality.

ThischapterwilldealwiththechemicalsynthesisofAPIs.However,allthe

principlesandregulationsalsoapplytoothermeansofpreparation,suchas

fermentationroutesorextractionfromnaturalsources.

質(zhì)量目標(biāo)，以本章所述，基于公道的科學(xué)原則，良好的質(zhì)量治理原則，適用于任

何API。事實(shí)上，這些原則適用于任何需要高質(zhì)量的化學(xué)品的生產(chǎn)。

本章將涉及原料藥的化學(xué)合成。然而，所有的原則規(guī)定也適用于其它的制備工藝,

如發(fā)酵路線大概從天然提取。

Finally,sinceitisassumedthroughoutthischapterthattheAPIwillbesubjectto

regulatoryrequirements,referencewillbemadetotheregulations.Ifthereaderis

dealingwithanunregulateditem,suchreferencemaybeignored,butthescientific

principlesonwhichtheregulationisbasedshouldbeseriouslyconsidered.

II.DEFININGANDASSURINGTHEQUALITYOFTHEACTIVE

PHARMACEUTICALINGREDIENT原料藥質(zhì)量的界說和質(zhì)量包管

Thissectionofthechapteraddresseshowto:

_definethenecessaryqualityattributes

_testforthem,

_designthemintotheprocess,and

_validatetheprocesstoassureconsistentproduction.

AsAPIsareregulatedarticles,theirqualityisdeterminednotonlybysatisfactorytest

results,butalsotheassurancethattheprocesswasconductedaccordingtoavalidated

process.

本節(jié)解決了如何：

_界說須要的質(zhì)量屬性

.查驗(yàn)

一將設(shè)計(jì)融入工藝

—驗(yàn)證工藝，以確保生產(chǎn)的一致性。

由于API是受管束物品，其質(zhì)量不但取決于令人滿意的測(cè)試結(jié)果，也認(rèn)為工藝

是由驗(yàn)證歷程來包管的。

A.DefiningtheAPIQuality原料藥質(zhì)量的界說

TheAPImusthaveitsfinalchemicalpurityandimpurityanditsfinalphysical

attributesspecified;somearticlesalsorequiremicrobiologicalanalysestobe

determined,dependingonthefinaldosageformandthemanufacturingprocess

involved.TheseattributesareestablishedtoassureanAPIwillperformsatisfactorily

inthepharmaceuticalmanufacturingprocessandwillresultinafinaldosageform;

i.e.,thedrugproductthatwillmeetitsinitialreleasespecificationsandfinalstability

requirements.Thechemicalpurityminimumisusuallysetat98%toassureproper

dosinginthedrugproductandtoassureaminimalamountofimpurities.Thephysical

parametersshouldbeestablishedwithknowledgeofthepharmaceuticalprocessand

theultimatefinaldosageform.Otherattributesusuallyincludecolorofthesolidform

andorasolution,meltingpoint,specificrotationifopticallyactive,crystal

morphology,andsoforth.AlistoftypicalAPIspecificationsisprovidedinAppendix

Aalongwiththerationaleforeachone.

API必須具有其最終的化學(xué)純度和雜質(zhì)，并規(guī)定其最終的物理屬性;一些還需要

微生物闡發(fā)，這取決于最終的劑型和所涉及的制造工藝上。這些屬性被創(chuàng)建以包

管一個(gè)API將在藥物制造歷程中令人滿意地執(zhí)行，并導(dǎo)致最終劑型即藥品將滿

足其最初版本的規(guī)格和最終穩(wěn)定性的要求。化學(xué)純度最低通常設(shè)定在98%,以

包管藥品的適當(dāng)劑量，并且確保最小量的雜質(zhì)。物理參數(shù)應(yīng)創(chuàng)建與制藥歷程和最

終劑型的知識(shí)底子上。其他屬性通常包羅固體形式的顏色和或溶液，熔點(diǎn)，比旋

度（如果有光學(xué)活性），晶體形態(tài)，等等。附錄A提供了典范API的范例列表。

WhensettingAPIphysicalattributespecifications,themostimportantaspectto

considerisitsuseinthepharmaceuticalprocess;namely,whetheritwillbewettedfor

granulation,dissolvedforsolution,dryblended,andsoon,andthetypeofdrug

producttobemade:tablets,capsules,solutions,sterileornonsterile,orother.Itis

alsoimportanttoknowhowthedrugproductwillbeusedbythepatient;fbrexample,

ifitwillbeusedasapowderblendedwithotherexcipients,carefulconsideration

shouldbegiventorateofdissolutionandtheeventualcolorofsolution(fbraesthetic

reasons)whendissolvedbythepatient(orhealthcaregiver)priortouse.Forthis

reason,finalAPIspecificationsarealwaysdefinedwiththecooperationofthe

pharmaceuticaldevelopmentarea.ThequalityassurancefunctionapprovesfinalAPI

qualitystandards,takingintoconsiderationallrequirements:processrelated,

governmental,andcustomer.

當(dāng)創(chuàng)建API的物理屬性時(shí)，要考慮的最重要的方面是其在制藥歷程中的使用;如

被潤(rùn)濕造粒，溶解于溶液中，干燥骰雜等，且可以制成的藥品類型有：片劑，膠

囊劑，溶液劑，無菌或非無菌的，或其他。同樣重要的是要明白藥品將用于患者;

例如，賦形劑的粉末應(yīng)考慮到由患者(或保健賜與者)溶解的速率和溶液在使用

前的最終的顏色(用于美觀的原因)。出于這個(gè)原因，最終的API范例始終說

明需與藥物開發(fā)領(lǐng)域的相助。質(zhì)量包管職能應(yīng)在最終批準(zhǔn)的API質(zhì)量標(biāo)準(zhǔn)中同

時(shí)考慮到所有要求：工藝相關(guān)的要求，政府和客戶的要求。

B.TestingtheAPIforItsDefinedAttributes原料藥質(zhì)量屬性的測(cè)試

EachqualityattributerequiredoftheAPImusthaveasoundandproventest

procedure.Inregulatorycomplianceterms,thismeansthetestmustbevalidated;that

is,tohavedocumentedproofthatitperformsreliably,isindicativeoftheattribute

underquestion,andisnotbiasedbyinterferingcomponents.Thereareeightspecific

componentsofavalidatedtest,andfbranexcellenttreatiseonthis,thereaderis

referredtothecurrentUSPortheICHguidanceonanalyticaltestvalidation.Most

regulatoryauthoritiesrequireatestforallsignificantAPIqualityattributesoneach

lotproduced.

API的每個(gè)質(zhì)量屬性都必須有一個(gè)健全的和可靠的測(cè)試步伐。在合規(guī)性方面，這

意味著必須在試驗(yàn)中驗(yàn)證；也就是說，已經(jīng)證明步伐的執(zhí)行可靠，而不是由滋擾

組分造成。一個(gè)驗(yàn)證歷程包羅8個(gè)特定的部分，讀者可參考現(xiàn)行USP或ICH闡發(fā)要

領(lǐng)驗(yàn)證的指導(dǎo)。大多數(shù)羈系部分都要求每批進(jìn)行API要害質(zhì)量屬性的測(cè)試。

Innearlyallcases,thepharmaceuticalmanufacturerrequiresacertificateofanalysis

(CofA)documentingtheresultsobtainedoneachlot,aswellasastatementfromthe

qualityofficethatthebatchmetitsestablishedqualitycriteria.

在險(xiǎn)些所有情況下，藥品生產(chǎn)商需要COA（闡發(fā)證書）來記錄每批的結(jié)果，證

明切合質(zhì)量部分規(guī)定的質(zhì)量標(biāo)準(zhǔn)。

C.DesigningQualityintotheProcess工藝中的質(zhì)量設(shè)計(jì)

Asdescribedabove,thepharmaceuticalmanufacturingprocessandenduseofthe

drugproductdosageformarethebasisforestablishingthelimitsofchemicalpurity

andphysicalattributes.Havingpredefinedtheseattributes,thesyntheticchemistand

chemicalengineerhavethetaskofdesigningqualityintotheprocess;thereby

assuringeverylotwillmeetitscriteria.Thisisperhapsthemostsignificantaspectof

chemicalprocessvalidationandacornerstoneofmostregulatoryrequirementsfor

qualityassurance.Afterthechemicalprocessisdeveloped,atechnicaldocument,

whichexplainshowandwhycertainreagents,steps,controls,etc.werechosenin

ordertobuildqualityintotheproduct,shouldbeprepared.

如上所述，藥物的制造歷程和最終用途的藥品劑型受到化學(xué)純度和物理屬性的限

制。為到達(dá)預(yù)界說的屬性,合成化學(xué)家和化學(xué)工程師有將質(zhì)量設(shè)計(jì)于工藝的任務(wù)，

從而確保每一批將切合其標(biāo)準(zhǔn)。這也許是化學(xué)工藝驗(yàn)證最顯著的方面和大多數(shù)規(guī)

矩要求的質(zhì)量包管基石?；瘜W(xué)歷程開發(fā)后，技能文件將解釋試劑，步調(diào)，控制等

的方法為什么和怎樣被選擇的將質(zhì)量設(shè)計(jì)于產(chǎn)物中。

Whenthemanufacturingteamtakesonthecommercialimplementationoftheprocess,

andgoesthroughtheformalmanufacturingvalidationprocess,theyshouldrely

heavilyonthistechnicaldocumenttoprovethequalityofthefinalAPI.Asstatedin

theintroduction,qualityisdesignedintotheprocessnotforregulatorypurposes,but

becauseitmakesgoodmanufacturingandbusinesssensetodoso.Manufacturers

wantaprocessthatsafelyandreliablydelivershighyieldandqualityforeconomic

andenvironmentalreasons.

當(dāng)制造團(tuán)隊(duì)需要對(duì)工藝進(jìn)行商業(yè)化生產(chǎn)，并進(jìn)行正規(guī)的生產(chǎn)驗(yàn)證歷程，在很洪流

平上依賴于該技能文件以證明最終API的質(zhì)量。正如在簡(jiǎn)介中說名，質(zhì)量是設(shè)計(jì)

于歷程中，不是出于羈系目的，而是因?yàn)橛辛己玫纳a(chǎn)和經(jīng)營(yíng)意識(shí)才這樣做。處

于經(jīng)濟(jì)和情況的原因制造商希望有一個(gè)寧靜，可靠地工藝來到達(dá)產(chǎn)物的高產(chǎn)量和

高質(zhì)量。

OneshouldbegintheapproachtodesigningqualityintotheAPI,withtheconceptof

designingaperfectsystem.Keepinmindthatallthesafety,environmental,and

economicreasonsfordevelopingaperfectchemicalsynthesisarepreciselyconsistent

withthegoalofdesigningqualityintotheprocess,andverywellserveallregulatory

processvalidationandcontrolrequirements.Ifoneimaginesaperfectprocess,there

willbenotoxicemissionsaboutwhichtobeconcerned,nosafetyconcernsorneed

forspecialsafetycontrols,andtheyieldofeachstepwillbe100%ofthedesired

intermediate,stereoisomer,andendproduct.Suchaprocesswouldbefreeofany

impuritiesandwouldassayfor100%purity.Thenextchallengeistodesignthe

synthesissothateachstepcanbepreciselycontrolledtoalwaysprovidethesameend

result.

用API質(zhì)量設(shè)計(jì)的要領(lǐng)來設(shè)計(jì)一個(gè)完美的系統(tǒng)。為開發(fā)一個(gè)完美的化學(xué)合成歷

程，精確切合將質(zhì)量設(shè)計(jì)于工藝的目標(biāo)，需考慮所有的寧靜、情況和經(jīng)濟(jì)原因，

還需切合工藝驗(yàn)證的規(guī)矩和控制要求。如果想象一個(gè)完美的工藝，沒有有毒物排

放，沒有寧靜問題或需要特殊的寧靜控制，每一步得到的中間體，立體異構(gòu)體和

最終產(chǎn)物的收率都是100%。這種工藝將是沒有任何雜質(zhì)，100%純度，下一個(gè)挑

戰(zhàn)就是設(shè)計(jì)合成路線精確控制每一步以得到相同結(jié)果。

Thedesignworkrequiresacompleteunderstandingofthechemicalreactionsinthe

syntheticprocessunderdevelopment.

Thenacleverdesigncanbedevelopedtoeliminateanyundesirablesidereactions.In

someinstances,thiscanbeachievedbysophisticateduseoffunctionalgroup

protectingagents,andinotherinstancesbychangingthesequenceoffunctionalgroup

introductionontotheendproductbuildingblockandsometimesbysimplecareful

controloverreactionparameters.Oncetheprocesshasbeenperfectlydesigned,

developed,andcontrolled,thelastconcernisoverthecontrolofqualityandreliability

oftherawmaterials,properfunctioningofequipment,anderror-freeoperationsby

personnel.Withthevisionofaperfectsysteminmind,onecanimaginehowtheAPI

qualitywouldbeperfectandconsistent.

設(shè)計(jì)事情需要對(duì)開發(fā)中的合成要領(lǐng)的化學(xué)反響有一個(gè)完整的理解。

然后，一個(gè)巧妙的設(shè)計(jì)可以開發(fā)用以消除任何不良副反響。在一些情況下，這可

以通過使用官能團(tuán)的掩護(hù)劑來實(shí)現(xiàn)，并且在通過改變官能團(tuán)引入的順序到最終產(chǎn)

物來構(gòu)建，有時(shí)需簡(jiǎn)單小心地控制反響參數(shù)。一旦歷程已經(jīng)完全設(shè)計(jì)，開發(fā)和控

制，最后值得存眷的是在質(zhì)量和原質(zhì)料，設(shè)備的正常運(yùn)作的可靠性，并通過人員

無誤差操縱的控制。隨著設(shè)想的完善制度的實(shí)行，可以想見的API質(zhì)量將是完

美的，一貫的。

D.ValidationoftheProcess工藝驗(yàn)證

Thisaspectoftheregulationsisperfectlyalignedwithbusinessinterests.The

regulationsrequirethatachemicalmanufacturingprocessbevalidated,whichthe

authorpersonallydefinesasproofofknowledgeofcontrol.

規(guī)矩這方面是與商業(yè)利益完全一致的。規(guī)矩要求化學(xué)品制造歷程必須進(jìn)行驗(yàn)證,

作者小我私家界說為控制知識(shí)的證明。

Whiletheterm6'validation99hasvariousdefinitionsinseveraldifferentregulations

(cGMPs),allessentiallymeanorimply"proofofknowledgeofcontrol.99Inessence,

thevalidationoftheprocessisthedescriptionoftheprocessafteralldevelopment

workiscompleted,withtheelaborationoftheproofofsyntheticpathway,controls

overprocessconditions,andfinally,soundanalyticalproofofqualityfromsamples

obtainedduringactualmanufacturingcampaignsintheplant.Criticalprocess

parameterssuchastime,temperature,andmixingconditionsshouldbedefined,

controlled,andmonitored.Thekineticsofthesyntheticpathwayisdocumentedina

processmanual.TheestablishmentofaprocessmanualforeachAPIisthefoundation

ofprocessvalidation.Inthismanual,onedescribesproofoftheknowledgeofthe

processandthecontrolsnecessaryforconsistentresults.Hence,thescientificdesign

processtobuildtheperfectprocessrequiresfullknowledgeofthechemistryofthe

process.Thatknowledgeisdescribedinthechemicalpathwayfromrawmaterialsto

thefinalAPI.

術(shù)語嗎僉證”有幾種差別的規(guī)定界說(cGMP),根本意味著或體現(xiàn)控制知識(shí)的證

明二在本質(zhì)上，該要領(lǐng)的驗(yàn)證是開發(fā)事情完成后的歷程的證明，用擬定合成途

徑，在控制的工藝條件，實(shí)際生產(chǎn)出可得到的樣品。要害的工藝參數(shù)，如時(shí)間，

溫度，和骰雜條件應(yīng)該被界說，控制和監(jiān)測(cè)。合成途徑的動(dòng)力學(xué)記錄在一個(gè)工藝

手冊(cè)中。對(duì)付每個(gè)API的工藝創(chuàng)建是工藝驗(yàn)證的底子。在這個(gè)手冊(cè)中，描述了工

藝知識(shí)和一致的結(jié)果比較的證明。因此，科學(xué)的工藝設(shè)計(jì)的完美歷程需要充實(shí)了

解化學(xué)知識(shí)。該知識(shí)論述了從原料到最終API的化學(xué)途徑。

Thescientificevidence,suchasintermediatestructureelucidation,spectrographic

analysis(IR,NearIR,massspec,UV,NMR,C13NMR,etc.),andtheproposed

chemicalmechanismfbreachtransformation,servesastheproofofthatknowledge.

Finally,duringthecourseoftheprocessdevelopment,fullknowledgeisgained

concerningthoseparametersandconditionsthataffectthekinetics,yield,andpurity

ofeachstep.Experimentstooptimizeeachstepforpurityandyieldleadtheprocess

engineertodescribethenecessarycontrolsandconditions.Thesecontrolsare

describedinaprocessmanualandareusedinthescale-upworkandultimate

full-scaleoperationinthechemicalplant.

科學(xué)證據(jù)，如中間結(jié)構(gòu)解析，光譜闡發(fā)（紅外光譜，近紅外光譜，質(zhì)譜，紫外光

譜，核磁共振，C13NMR,等等），以及所提出的每個(gè)轉(zhuǎn)化的化學(xué)機(jī)理，都作

為這種知識(shí)的證明。

最后，工藝開發(fā)歷程中應(yīng)充實(shí)了解，得到關(guān)于那些影響動(dòng)力學(xué)，產(chǎn)率和純度的每

個(gè)步調(diào)的參數(shù)和條件的知識(shí)。為優(yōu)化每一步的純度和收率所進(jìn)行的實(shí)驗(yàn)，都作為

工藝工程師用來描述須要的控制手段和反響條件。這些控制在流程手冊(cè)中有描述,

并在化工場(chǎng)進(jìn)行范圍化生產(chǎn)，并最終得到全面運(yùn)轉(zhuǎn)使用。

E.Reality實(shí)際

Werealizethattheperfectsyntheticprocesswill,inalllikelihood,betooelusive.

Eventually,wemustmakethedecisiontofocusourresourcesonthebestprocess

availableafterthoroughdevelopmentworkyieldsasoundandreliableprocess.Each

syntheticchallengerepresentsrealityofthebusinessofAPImanufacturing,andsoat

somepoint,thefeasibilityoffurtherstudiesvs.commercializingwhathasbeen

achievedtodatemustbeevaluatedonarisk（loosingprecioustimeinthemarket）to

reward（achievingasuperiorprocess）basis.Itissufficienttosayherethattoensure

qualityofthefinalAPI,thedevelopmentoftheprocessprovidesthenecessary

informationtodesignin-processcontrolsneededtomonitortheprogressofeachstep.

Thesecontrolsarethechemicalandphysicalmonitorsthatinformtheoperatorthat

thesynthesisisproceedingaccordingtotheoriginaldesign.Theyareusedalsoto

informtheoperatorwhenthereactioniscompleteandwhenthenextstepmayoccur.

Inmanycases,especiallywhentheprocessiswelldefinedanddesigned,including

thequalityofstartingmaterialsandreagents,agoodcontrolissimplytheuseoftime,

basedonaknowledgeofthekineticsofthereaction.

我們意識(shí)到在所有的可能性中完美的合成歷程是很難的。最后，我們必須會(huì)合資

源提供最佳的工藝。每次合成的挑戰(zhàn)都代表原料藥制造業(yè)的現(xiàn)實(shí)，因此在某些時(shí)

候，進(jìn)一步的研究與商業(yè)化風(fēng)險(xiǎn)必須進(jìn)行評(píng)估其可行性（失去名貴的時(shí)間在市場(chǎng)

上）去得到（實(shí)現(xiàn)一個(gè)卓越的技能）。它足以確保最終的API的質(zhì)量，該要領(lǐng)的

生長(zhǎng)提供了須要的信息，設(shè)計(jì)過程中的控制，以監(jiān)測(cè)每個(gè)步調(diào)的進(jìn)展是需要的。

這些控制是化學(xué)和物理監(jiān)測(cè)，即見告操縱者該合成是憑據(jù)原設(shè)計(jì)跟進(jìn)。它們還用

來見告操縱時(shí)反響完全和可能產(chǎn)生的下一個(gè)步調(diào)。在許多情況下，特別是在工藝

已被很好界說和設(shè)計(jì)時(shí)，基于化學(xué)反響的動(dòng)力學(xué)知識(shí)，包羅起始物料和試劑的質(zhì)

量，良好的控制能很大的節(jié)省時(shí)間。

In-processcontrolsshouldalwaysbe''intheprocess/9thatis,"on-line,99andnot

requiringasampletobewithdrawnandsenttoalaboratoryfortestingandevaluation.

Undersomeconditions,itmaybenecessarytotakesamples,butthisshouldbe

avoidedwheneverpractical.

歷程控制應(yīng)始終是歷程中，而不是要求一個(gè)樣品被取出并送到實(shí)驗(yàn)室進(jìn)行測(cè)試和

評(píng)估。在某些情況下，可能有須要采取樣品，但應(yīng)制止。

In-processcontrolsareprobes,ormonitors,insertedintothereactionvessel,orthe

gaugesthatmeasureandrecordpressureandtemperatureofvaporsabovethereaction

medium.Theattributesthataremeasur