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DOCUMENTS "COM"
COM(76)189
Vol.1976/0059

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COMMISSION OFTOBEÜSOPEAN COMMÜOTHES
COM(76)189final.
Brussels,10May1976.
Proposaifora
COUNCILDIRECTIVE
ontheapproximation ofthelawsofmemberstatesrelatingto
veterinarymedicinalproducts
Proposaifora
COUNCILDIRECTIVE
ontheapproximation ofthelawsofmemberstatesrelatingto
analytical,pharmaco-■toxicological andclinicalstandardsandprotocols
inrespectofthetestingofveterinarymedicinalproducts
(submittedtotheCouncilbytheCommission)
COM(76)I89final.

PROPOSAL FORACOUNCILDIRECTIVE ONTHE
APPROXIMATION OPTHELAWSOPMEMBERSTATES
RELATING TOVETERINARY MEDICINAL PRODUCTS

EXPLANATORY JMIORA1IDUI1
1.Generalconsidérations
Medicinalproductsforveterinaryuse,likethoseforhumantherapy,are
governed "bydifferentlegalprovisionsfromoneMemberStatetoanother.
TheneedforCommunityrulesisobviousfromtheeconomicpointofview.
Althoughthenumberofpreparations isdistinctlysmallerthaninhuman
medicine-theproportion maybeassessedat1to10-theconsumptionofand,
therefore,thetradeinthesepreparations areconsiderable .Stock-raising
isbecomingmoreandmoreindustrialized .Theconcentration andintensification
ofstock-raising whichresultsfromthisandtheselectionofhighlyproductive
breedsincreasethorisksofdiseasesandtheireconomicconsequences .With
theachievementofthocommonagricultural market,theobjectivesofproduction,
profitability ,freedomofmovementandundistortedcompetition havebecome
vitalinthisfield.
Theneedforrulesisevenmoreevidentfromthestandpointofpublichealth,
Withthegrowingconsumption ofanimalproducts,itisessentialthatthe
consumerofthetreatedanimalshouldsuffernoharm.Atthistime,when
problemsofqualityareagainclaimingattention,itishardlynecessaryto
stressthebenefittohealthwhichrulesinthisfieldwouldconfer.
Thisproposalforadirectiveisbasedonthoprinciplethattherequirements
laiddownforveterinarymedicinalproductsshouldnotbelessstringentthan
thosespecifiedforpharmaceutical productsforhumanuse.Thisisinthe
interestsofconsumersofproductsofanimalorigin,whomustsuffernoharm,
andalsointheinterestsofeffectivetherapy.

-2-
That iswhy ,wherever possible ,theprovisions concerning proprietary medicinal
products forhuman use (l)have been taken across tothis field .Nevertheless ,
inorder tomake allowance forproblems peculiar totheveterinary field ,it
wasnecessary toaddcertain special provisions ,
3.The scope ofthedirectives relating tohuman useandthat ofthis Directive
donot coincide .The structures ofthe two markets aredifferent *Onthe markets
ofcertain countrios ,veterinary medicinal products arecommercialized inthe
form ofready-made medicinal products andnotproprietary medicinal products ,
inorder tokeep down thecost ofpackaging .Forthesame reasons international
trade iscarried onmainly inready-made medicinal products .
Inorder toinclude most oftheproducts entering into international trade it
istherefore necessary towiden thescope oftheDirective ,This isalso
necessary forreasons ofcompetition ,since thestrict regulation ofone
category ofproducts would cause production toswing towards other less super­
vised categories ,andthis would ultimately boharmful topublic health .
Another peculiarity ofveterinary medicinal products isthedanger ofresidues
inanimal products .Itmust beborne inmind that people maybeharmed by
ingesting products derived from animals towhich medicinal products have been
administered .This raises thequestions ofthepersistence ofthemedicinal
product ,theroute andduration ofelimination ,andthenecessary waiting
period between use ofthemedicinal product andconsumption oftheanimal
product .This problem ofresidues only arises inthecase ofproducts
administered toanimals which arelikely toprovide Manwith food .Less
stringent demands might therefore have been expected inthecase ofmedicinal
products administered tocertain animal species ,pets ,forinstance .Itnever­
theless seemed hazardous tocreate twoseparate categories ofmedicinal
products inview ofthecorrupt andfraudulent practices which might have
ensued andtheproblems ofsupervision which would then have arisen .It
appeared wiser toallow certain waivers within theframework ofthe standards
andprotocols applicable totests onveterinary medicinal products ,
(l)Council Directive No65/65/EEC,OJ22of0.2.1$65
Council Directive No75/3l8/EEC»OJL147of9.6,1975 ./•
Council Directive No75/319/EEC,OJL147of9,6,1975

The aim ofthis work ontheapproximation oflaws istointroduco free move­
ment ofveterinary modicinal products while providing every safeguard for
public health .
Having taken steps tosafeguard public health attheproduct testing ,manu­
facturing andmarketing stage ,thenext problem which arose wasthat ofthe
free movement ofthese products .
Theintroduction ,atthis stage ,offreedom ofmovement might seem feasible
since theposition with regard toveterinary medicinal products isnot
identical with that ofmodicinal products forhuman use .Thepublic health
hazards mayseem less serious ,since theanimal isused asanintermediary
andtherefore acts asascreen between themedicinal product andHan .
Community rules adopted foragriculture have mado itpossible toonsure
freedom ofmovement foragricultural products while securing theprotection
ofpublic health .
Those arguments were notdevoid ofweight butthey clashed with other arguments
concerning theneed toprogross bystages inafield which isclosely related
tohealth andisofprime importance fortheeconomy ofcertain countries .
Instead ofweighing upconflicting arguments which contribute nothing towards
health andpostpone free movement indefinitely ,itappeared preferable toput
forward more moderate proposals forintroducing ,inthecase ofveterinary
modicinal products ,thesystem ofmovement already adopted with regard to
modicinal products forhuman use .This should enable theperiods fortho
adoption andimplementation ofthotexts toboshortened andhence make it
possible tointroduco free movement forveterinary modicinal products more
rapidly than over-ambitious proposals would allow .

-4T
II.Commentary oncertain articles
Article 1
Itgoes without saying that theword "animal "refers tothewhole ofthe
animal kingdom andnotmerely tofarm animals .Newdefinitions tosupplement
those inCouncil Directive 65/65/EECarenecessary asthescope ofthepresent
Directive hasbeen widened tomake allowance forthe special circumstances
which prevail inthis sector .Between thedomain ofthemedicinal product
defined bytheDirective of19^5 andthat ofadditives infeeding-stuffs ,
defined byCouncil Directive No70/524of23November 1970 (0JNoL270of
14December 1970 ),there isawhole range ofproducts that must becovered
bjrtheregulations ifmanufacturers aretobeprevented from evading the
requirements bymarketing under uncontrolled forms .
Theready-made veterinary medicinal product differs from theproprietary
medicinal product bytheabsence ofaspecial name (trivial name ).Ithas
only achemical name oraninternational non-proprietary name .Furthermore ,
itisnotnecessarily offered forsale inaspecial pack butmaybesupplied
inbulk .Itisspecified that theready-made product ismarketed ina
pharmaceutical form which maybeused without further processing and itis
therefore atthis stage that authorization must beobtained for it.
Thepre-mix formedicated feeds isdefined fundamentally byitspurpose :itis
intended forulterior useinamedicated feed .This ishow itisdistinguished
from theready-made product which ,maybeused without further processing and
isnotintended forthis ulterior use.Ontheother hand ,apre-mix isnot
necessarily amixture :itisamedicinal preparation atthestage preceding
mixing *
/.

-5-
Incontrast fthemedicated feed isamixture ofoneormore medicinal
preparations with oneormore feeding-stuffs ,made before marketing .It;can
beused Without further processing andthis distinguishes itfrom thepre-mix .
Itstherapeutic purpose differentiates itfrom thecompound feeding-stuff .
Article 2
1.Apart from theeconomic goals tobereached ,thechief concern wastoensure
that substances harmful toMan are not administered tohimvia his food .
Amedicinal preparation isaproduct likely tobehazardous andmust there­
fore beuade subject toauthorization irrespective oftheway inwhich it
will beemployed subsequently .Aside from theeconomic considerations
already mentioned ,this isthereason which has ledtothewidening ofthe
scope ofthis Directive asoompared with theproposed directive onproprietary
medicinal substances for human use .
2.Ontheother hand ,theprovisions ofthis Directive donotadequately cover
certain specific cases (sera andvaccines ,medicinal products based on
radioactive isotopes )anditisadvisable nottoapply them tothese products
/
atprésent .
Similarly ,itwasnotconsidered advisable tomake these provisions mandatory
inthecase ofproducts which canhave noeffect onintra-Community trade ,
namely ,veterinary medicinal products notprepared inadvance ;this refers
tomedicinal products which correspond todrugs prepared according to
prescription inhuman medicine ,i.e. medicinal products prepared bya
veterinarian foroneparticular animal ,following diagnosis .
Finally ,inorder tomake thepresent rules effective ,ithasbeen necessary
toregulate oneaspect ofthemanufacture ofmedicated feeding-stuffs
/Article 2(3YJpending rules applicable tomedicated feeding-stuffs ,

Article 3
Paragraph 1ofthis Article iswholly comparable totheprovisions governing
proprietary medicinal products forhuman use .
Paragraph 2has "been made necessary bythespecial situation which could arise
inthis sector ;fora"parallel "market ,subject tonosupervision whatsoever ,
might emerge iftherule simple stated that anymedicinal product placed on
themarket must besubject toprior authorization .Itwould bepossible toget
round therules .Thefirst step would betoprocure ,asarawmaterial ,such
andsuch asubstance forwhich noprophylactic orcurative properties are
claimed ;noauthorization would benecessary since itwould bearawmaterial
andnotamedicinal substance .Thereafter ,thepurchaser would employ this
substance asmedication forhisownlivestock ;noauthorization would be
necessary since this medicinal product would nothave been placed onthe
market assuch .
Such apossibility would beunacceptable from thepoint ofview ofboth public
health andtheeconomy .
Ithastherefore been necessary togobeyond theidea ofmarketing andto
}aydown an'unqualified prohibition ofadministration toananimal ofa
medicinal product ,inanyform whatsoever ,which hasnotbeen authorized
pursuant totheprovisions ofthis Directive ..This provision assumes itsfull
meaning ifreference ismade totheconcept ofamedicinal product aslaid
down inArticle l(2)ofCouncil Directive No65/65of26January 1965 *
Itisvery certain that suoh aprovision gives rise todifficult problems of
supervision .Atthesame ,time ,however ,public authorities must beable to
counter thecorrupt practices which could stom from thepurchase ofsubstances
notsubject totheDirective 'sprovisions andyetemployed foratherapeutic
purpose .Ifsuch practices arediscovered they must bepenalized ;this justifies
such aprovision even ifitisdifficult toimplement it.
Anexception must bemade inorder toallow tests tobecarried outonmedicinal
products forwhich authorization hasnotyetbeen granted .

Article 4
Paragraph 5
Thetherapeutic indications must betaken inabroad sense :the "therapeutic
effect "concept must beunderstood tobetheeffect promised bythemanu-
facturer# Mutatis mutandis ,thetherapeutic indications cover theindications
quoted formedicinal products alleged topossess curative orprophylactic
properties andalso those quoted formedicinal products intended formaking
amedical diagnosis orrestoring ,correcting ormodifying physiological
functions inanimals .
Paragraph 6
Thephrase "dosage forthevarious animal species forwhich themedicinal
product isintended must beinterpreted with common sense :ifadifferent
dose hastobeadministered tocalves ,cows ,heifers etc.,thedosage must
ofcourse begiven forthese sub-categories .
Paragraph 7
Theperson responsible forplacing theproduct onthemarket must provide
allnecessary information concerning theprecautions tobetaken during use
oftheproduct inorder toensure thesafety oftheperson administering it«
Article 10
Itmaybeforbidden tjylawtousecertain substances forparticular purposes ;
anexample isthouseofoestrogens tofatten cattle .Butifthese substances
exert atherapeutic effect ,they must beallowed toqualify forauthorization
asmedicinal products .Inorder toreconcile these requirements ,authorization
mayberefused ifthemedicinal product isoffered forsale ,forause
prohibited under other Community provisions (Paragraph 3).Ontheother hand ,
this refusal would berescinded ifthis possible usewere nolonger
advertised .

Article 11
1.Inorder toallow themarketing ofmedicinal products which areuseful but
which also present definite hazards ,theauthorization mayentail the
obligation toprint thenecessary warnings onthelabel andthepackage
insert .Thereference toclinical andpharmacological trials isdesigned
toconfer anobjective character onthis provision .The second paragraph
ofArticle 13enables the authorities totake account ofitems of
information which emerge after themedicinal product ismarketed andto
reconsider theneed tomake warnings obligatory .
2.Atpresent thequestion oftracer substances does not appear important
enough torequire astudy atCommunity level ofalltracer substances and
ofallmedicinal products which must betagged .Nevertheless itwould be
desirable forHember States nottospecify different tracer substances .
Ifjoint consultation proved unsatisfactory andifthis problem were to
hamper freedom ofmovement ,approximation measures would then benecessary .
Inanyevent ,themanufacturer should beinformed about theobligation to
employ atracer substance before andnot after hedetermines theformula
ofhismedicinal product .
Artie .aiv
This Ar\j.cle makes itincumbent ontheperson responsible forplacing the
product <\ -themarket tomodify histesting methods ifanimprovement in
testing ma£result therefrom .
Italso makeaitincumbent onhimtonotify thecompetent authorities ofany
newfactors wh,ch appear after thegrant ofmarketing authorization :
-newfactyrs over which theperson responsible formarketing hasno
control ,such asa^d^-effects ,interactions ,contra-indications ,etc.
(second paragraph ):

-9-
-anynewfactorswhichresultfromitsusesmodifications inthe
composition,dosage,indicationsetc.(thirdparagraph).Naturally,in'accordance
withtheprovisionsoftheDirective,hewillhavetogivethereasonsfor
theseproposedchanges.
Itdidnotappearto"benecessarytospecifytheobligations ofthecompetent
authorities ;theyfollowfromtheprovisionsoftheDirective.Theinvestigation
measureswhichtheywillbeledtotakewilldependonthenewfactors
communicated "bythepersonresponsible and,inaccordancewiththenational
regulations ,theywillbeledeithertograntfreshauthorization ortoagree
tothemodification simplybyalettertothepersonresponsible.
Article16
InregardtotheCommitteeforVeterinaryMedicinalProductsitisproposedto
applyprovisionsbasedonthosespecifiedfortheCommitteeforProprietary
MedicinalProductsinChapterHIofDirective75/319/EEC*forthereasons
putforwardintheGeneralConsiderations ,
Article23
Itisproposedtoapplyalltheprovisionsconcerningmanufacture andimport
fromthirdcountries,containedinDirective75/319/EEC*toveterinary
medicinalproducts.Moreover,itshouldbenotedthatveterinarymedicine
appearsamongthescientificdisciplinelistedinArticle23ofDirective
75/319/EEC:anarticlewhichlaysdowntheminimumqualifications required
ofpersonswhoassumeresponsibility forthemanufacture andtestingcontrols
ofproprietary medicinalproductsforhumanuse.

-10-
Article33
Paragraph8
Theexpirationdatehasbeenmademandatoryinallcasesinordertoensurethe
correctuseofmedicinalproductsandtoavoidwastagewhichmayhecausedby
theabsenceofthisitemofinformation.Inordernottogivetheuseran
unjustifiedfeelingofsecuritywhenthemedicinalproduct,althoughnotout­
dated!mayhavedecomposedowingtobadstorage,conditions,thenextparagraph
makesitobligatorytomentionanyparticularstorageprecautionsthatare
necessary.
Article35
Inparticular,thisconcernscapsulesonwhichitwouldbedifficulttoprint
eventhename.
Article39
Thepackageinsertmust,withoutexception,beincludedinthepackageofthe
veterinarymedicinalproductforthepurposeofinformation andthecorrectuse
oftheproduct.Forexample,thefarmermustbeinformedconcerningthe
significance ofthewaitingperiod.Acertainnumberofitemsaxeneededso
thatthepackageinsertmayfulfilthisobjectandthoseitemsmustcorrespond
totheinformation anddocumentssuppliedpursuanttoArticle4andverified
bythecompetentauthoritiesinaccordancewithArticle10.
Ontheotherhand,thepackageinsertmustnotcontainanyadvertisingmatter}
itmustconcernsolelythemedicinalproductwhichitaccompanies.Inthe
interestsofeconomy,thisdoesnotprecludementioningthevariousformsof
thismedicinalproductononeandthesamepackageinsert.
Similarly,thenameofanothermedicinalproductmaybeincludedonitifthe
marketingauthorization prescribessuchareferencepursuanttothefirst
paragraphofArticle11.Thiswouldapply,forinstance,totheantidote.

Instructions forcorrectadministration axenecessarywhenthemedicinal
productsarecompletelyeffectiveonlyincertainfunctionalstatesofthe
organism(e.g.whenfasting)orincertainstagesofthedisease(e.g.
treatmentofparasitoses)orincombinationwithcertainconcomitantmeasures
(e.g.stimulationofcirculation).

12-
THECOUNCIL OFTHEEUROPEAN COMMUNITIES ,
Having regard totheTreaty establishing theEuropean Economic Community ,
andinparticular Article 100thereof f
Having regard totheproposal from theCommissioin t
Having regard totheOpinion oftheEuropean Parliament f
Having regard totheOpinion oftheEconomic andSocial Committee ,
Whereas theprimary purpose ofanyrules forthe-production and
distribution ofveterinary medicinal products must be.theeafcguarding ofpublic
health ;
Whereas ,however ,this objective must beachieved bymeans wnich will not
hinder thedevelopment ofindustry ariltrade inmedicinal products within the
Community ;
Whereas ,insofar asthoMomber States already have certain provisions laid down
bylaw,regulation orAdministrative action governing veterinary medicinal
products ,such provisions differ inoocontial principles :andwhereas this
?esults >inthehindering p£trade in -.nedijcinalj products within tho •
Community andthereby directly affeels thoestablishment andfunctioning of
tho common market ;
i '
Whereas such hindrances must accordingly beremoved ;andwhereas this entails
approximation oftherelevant provisions ;'
Whereas theprovisions ofthis Directive which concern veterinary medicinal
products arenotadequate ,although appropriate ,forveterinary medicinal
products used toconfer active immunity ,todiagnose thestate ofimmunity
andtoconfer passive immunity andformedicinal products based onradioactive
isotopes ;whereas itistherefore advisable nottoprescribe their application
tosuch products forthepresent ;
/.

-13-
Whereasmedicatedfeedxng-fctuffs donotcomewithinthenmbitofthisDirective,
butwhereasitisnecessary,gonuch.forpublichealthaooaononioreasons',to
prohibittheuseofunauthorized medicinalproductsinthemanufacture of
medicatedfeeding-stuffs ;
Whereasmarketingauthorization shallberefusedwhereamedicinalproduct
lackstherapeuticeffect'orwherethereisinsufficient proofofsucheffect
promisedbythemanufacturers ;
Whereasitisadvisable,inordergraduallytoachievefreedomofmovement "for
veterinarymedicinalproducts,tofacilitatethegrantingofnarkoting-fewftttdrisar -
tionsinseveralMemberStatesforoneandthesamemedicinalproduct;
Whereas,forthispurpose,aCommitteeforVeterinaryMedicinalProductsshould
besetup,oonpoood^representatives oftheMemberStatesandofthe••'
Commission,responsibleforgivinganopinionastowhetheraparticular
veterinarymedicinalproductcomplieswiththerequirements setoutinthis
Directivs;
WhereasthisDirective isonlyonestageintheachievement oftheaimof
freedomofmovementat-veterinarymedicinalproducts;whereas,forthispurpose,
newmeasureswillprovenecessary,inthelightofoxporicrfoegained--•
especiallywithinthesaidCommittee,forthoronove.1ofthe
remainingbarrierstofreedomofmovement;
Whereas,inordertofacilitatethemovementofveterinarymedicinalproducts
andtopreventthecheckscarriedoutinoneMemberStatefrombeingrepeated
inanother,minimumrecjuirementsformanufactureandimportsfromthird
countriesandthegrantofauthorizationrelatingthereto,shouldbeapplied!
toveterinarymedicinalproducts,asspecifiedinCotuioilDirective
75/319/EEContheapproximationofprovisionslaiddownbylaw,regulationor
administrative actionrelatingtoproprietarymedioinalproducts*
HaSADOPTEDTHISDIRECTIVE:
(1)OJNoL147,9.6.1975,P.13

-14-
ChapterI-Definitions andscopeofc,pplic-vtiou.
Article1
1.ThedefinitionslaiddowninArticle1ofCouncilDirectiveNo65/65
da4hoapjir6iiir..'.atlonofu-provicsions XoiSfioou-bjr-lariv..,,..";v
regulationoradministrative actionrelatingtoproprietary medicinal
products^shallapplytotMsDirective,
2.Furthermore,forthepurposesofthisDirective,thofollowingf.cfinitionashall
apply
–votorinaryinodicinalproductahallirofiuCi.any^.no^-ioinalcpx^uoli intendedfor
animais,
-Ready-madeveterinarymedicinalproductfltiflllnoiui'aliyrimtn^riary "^odiciiial
productpreparedinadvanceandmarketedinapharmaceutical formwhich
may'"beusedwithoutfurtherprocessing;
-pre-mixformedicatedfeeding-stuffs shallrj^^rafayrirDtcriiKiiy'3iQ^icinal
productpreparedinadvancewithaviewtothesubsequentmanufacture
ofmedicatedfeeding-stuffs ,"
I
-medicatedfeeding-stuffs 'shall-:\cananyiiixturc^ofc.vcteriiiary"' r.adicinr.l
productorproductsandfeedorfeedswhichisreadyprepare-for
uarkotfcigandiatondodtobofodtoaaii.ialstri-thoutfurtherprocaooing,
bcccu3oofitscurativaoreprpvoutive proportionorothcrc&roportico
ofthemedicinalsubstancecoveredbyArticle1(2)ofthesaid
CouncilDirective*
3.Theadditivesincorporated inanimalfeeding-stuffs andthesupplementary
animalfeeding-stuffs coveredbyCouncilDirectiveNo70/524-'.3
2)concerningadditivesinfeeding-stuffs 'shall,forthepurposesof
thepresentDirective,notbeconsideredasmedicinalproducts.
Article2
1.TheprovisionsofthisDirective
^OJNo22of9.2.1965»P.20
^OJNoL270of14.12.1970\snailapplytoveterinarymedicinalproducts

-15-
whether offered forsale intheform ofproprietary medicinal products ,
ready-made veterinary medicinal products orpre-mixes .
2.Theprovisions ofthis Directive shall notapply to:
(a)medicated feeding-stuffs ,
(b)veterinary medicinal products used with aview toproducing active
immunity ,diagnosing thestate ofimmunity andproducing passive
immunity ,
(c)veterinary medicinal products based onradioactive isotopes ,
(d)veterinary medicinal products notprepared inadvance andintended
foroneparticular animal .
3.However ,pending separate provisions formedicated feeding-stuffs ,a
pre-mix shall notbeuood forthc:Tianufaoturo ofnadioatod fooding-ctuffo
ifithas not received the authorization referred toinArticle 3.
Chapter II–Application formarketing authorization
forveterinary medicinal products
Article 3
1..*&veterinary medicinal product shall notbonarkctcd ina:*e:ibor Stat .;if
authorization hasnotbeen previously issued bythecompetent authority
ofthat Member State .
2.^veterinary medicinal product ahall notbeacTutnictcrod toaninnla iftlio
authorization provided forinthepreceding paragraph hasnotbeenlissued ,
except where tests ofmedicinal products referred toinArticle 4{10)
■/
are concerned .
Article 4
Forthep'trpose ofobtaining themarketing authorization provided forin
Article 3|theperson responsible forplacing theproduct onthemarket
shall lodge anapplication with thecompetent authority oftheMember State .

-16-
Thefollowingparticulars anddocumentsshallbeappendedtothisapplication :
1.nameorcorporatenameanddomicileorpemanont .addressof~thcporsonresponsible
placingthemedicinalproductonthomarketand,whereapplicable,ofthe
manufacturer -,also;
2.nameofthemedicinalproduct(trivialname,commonname,withorwithout
atrademarkornameofthomanufacturer }scientific nameorformula,
withorwithoutatrademarkornameofthemmufacturer)j
3.qualitative andquantitativeparticularsofallthocomponentsofthe
medicinalproduc-'6®grossedinthe/usualterns,"butexcludingempirical :chemical
formulae,withmentionoftheinternational non-proprietary namere­
commendedbytheWorldHealthOrganization ,'ifsuchnameexists;
4.briefdescriptionofthomethodofpreparation ;
5.therapeuticindications,contra-indications andside-effects ;
6.dosageforthevariousspeciesofanimalforwhichtho-medicinalproductis
intended,itspharoaceutical fora,methodandnoansofadministration and
expectedshelflife;
7.reasonsfortheprecautionaiy andsafetymeasurestobotakenwhenusing
themedicinalproduct,ifapplicable;
8.indicationofthenecessarydelay.betweentho.administration of.n*
themedicinalproducttoanimalsundernormalconditionsofuseandthe
productionoffoodstuffsfron-such,animals^inordor"toensurethatsuchfood
doesnotcontainanyresidueswhichmightjeopardizethehealthofthe
consumer;

9.Descriptionofthotestingmethodsemployed "bythemanufacturer (qualitative
andquantitative analysisofthecomponentsandthefinishedproduct,special
tests,e.g.sterilitytests,testsforthepresenceofpyrogonicsubstanoes,
forthopresenceofheavymetals,"biologicalandtoxicitytests,testson
intermediateproducts);
10.Résultaof:
-physicochemical ,biologica!ormicrobiological tests;
-toxicological andpharmacological tests:
-clinicaltrials.
Theresultsofthetoxicological andpharmacological testsshallrelatemore
particularlytothemetabolismoftheactivecomponentsintheanimalandinparti­
cular;,-tothemodeanddurationoftheirelimination,ifsuchdataare
importantforthepurposeofchockingthe1indicatoddolayi
Notwithstanding theforegomg,
a)alistofpublishedreferencesrelatingtothetoxicological and?
pharmacological teststhfcclinicaltrials,andthedataconcerning
thedelayshallbosubstitutedforthorelevanttostresults
inthecaseof:.
i)amedicinalproductwithanestablisheduse,whichhasbeen
adequatelytestedonanimalssothatitseffects,including
sido-cffects,arealreadyknownandareincludedinthopublished
references ;
ii)anewmedicinalproduct,inwhichtheactive
componentsarcidenticaltothoseofaknownmedicinalproduct
withanestablisheduse;
iii)anewmedioinalproductcontainingonlyknowncomponentsthat
havealreadybeenusedtogether ""•incomparableproportions
inadequatelytestedmedicinalproductswithanestablisheduse;

-18-
b)inthecaseofanowmedioinalproductcontainingknowncomponents
nothithertouseditogether fortherapeuticpurposes,
referencestopublisheddatashallbosubstitutedfbrthetests
ofsuchcomponents ;
11.oneormorespecimensormock-upsofthesalespresentation ofthe
medicinalproducttogetherwithapackageinsert;
12.adocumentshowingthatthemanufacturerisauthorizedinhisowncountry
toproducemedicinalproducts;
13.anyauthorization torplacethe-relevantnedicin&i?procllietontheHaricot,
whichnay,havu"beenobtain^1-inanotherIlonbefrSt&toorinathirdcountry.
Article5
MemberStatesshallmakeallnecessaryarrangements tx>ensure >that,thec'dominsstits
andparticularslistedinpoints8,9and10,ofthe^secondparagraphofArticle4>are
draftedbyexpertswiththerequisitetechnicalorprofessional
qualifications beforebeingsubmittedtothecompetentauthorities.
Thesedocumentsandparticularsshallbesignedbytheexperts.
Article6
Accordingtotheirparticularqualifications ,therileoftheexpertsshallbe:
1.tocarryoutsuchworkasfallswithintheirparticulardiscipline
(analysis,pharmacology andsimilarexperimentalsciences,clinic&l
trials)andtodescribeobjectivelythequantitative andqualitative
resultsobtained:r■
•A

-19-
2.todescribetheirfindingsxnaccordancewithCouncilDirectiveof•«•...
ontheapproximation ofthelawsofIlemberStatesrelatingtoanalytical,
pharmaco-toxicological andclinicalstandardsandprotocolsinrespectof
thetestingofveterinarymedicinalproducts,andinparticulartostate:
I
a)inthecaseofanalysts,whethertheproductoonfoins>withthe j
statedcomposition,providing anyreasonsforthetestingmethods i
whichthemanufacturer nayuse;
b)inthecaseofphamacologistff similarlyqualifiedspecialists,
-thetoxicity -oftheproductandthepharmacological
propertiesobserved,
-whether,afteradministration ofthemedicinalproductundernormal
conditionsofuseandobservanceoftheprescribeddelay,food
stuffaobtainedfromthetreatedanimalscontain -residueswhichmight
constituteahoalthhazardtothoconsuner|
c)^inthecaseofclinicians,whethertheyhavefoundeffectsinaninalstreated
withtheproduct ~corresponding totheinformationfurnishedby
themanufacturer pursuanttoArticle4,whethertheproductiswell
tolerated,whatdosagetheyrecommendandwhatarethecontra-indications
andside-effects ,ifany;
3.togivereasonsfortheuseofthereferencestopublisheddatareferred
toinprovisosa)andb)ofiton10inthosecondparagraphofArticle4»aooordi
totheconditionslaiddownbyCouncilDirectiveof onthe
approximation ofthelawsofMemberStatesrelatingtoanalytical,
pharmaco-toxicologicalandclinicalstandardsandprotocolsinrespect
ofthetestingofveterinarymedicinalproducts.

Theexperts' detailed reports shall form pairfc ofthedossier which the
applicant shall lodge with thecompetent authorities .
Chapter III - for application for authorization
Authorization -Renewal ofauthorization
Article 7
Member States shall take allappropriate measures toensure that theprocedure
forgranting -authorization toplace aveterinary medicinal product onthe
market iscompleted within 120days fron thedate ofsubnission "of~theapplication#
Inexceptional cases this time-limit shall boextended forafurther 90days®
The applicant shall benotified ofsuch extension before theexpiry ofthe
initial time-limit .
Article 8
Inorder toexamine theapplication submitted pursuant toArticle 4,the
competent authorities oftheMember States shall :
1, check that theparticulars submitted insupport oftheapplication
comply with thesaid Article 4and ,onthebasis ofthereports drawn up
bytheexperts pursuant toArticle 6,ascertain whether theconditions for
theissue ofthemarketing authorization have been fulfilled }
2. submit themedicinal product fortesting byaState laboratory ora
laboratory designated forthis purpose ,inorder toensure that thetesting
methods ofcontrol employed bythemanufacturer anddescribed inthe
dossier ,inaccordance with itoa 9ofthesooond paragraph ofArticle 4f&re
satisfactory ;
3» where appropriate ,require theapplicant ' "fc0supplement the
dossier asregards theitems listed inArticle 4.Where thecompetent
authorities avail themselves ofthis courso ofaction ,thetlno-liaite
specified

-21-
inArticle1shallbedeferreduntilthosupplementary -datarequiredhave
beenprovided.Similarly,thosetime-limitsshallbedeferredforthe
periodallowedtotheapplicant,whereappropriate,toexplainhimself
orallyorinwriting.
Article9
MemberStatesshalltakeallappropriate measuresinordorthat:
1*thecompetentauthorities mayascertainthatthomanufacturers andimporters
ofveterinarymedicinalproductsfromthirdcountriesareabletocarry
outmanufactureincompliancewiththedetailssuppliedpursuanttoitoa4of;
thosecondparagraphofArticle4and/ortocarryoutthetestsinaccordance
withthonethodsdescribedinthodossierunderiten9ofthesecondparagraph
ofArticle4j
2.thecompetentauthorities mayauthorizemanufacturers andimportersof
veterinarymedicinalproductsfromthirdcountries,inexceptional and
justifiedcases,tohavecertainstagesofmanufactureand/orcertainof
thetestsreferredtoinparagraph1carriedoutbythirdparties;in
suchcasestheinvestigations bythocompetentauthoritiesshallalso
uocarriedoutinthoseestablishments .
Article10
Thoauthorization providedforinArticle3shallbewithheldif,after
examination ofthedocumentsandparticularslistedinArticle4*itappears:
1.thatthomedicinalproductisharmfulasregardsthoconditionsofusestatedat
ithetinoofapplicationforauthorization ,orthatthereisnotherapeuticeffec
insufficient proofthereofbythoapplicantasregardstheepeoiosofkninal
whichistobetreated,orthatthequalitativeorquantitative composition
*-*'ofthemedicinalproductisnotasdeclaredt
i
•A I

-22-
2.that thewaiting period recommended bytheapplicant isnotlong enough
toensure that foodstuffs obtained from thetreated animal donot contain
residues which might jeopardize thehealth oftheconsumer ,oris
insufficiently substantiated }
3.that themedicinal product isoffered for sale forauseprohibited under
other Community provisions .
Authorization shall also "bewithheld ifthedossier submitted tothecompetent
authorities does notcomply with Articles 4»5and .6.
Article 11
Thegrant ofauthorisation provided for inArticle 3shall •
require itheperson responsible forplacing theveterinary
medicinal product onthemarket tb-1indicate onthecontainer and/orthe
outside wrapping andthopackage insert other particulars essential forsafety
orhealth protection , including anyspecial precautions relating to
useandanyother warnings resulting freer theclihical -and ^phamacoiofeical-'.i
trials specified inIteor 3£>ofArticle 4»oi-fron experience "gained ,during the
useofthemedicinal product once ithasbeen marketed .
Authorization shall also require theinclusion "ofatraocr *-
substance inthomédicinal product .
Article 12
Thegranting ofauthorizati6n shall notdininish thelegal -lability ofthe
manufacturer and,where appropriate ,oftheperson responsible forplacing
theveterinary medicinal product onthemarket .
Article 13
Theperson responsible formarketing shall aeonpt thetost method provided
foriniten 9'ofarticle accordance with theadvancement oftechnology
andtheprogress ofscience ifsuch adaptations ensures more reliable
testing ofthomedicinal product .
■ •/.

Theperson responsible forplacing theveterinary medicinal product onthe
market shall forthwith inform thecompetent authorities Qfanynew
information which entails amendment oftheparticulars anddocuments referred
toinArticle 4oradditional examination andmore especially anyprohibition
orrestriction prescribed bythecompetent authorities oftheStates inwhich
themedicinal product ismarketed .
Theperson responsible forplacing theveterinary medicinal product onthe
market shall immediately inform thecompetent authorities ofanyalteration he
proposes tomake intheparticulars anddocuments referred toinArticle ;4.
Article 14
Authorization shall bevalid forfive years andshall berenewablV forfive~
year periods ,onapplication bytheholder within thethree months preceding
the .\date ofexpiry ,inaccordance with theprevisions ofArticle 13•
Chapter IV-Committee forVeterinary Medicinal Products
Article 15
lsInorder tofacilitate theadoption ofacommon position bytheMember
States withxegard tonarke>ingjwthoriMtions raComittee forVeterinary
Medicinal Products ,hereinafter called the "Committee ",ishereby setup;
itshall bocomposed ofrepresentatives oftheMember States andofthe
Commission ,
2,TheCommittee shall ,when sorequested byaMember State ,examine questions
relating totheimplementation ofArticles 10,20and33»inaccordance
with Articles l6-2l !
3.TheCommittee shallldraw upitsownrules ofprocedure .
Article 16
1.TheMember State whioh hasissued amarketing authorization fora
veterinary medicinal product shall tr€fa3&-i.t totheCommittee adossier con­
taining a>copy of this authorization together with theparticulars and
d6c\rihonts specified inthesecond paragraph ofArticle 4»iftheperson
responsible fornarkoting requested their transmission toatleast five

-24-
othei^MenhÊin States-1
2.TheCommitteeshallforthwithtemsnit -the1doS&ier-to^the^o&pfetent
authoritiesofthespecifi-etirMenbefrStattesv-
3.Suchtransnission..shall "bedeemedto"be^equivalent"td-»thfcsubmission "bfan-"'■
applicatiomf or.-narketin^authorization tothe.saidauthorities'within "the
□eamngofArtiole4.
Article17
1.If,withinaperiodof120daysafterthedateoftranfenission-referred ■:
toinArticle16(2),hoobjectionhas"beeniftotlfiedto'theGoianittee "bythe
competentauthoritiesoftheMemberStatesspecified,theCommitteeshall
formallyrecordthefactandforthwithinformtheMemberStatesconcerned,
2.WhereaMemberStateconsidersthatitisunabletoauthorizethemarketing
oftheveterinarymedicinalproduct,itshallforwardits£eai3b&eiiobjection,
foundedinArticlerl?withinthe.Said"periodof120days#
Article18
1.InthecasesreforredtoinArticle17(2),theCommitteeshallconsiderthe
matterandshalldeliveritsreasonedopinionwithin-60daysfromthe
expiryofthetimelimitlaiddowninArticle17.
2.TheopinionoftheCommitteeshalldealwiththecomplianceoftheveterinary
medicinalproductwiththeconditionssotoutinArticle10,
TheCommitteeshallforthwithinformtheMemberStatesconcernedofits
opinionor,intheeventofdissenaionjoftheopinionsofitsmembers.
3.TheMemberStatesconcernedshallreachadecisionontheapplicationfor
marketingauthorization notlatenthan30daysafterthedateonwhichthe
informationprovidedforinArticle17(l)orparagraph2Hereof'''*
isgiven.TheyshallforthwithinformtheCommitteeoftheirdecision.

Article19
1*Ifseveralapplications havebeensubaiftedin-accordancefoLthArticle4
formarketingauthorization fortheaaneveterinarymedicinal
product,andoneormoreMemberStateshasgranted-suohauthorization while
oneormoreoftheotherMemberStateshaverefusedit,oneoftheMember
StatesconcernedmaybringthematterbeforetheCommittee.
ThesameshallapplywhereoneormoreMemberStateshavesuspendedor
witfcdraira marketingauthorization whileone"orofthootherHonberStates
havenotdoneso,
2.TheCommitteeshallconsiderthematterandshalldelivoritsreasoned ;opinion
within12©daysatthelatest#
3.TheopinionoftheCommitteeshallonlydealwiththegroundsonwhich
authorization wasrefused,suspendedorwithdrovnu
TheCommitteeshallforthwithinformtheMemberStatesconcernedofits
opinionor,intheeventofdissension .,oftheopinionsofitsmembers.
4*TheMemberStatesconcernedshallgivenoticefwithin30daysfoftheaction
theyintendtotakefollowingtheCommittee'sopinion.
Article20
TheCommitteeshallsetatine-limitforirfroshexanination ionthebasisof
particularsrelatingtotheconditionslaiddowninArticles10,26or40
obtainedinthemeantimebyMemberStatesandinparticularbythosewhich
haveauthorizedtheveterinarymedioinalproduct.

-26-
Article21
ThecompetentauthoritiesofMemberStatesshall^iill-sp&sififec&Ses-where-the
interestsoftheCommunityareinvolved,referthemattertotheCommittee
beforereachingadecisiononanapplicationformarketingauthorization ,
itssuspensionor ....
Article22
1.TheCommissionshallreporttotheCouncilannuallyontheoperationofthe
procedurelaiddowninthisChapteranditseffectsonthedevelopment of
intra-Community trade.Itshallnatoit&^firartfrepiErtiirwoyeargai*terr"":
theentryintoforceofthisDirective.
2.InthelightofexperiencetheCommissionshall,notlaterthanfouryears
aftertheentryintoforceofthisDirective,submittotheCouncila
proposalcontainingappropriatemeasuresleadingto%theabolitionof
anyremainingbarrierstothe,freemovementofveterinarymedicinalproducts,
stillineSlstehce* -. t
BieCouncilshalltakeadecisionontheCommissionproposalnotlater
thanoneyearafteritssubnission»

-27-
Chapter V-Manufacture andimports from third countries
Article 23
1.Member States shall take allappropriate measures toensure that the
manufacture and •iaportg ->from third countries ofveterinary medicinal
products arosubject totheholding ofanauthorization .
2.Theprovisions concerning manufacture andimports from third countries
referred toinChapter IVofthesecond Directive 75/319/SECshall apply#
Chapter VI-Supervision and sanctions
Article 24
The competent authority oftheMember State concerned shall ensure bymeans
ofinspection ^that thelegal requirements relating tpveterinary medicinal 1,
products arecomplied with .
Such inspections shall becarried outbyofficials representing thecompetent
authority whoshall be°>empowero4 -tot
1..Inspect jianufacturing orcommercial establishments andanylaboratories
entrusted bytheholder oftheauthorization referred toinArticle 23(l)
with thetask ofcarrying outchecks pursuant toArticle 9(2);
2. Tafco sampless
3.••> anydocuments relating totheobject oftheinspection ,subject
toQiUPront /provisions intheMember States atthetime ofnotification
ofthis Directive which place restrictions onthese powers with regard to
thedescription ofthemethod ofpreparation .
♦A

-28-
Artide 25
Member States shall talce allappropriate measures toensure that theperson
responsible formarketing aveterinary medicinal product and,where appropriate ,
theholder oftheauthorization referred toinArticle 23(1 )furnish proof
ofthetests .carried outonthefinished product and/oronthecomponents
and -intermediate products ofthemanufacturing process ,inaccordance with
themethods laid down forthepurposes of ~marketing authorization .
Artitle 26
Thecompetent authorities oftheMmber^6tatfcsi&ha1Ll^suspend TXTr3rttfi&r8^ftax!kDting
authorization when itisclear that :
1,themedicinal product maybeharmful under theconditions ofusestated at
thetime ofapplication forauthorization orsubsequently ,orthat thenedi-■
cirtal product lacks therapeutic effect orthat itsqualitative and
quantitative composition i3notasdeclared ;
2»therecommended -.delays " isinadequate toensure that foodstuffs
obtained from thetreated animal donotcontain residues which might
endanger thehealth oftheconsumer ;
3.themedicinal product isoffered forsale forausewhich isprohibited
byother Community provisions ;
4.theinformation given inthedossier pursuant toArticles 4and 13is
incorrect ;
5.thetests referred toinArticle 25have notbeen oarried out ;
6.theobligations referred tointhesecond paragraph ofArticle 11have
not been fulfilled .
Thetherapeutio effect isaiBBing when itisestablished that themedicinal
product cannot produce thereapeutic results inthespeoifes ofaninal for -which
the treatment isintended .
Authorization nayalso besuspended orwithdrawn whoret
•••/•••

-29-
–theparticulars supporting theapplication ,asprovided forinArticle 4,
have notbeen amended inaccordance with thefirst andthird paragraphs of
Article 13;
–anynewinformation referred tointhesecond paragraph ofArticle 13
hasnotbeen communicated tothecompetent authorities .
Article 27
1.Notwithstanding theprovisions ofArticle 26,/-Member States shall take
allnecessary measures toensure that supply oftheveterinary medicinal
product isprohibited andthat such medicinal product iswithdrawn from
the market where :
a«itisclear that themedicinal product isharmful under theconditions
ofuse stated atthetime oftheapplication forauthorization or
subsequently ,pursuant tothethird paragraph ofArticle 13;
b«themedicinal product laoksi thorapoutic ,6ffoct ICHVthespecies^af ;animal for
which thetreatment wasintended ;
c.thequalitative andquantitative composition ofthemedicinal product
isnot asdeclared ;
d.therecommended ■dclajr' : ■isinadequate toensure that foodstuffs
obtained from thetreated animal donotcontain residues which might
endanger thehealth oftheconsumer ;
e.thetests referred toinArticle 25have notbeen carried outorwhere
another requirement orobligation relating tothegrant ofthe
authorization referred toinArticle 23(1 )hasnotbeen complied
with .
2.Thecompetent authority mayconfine itsorder prohibiting supply and
the withdrawal from themarket solely tomanufacturing batches
over which there isadispute .

30-
Article2o
1.ThecompetentauthorityofaMemberStateshallsuspendorwithdrawrfche
authorization referredtoinArticle23foracategoryofpreparations or
forallpreparations whenoneoftherequirements laiddownforthe
obtainingofthisauthorization isnolongermet.
2.ThecompetentauthorityofaMemberStatemay,inadditiontothe
measuressetoutinArticle27»eithersuspendmanufacture or
imports ^ofveterinarymedioinalproductsfromthirdcountriesor
suspendorwithdraw ;"the^^^rizatiion"referred "toTLn-ttrfctole "23'Tota
categoryofpreparations orforallpreparations intheeventofnon-
observanceoftheprovisionsregardingmanufacture orimpori©from
thirdcountries.
Article29
MemberStatesshalltakeallappropriate measurestoensurethatthecompetent
authorities concernedcommunicatetoeachothersuchinformationasisappropriate
tosecurecompliance withtherequirements fortheauthorization referredto
inArticle23(l)orformarketingauthorization.
\
Article30
AlldecisionstakenpursuanttoArticles10,26and27tallnegativedecisions
takenpursuanttoArticles andiilSfe)nfi-MiierDirective*and"all;'decisionsto
withhold'aujfchxjrizationtonarflifaeturei®r-to-^importfrocrthird1countries't>rto
suspendorwithdraw .manufacturing authorization shallstateindetail.,the
reasonsonwhiohtheyarebased.Suchdecisionsshallbenotifiedtothe
partyconcernedwhoshallatthesametimebeinformedoftheremedies
availabletohimundercurrentlegislationandthetine–limitwithinwhioh
suchre&edie®fcfljs-t.besought#
Authorizations toplaceveterinarymedicinalproductsonthemarketand
decisionstorevokesuchauthorizations !shall-bfc-publishedbyeachKenber"State
initsofficialgazette.

I
-31-
'Article 31
-■Decisions togrant authorization tomarket , withhold ,suspend orwithdraw
authorization ,toprohibit supply ,towithdraw aproduct from themarket
ortosuspend manufacture orimports ■from third countries ofveterinary
medicinal products shall -only^lse ^talesnonthegrounds setoutinthis
Directive .
Article 32
Each Member State shall take all •appropriate measures toensure that
decisions authorizing marketing ,refusing orwithdrawing &marketing authorization ,
cancelling adecision refusing orwithdrawing aarketiag ^(author !2atidn ,prohibiting
i'i3upply orwithdrawing aproduct from themarket ,together with thereasons
onwhich such decisions arebased ,arebrought totheattention ofthe
Committee forthwith .
•••/ •••

-32-
ChapterVII-Labellingandpackageinserts
inthepackagingofveterinary
medicinalprodtttts
Article33
Thefollowingparticularsshallappearinlegiblecharactersoncontainers
andouterpackagesofmedicinalproducts:
1.Nameofthemedicinalproduct,v;hichmcybeatrivialnameoracommonname
withorwithoutatrademarkornameofthemanufacturer orascientific
nameorformulawithorwithoutatrademarkornameofthemanufacturer ,
2.Nexttothenameofthemedicinalproduct,itsqualitative andquantitative
compositionexpressedinactivecomponentsperdose-unitorasapercentage ,
aocordingtothepharmaceutical formand,inadditioninthecases-rcfeirreEl
tointhesecondparagraph -ofArticle11thetracersubstances^
Theinternational non–proprietary name3recommended bytheWorldHealth
Organization shallbeusedwhereverthqyexist.
3.Referencenumberforproductionidentification (manufacturer'sbatch
number).
4.Numberoftheauthorization forplacingthoveterinarymedicinalproduoton
themarket•
5.Nameorcorporatenameandpermanentaddressorhoa&qwartorsoftheperson
responsiblefor,plaoingthoveterinarynodicinalproductonthe-market'and.,
whorbapplicable,ofthemanufactureralso.
6.ThespeciesofanimalforwhichthemedicinalproductisintGilded)thenothod
andmeansofadministration .
7-Ueiay.ifanyi.

-33
8.Date -of .expiry-%
9.Special storage precautions ,ifany,
10.Theparticulars idd'dcxm inthefirst paragraph ofArticle 11,if
necessary ,
11# Thewords "Forveterinary use".
Hiepharmaceutical form andthecontents byweight , volume or
number ofdose-units need only "beshown ontheouter package •
– •»■ , - /
•;•••«:'•. < • .Hheprovisions ofthe
Annex ,Part 1,AtoCounoil Directive of•••.••••••••• ontheapproximation of
thelaws ofMember States relating toanalytical ,pharmaco –toxicologioal and
clinical standards andprotoools inrespect ofthetesting ofveterinary
medicinal products insofarasthey concern ,theactive components ofveterinary
medicinal products described qualitatively andquantitatively shall apply tothe
particulars given inpoint 2» Article 34
Asregards ampoules ,theparticulars listed inthefirst paragraph of
Article 33shall begiven ontheouter package •Ontheactual containers ,
however ,only thefollowing particulars shall "benecessary *
–naine ofthemédicinal product ,
–quant ityofactive substances ,
«-means ofadministration
–reference number forproduction identification
(manuf actuer *sbatch number )
–date ofexpiry
–thewords "Forveterinary use".

-34
Article35
Asregardssnailsingle-dosecontainers,otherthanampoules,onwhichit
isimpossibletogivetheparticulars mentionedinArticle34|therequire­
mentsofArticle33shallapplyonlytotheouterpaokage.
Article36
Asregardsnarcotics,inadditiontotheparticulars mentionedinArticle
33,"boththeouterpackageandthecontainershallhearaspecialsign
consistingofadoubleredline.
Article37
Wherethereisnoouterpackage,alltheparticulars whichshouldfeature
onsuch •packagepursuanttotheprecedingArtiolesshall"beshownonthe
container.
Article3°
Theparticularsmentionedinitems6,7,8,9,10and11ofthefirstparagraph
ofArticle33andinthe3rdand6thindentsofArticle34shallappear
ontheouterpackageandonthecontainerofmedicinalproductsinthe
language orlanguagesofthecountryinvhiohtheyarebeing
placedonthemarlcet.
Article39
MemberStatesshalltakeallappropriate measurestoensurethatthepackage
-insertwhichmustbeinoiudedinthepackagedZh,veterinarymedicinal
productrelatessolelytothatmedicinalproduct.
Thepackageinsertshallcontainonlythefollowingparticulars ,which
shallconformwiththeinformation anddocumentsprovidedpursuantto
Article4andwhichhave"beenapprovedbythecompetentauthorities :

-35-
i
a)Name oroorporate name andpermanent address orhoadcjuartors of'theperson
responsible forplaoing thewterinorynoedicinal product onthemarket and,wheit
applicable ,ofthemanufacturer also f
b)Name ofthemedioinal product andastatement ofitsactive oanpononts
expressed qualitatively andquantitatively .
Theinternational non–proprietary names reoommended bytheWorld Health
Organization shall beused wherever they exist .
c)Themain therapeutio indioationB *,oontra –indications andside-effect3
insofarasthoro particulars arcnocossary forthouseofthemedicinal
products j
d)Thespcoies ofanimal forphiohthemedioinal product isintended ,thedosage
-suitable forthis speoies ,thonothod andmentis ofadministration andadvice
onoorroot administration ,ifnecessary ;
e)Ifnecessary ,alldetails concerning thedelay .{
f)Special storage precautions ,ifnecessary ;
g)Theparticulars required bythefirst paragraph ofArtiole 11,if
necessary .
Article 40
Where theprovisions ofthis Chapter arenotobserved andaformal notice
addressed totheperson ooncerned hasboon ineffective ,thecompetent
authorities oftheMember States maysuspend orwithdraw theauthorization to
place theveterinary medioinal product onthemarket .
Alldeoisions taken byvirtue ofthepreceding paragraph shall state indetail
thereasons onwhich they arebased .Adecision shall benotified totheparty
concerned ,along \fith theremedies available tohinunder current legislation ,
andthetine allowed forcooking such rcmedios *

-36-
Article41
The.-requirements ofIfcnbcr^taios^cacnKJorning' craidltions©fsupplytothepablio,
themarkingofpricesonmedicinalproductsforveterinaryuseand
industrialpropertyrightsshallnotheaffeotedhytheprovisionsofthis
Chapter.
ChapterVIII–Implementing provisions andtransitional
neasures
Article42
MemberStatesshall "bringintoforcethelafos,regulations andadministrative
provisions ••necessary tocomplywiththisDirectivewithineighteen
monthsofitsnotification andshallforthwithinformtheCommissionthereof.
MemberStatesshallensurethatthemainprovisionsofnationallav/which
theyadoptinthefieldgovernedbythisDirectivearecommunicated to
theCommission.
Article43
1.Asregardstheauthorizations referredtoinArticle23whichareissued
beforetheexpiryofthetine–limitlaiddowninArticle42,Member
Statesshallgrantanadditionalperiodofon©yoartothe-undertakings
concernedtoenablethemtocomplywiththeprovisionsofChapterV.
2.TheotherprovisionsofthisDirectiveshallbeappliedprogressively ,
withinfifteenyearsofthenotificationreferredtoinArtiole42,to
veterinarymedicinalproductsplacedonthemarketbyvirtueofprevious
provisions.

3.Member States shall notify theCommission ,within three years following
^thenotification ofthisDirective ,ofthenumber ofveterinary medicinal
products covered byparagraph 2,and,ineach subsequent year ,ofthe
number ofsuch products forwhich themarketing authorization referred
toinArtiole 3hasnotyetbeen issued .
Article 44
This Directive isaddressed tothe Member States .

PROPOSAL FORACOU1TCILDIRECTIVE
01TTHEAPPROXII1ATIOilOFTHELAWSOFJJEIBERSTATES
RELATINGTOAITALYTICAL,PHABMACO-TOXICOLOGICAL AJTD
CLUICAL..STANDARDS' AED^PROTOCOLS ■
?TTRESPECTOFTHETESTHTGOFVETERHTARY MEDICI1TALPRODUCTS

Explanatory memorandum
Aswithproprietarymedicinalproductsforhumanbeings,itisnecessary,
inthecaseofveterinarymedicinalproducts,tomakecertainadditionsto
theprincipleslaiddown"bythebasicDirectiveinordertoallowveterinary
medicinalproductsfreedomofmovementsBydefiningthedatatohesupplied
concerningthecharacteristics ofmedicinalproducts,bysettingouta
commonplanforthepresentation ofthesedataandbylayingdownthebroad
linesfortestingmedicinalproducts,thisDirectivewill,atoneandthe
sametime,assistmanufacturers ,competentnationalauthorities and-the
CommitteeonveterinarymedicinalproductsenvisagedintheCouncil
Directive •••••of...•••••ontheapproximation ofthelawsof
MemberStatesrelatingtoveterinarymedicinalproducts.
Thisproposalwasdrawnuponthebasisofthestudiesmadeinthefieldof
proprietarymedicinalproductsforuseinhumanbeings.However,the
specialproblemsraisedbyveterinarymedicinalproductshaveledtoacer­
tainnumberoforiginalprovisionsbeingmade.
Inthefirstplace,itisimportanttoprotectthehealthofpeoplewho
consumeanimalproducts.Advancedphamaco–toxicological studieshavebeen
plannedinordertodeterminethepossiblepresenceofresiduesinfood­
stuffsobtainedfromtreatedanimalsandtheeffectsofsuchresidues.
Thesetestscrustmakeitpossibletoestablishthenecessarywaitingperiod
fromthetimewhenthemedicinalproductisadministered totheanimal
untilfoodstuffsareobtainedfromtheanimal,inordertoeliminatehuman
healthhazards.Itisalsoimportant,however,tooonsidertheprotection
ofthetreatedanimal,sinoe,afterall,thisistheprimeobjectofveterinary
medicinalproducts;butthisgivesrisetoadifficultquestion,i.e.the
extentoftheassuranceswhichthecompetentauthorities mayrequireasto
thesafetyoftheproductfortheintendedspeciesofanimal.Inthecase
ofmedicinalproductsforhumanusetheanswerisobvious–everypossible
assuranceisrequired.Whereveterinarymedicinalproductsareconcerned
theanswerisnotsoeasy.

Fromthescientificstandpointitisclearthatallthetoxicitytests
(singledosetoxicitytests,repeateddosetoxicitytestsandtolerance
tests)must"becarriedoutineverycase.Bymeansofthefirsttypeof
testitispossibletodeterminewhethertheproductishighlyorfairly
toxicandgenerallytodescribetheacutesymptomsofintoxication .The
secondtypeoftestprovidesinformation concerningthemechanismofthe
intoxication processandmakeitpossibletoidentifytheside-effects
whicharemaskedintheacutetoxicitytests.Similarly,thetolerance
testsintheintendedspeciesofanimalenablethemaximumtolerateddose
andtheintolerance symptomstobeestablished.
Promtheeconomicstandpointonemustnevertheless considerwhetherallthese
teststosafeguardthehealthofthetreatedanimalwillexcessivelypenalize
veterinarymedicinalproductsasagainstmedicinalproductsforhumanuse.
Inthecaseofveterinarymedicinalproducts,thetoxicitytestsare
numerous:onerangeoftestsisintendedtoprotectthetreatedanimal's
health,anotherrangeisintendedtoprotecttheconsumerofanimalproducts
(residuetests).Onemustthereforepreventthecostburdenimposedonveter­
inaryresearchfromhandicapping thesalesprospectsofsuchmedicinal
S;
productstooheavilyandthusfosteringillegaldealingsinthismarket,
whichwouldruncountertotheaimspursued.
Acompromisesolutionisthereforeproposed:itisdesirablethatallthe
testsfortoxicitybocarried-out?nevertheless juct,jit*.ol
consideringinparticularthedirectionsfortheuseofthemedicinalproduct*
theinvestigator maysubmitreasonsfornotcarryingouttherepeateddose
toxicitytests;thesereasonswillofcoursebeappraisedbythecompetent
authorities whocanalwaysinsistthatthesetestsobecarriedout.

THEC0U1TCILOPTHEEUROPEA1TCOiSIUlTITIES ,
HavingregardtotheTreatyestablishingtheEuropeanEconomicCommunity,
andinparticularArtiole100thereof,
HavingregardtotheproposalfromtheCommission,
Whereastheapproximation begunbyCouncilDirective of........
ontheapproximation ofthelawsoftheIlemberStatesrelatingtoveterinary
medicinalproductsshouldbecontinuedandtheimplementation oftheprinciples
laiddowninthatDirectiveshouldbeensured;
Whereasamongexistingdisparitiesthoserelatingtothecontrolofveterinary
medicinalproductsareoffundamental importanceandpoint10ofthe-secondpara­
graphofArticle4ofthesaidDirectiverequiresthatapplicationsfor
authorization toplaceaveterinarymedicinalproductonthemarketshould
beaccompanied byparticulars anddocumentsrelatingtotheresultsof
testsandtrialscarriedoutontheproductconcerned;
Whereasstandardsandprotocolsfortheperformanceoftestsandtrialson
veterinarymedicinalproductsareaneffectivemeansofcontrolofthese
productsandhenceofprotectingpublichealthandcanfacilitatethemove­
mentoftheseproductsbylayingdownuniformrulesapplicabletotests
andtrialsandthecompilationofdossiers;
WhereastheadoptionofthesamestandardsandprotocolsbyalltheMember
Stateswillenablethecompetentauthoritiestoarriveattheirdecisions
onthebasisofuniformtestsandbyreferencetouniformcriteriaandwill
thereforehelptoobviatedifferencesinevaluations

-4-
Whereasthephysico-chemical ,"biologicalormicrobiological testsprovided
forinpoiht..10pfth®secondpajrttgraphT>f^ftrticlo4»~tho'said:Directive
arecloselyrelated-topoints3»4»6and$,ofthe6aid
paragraphanditisthereforenecessarytospecifythedatato"beprovided
underthesepointsj
Whereasthewaitingperiodreferredtoinpoint8ofthesecondparagraphofthe
saidArticle4nusthecieteminedin
accordancewiththeresultsofthetestsandtrialsprovidedforinpoint10
"thereof;
Whereastheconceptsofharmfulness andtherapeuticefficacyreferredtoin
Article10ofthesaidDirective ,canonlybe
examinedinrelationtoeachotherandhaveonlyarelativesignificance
dependingontheprogressofscientificknowledgeandtheuseforwhichthe
medicinalproductisintended;whereastheparticulars anddocumentswhich
mustaccompanyanapplicationforauthorization toplaceaveterinarymedi­
cinalproductonthemarketmustdemonstratethatpotentialhazardsare
outweighedbythetherapeuticefficacyoftheproduct 5whereas^failingsuch
demonstration ,theapplication mustberejected ?
Whereasitisthequalityofthetestsandtrialswhichispre-eminent }where­
asthetestsandtrialscarriedoutpursuanttotheseprovisionsmustthere­
forebetakenintoconsideration irrespective ofthenationalityofthe
expertswhoperformthemandthecountrywheretheyarecarriedoutj
Whereastechnicalprogressrequiresrapid of"theprovisionsofthe
AnnextothisDirective|wh©3jeastonake,iteasiertoadapttothemeasures
requiredforthispurpose,shouldbe•-aprocedureto^nsur©
closecooperation betweentheMemberStatesandtheCommissionwithinthe
StandingCommitteeonMedicinalProducts.
HA.SADOPTEDTHISDIRECTIVE :
/•

Article 1
Member States shall take allappropriate measures toensure that
theparticulars anddocuments which must accompany applications forauthoriz­
ation toplace aveterinary medicinal product onthemarket pursuant to
points 3,4,6,8,9and10oftheSQcond pajnagraph of:Artiole 4oftheCouncil
Directive of......... onthe approximation ofthe laws of
Member States relating toveterinary medicinal products aresubmitted
bythe persons concerned inaccordance with theAnnex tothis Directive .
Where ,under point 10(a)or(b)ofthesacon ^paragraph ofArticle 4
ofthesaid Directive ,:references topublished dataware
submitted ,theprovisions ofthis Directive shall apply inlike manner .
Article 2
Theamendments necessary foradapting therequirements oftheAnnex
tothis Directive totechnical progress shall beadopted inaccordance with
theprocedure laid down inArticle 3(5)an^(6)(asamended )oftheCouncil Direct :
of relating toanalytical ,pharmaco-toxicological andclinical
standards andprotocols inrespect ofthetesting ofproprietary medicinal
products .
TheCommittee referred toinArticle 3(&si.anended )ofthosaid
Directive mayexamine anyquestion relating totheapplication ofthis
Directive which isbrought upbyitsChairman ,either onhisowninitiative
orattherequest oftherepresentative ofaMember State .
Article 3
Member States shall put *into force laws ,regulations andadninistrati
provisions needed inorder tocopply yith thisDirootiv© within 18months ofits
notification and :shall forthwith infom theCommission thsreof ,
Member States shall ensure that
thetext ofthemain provisions ofnational lawwhich they adopt inthe
field covered bythis Directive are ooonunioated totheCommission#
Article 4
This Directive isadressed to'the Member States./■

A1T

Part1
ANALYTICAL (PHYSIC0-0HEMICAL,BIOLOGIC/.LORMICROBIOLOGICAL )TESTSOF
VETERINARY MEDICINAL PRODUCTS
A.Qualitative andquantitative particulars of.thecomponents
Theparticulars anddocumentswhichmustaccompanyapplications for
marketingauthorization$pursuant toArtiole4»point3tsecondparagraph,of
CouncilDirective.............of ontheapproximation
ofthelawsofMemberStatesrelatingtoveterinarymedicinalproductsshall
besubmittedinaccordancewiththefollowingrequirements :
1."Qualitativeparticulars"ofallthecomponentsofthemidiciaal
produotmeansthedesignationordescriptionoft
-theactivesubstance(s)
–thecomponent(s)oftheexcipients,whatevertheirnatureorthe
quantityused,includingcolouringagents,pa»MEr*aifci»w,stafoi-licere *
thickeners,emulsifiers,anti-agglutinating agents,flavouringand
aromatiosubstances?*gaspropellante,etc....
–componentsofthepharmaceutical form(e.g.capsule,cachet)intended
tobeingestedorotherwiseadministered toanimals.
Theseparticularsshallbesupplemented byanyrelevantdataconcerning
theoontainerand,whereappropriate,thewayofclosingit.
2.The"usualterminology",tobeusedindescribingthecomponentsof
medicinalproduots,means,without prejudioetotheapplicationofthe
otherprovisionsofArtiole4ipoint3»ofthesaidDirective:
–compulsorily ,inrespectofsubstanceswhichappearintheEuropean
Pharmacopoeia or,failingthis,inthenationalpharmacopoeia ofone
oftheMemberStates,theprincipaldesignationusedintherelevant
monograph,withreferenoetothepharmacopoeia concerned;

-8-
-inrespectofothersubstances,theinternational non-proprietary
namerecommended "byYJHO,whichnaybeaccompaniedbyanothernon-
proprietary name,or,failingthese,theexactscientific ,designation ;
substancesnothavinganinternational non-proprietary nameoran
exactscientificdesignationshallbedescribedbyastatementof
howandfromwhattheywereprepared,supplemented ,whereappropriate,
anyotherrelevantdetails;
-inrespectofcolouringagents,designationbythe"E"codeassigned
totheminafutureCouncilDirectiveontheapproximation ofthe
rulesoftheMemberStatesconcerningthecolouringagentsauthorized
foruseinproprietarymedicinalproducts.
3.Inordertogive"quantitative particularsofallthecomponentsof
themedicinalproduct"itisnecessary,dependingonthepharmaceutical form
concerned,tospecifyinregardtotheactivesubstance(s)theweightorthe
numberofinternational units,eitherperdosage-unitorperunitofweight
orvolumeandinregardtothecomponentsoftheexcipient,theweightor
thevolumeofeachofthem,withdueallowanceforthedetailsprovidedin
sectionBbelow.
Thisinformationshallbesupplemented :
-inrespectofparenteralpreparations ,bytheweightofeachactive
substanceintheunitcontainer,takingintoacoounttheusablevolume
oftheproductj
-inrespectofmedicinalproductstobeadministered indrops,by
theweightofeachactivesubstancecontainedinthenumberofdrops
corresponding toanaveragedose3
-inrespectofsyrups,emulsions,granulesandotherpharmaceutical
formstobeadministered inmeasuredquantities,bytheweightof
eachactivesubstaneepermeasuredquantity.
Activesubstancespresentintheformofcompoundsorderivativesshall
bedescribedquantitatively bytheirtotalweight,andifnecessaryorrelevant,
bytheweightoftheactivemoietyormoietiesofthemolecule(inthecase
ofchloramphenicol palmitate,forexample,theweightoftheesterandthat
ofthecorresponding chloramphenicol shallbegiven).

-9-
The"biologicalunitsofactivityofproductswhichhavenotbeen
definedchemically,andonwhichthereisinsufficient "bibliographical in­
formation,shallbeexpressedinsuchawayastoprovideunambiguousinfor­
mationontheactivityofthesubstance,e.g.bystatingthephysiological
effectonwhichthemethodofdeterminingthedoseisbased.
B#Descriptionofmethodofcysee^gti-on
The"briefdescriptionofthemethodofpreparation"accompanying the
applicationformarketingauthorization pursuanttoArticle4,secondparagraph,
point-4#"■of..CouncilDirective.............. of shallbedrafted
insuchawayastogiveanadequateideaofthenatureoftheoperations
employed.
Forthispurposeitshallincludeatleastt
-mentionofthevariousstagesofmanufacture ,sothatanassessmentcan
bemadeofwhethertheprocessesemployedinproducingthepharmaceutical
formmighthavebroughtaboutanadversechangeinthecomponents }
-inthecaseofacontinuousprocess,fulldetailsconcerningprecautions
takentoensurethehomogeneityofthefinalproductj
theactualmanufacturing formula,withthequantitativeparticularsof
allthesubstancesused,thequantitiesofexcipients,however,being
giveninapproximate termsinsofarasthepharmaceutical formmakes
thisnecessary;mentionshallbemadeofanysubstancesthatmaydisappear
inthecourseofmanufacture ;
-astatementofthestagesofmanufactureatwhichsamplingiscarriedout
forin^>processcontroltests,whereotherdatainthedocumentssupporting
theapplication showsuchteststobenecessaryforqualitycontrolofthe
medicinalproduct.

-10-
C.Checkin.T ofbr.sic substances
Forthepurposes ofthis paragraph ,''basic substances 1'shall mean all
thecomponents ofthemedicinal product and ,ifnecessary ,ofitscontainer ,
asreferred toinparagraph A,point 1,above .
Theparticulars anddocuments which must accompany theapplication
formarketing authorization pursuant toArticle 4»second paragraph ,points
9and10,ofCouncil Directive •••••••••• of•••..•••• shall include the
results ofthetests relating toquality control ofallthecomponents used .
These particulars anddocuments shall besubmitted inaccordance with the
following provisions .
1.Basic substances listed inpharmacopoeia ^
Themonographs ofthe Hhiropean Pharmacopoeia shall beapplicable to
allsubstances appearing init.
Inrespect ofother substances ,each Ilember State mayrequire observance
ofitsownnational pharmacopeia with regard toproducts manufactured inits
territory .
Components fulfilling therequirements oftheBuropean Pharmacopoeia
orthepharmacopoeia ofoneofthe Ilember States shall bedeemed tocomply
sufficiently with Article 4isecond paragraph ,point 9»ofCouncil Directive
of Inthis case ,thedescription oftheanalytical
methods maybereplaced byadetailed reference tothepharmacopoeia in
question .
Reference toanyofthepharmacopoeias ofnonMember countries may
bepermitted incases where the substance isdescribed neither inthe
European Pharmacopoeia nor inthenational pharmacopoeia concerned !inthat
case themonograph shall besubmitted ,aocompanied where necessary bya
translation forwhich theapplicant shall beresponsible .

Colouringagentsshall,inallcases,satisfytherequirements of
afutureCouncilDirectiveontheapproximation ofthelaxraoftheHember
Statesconoemingthecolouringagentsauthorizedforuseinproprietary
medicinalproducts *
Forroutinetestsoneach"batchofbasicsubstance,onlythatpart
ofthepharmacopoeiarelatingtoverificationtests(purityandstrengths)
shallbemandatory;thefullrangeofidentitytestsneednotnecessarily
beperformedwhorethose-thathavebeenperformedpermitanunambiguous
characterization .Inthiscase,thereferencetothemonographofthepharma­
copoeiamentionedaboveshallinoludedetailsrelatingtothisaspect.
2.Basicsubstancesnotinapharmacqpoei^
Componentswhicharenotgiveninanypharmacopoeia shallbedescribed
intheformofamonographunderthefollowingheadings:
(a)Thenameofthesubstance,meetingtherequirementsofparagraphA,
point2,shallbesupplemented byanytradeorscientificsynonyms;
(b)Thedescriptionofthesubstance,setdowninaformsimilartothat
usedinadescriptiveitemintheEuropeanPharmacopoeia ,shallbeaccompanied
byanynecessaryexplanatoryevidence,especiallyconcerningthemolecular
structurewhereappropriate ;itmust,insuchacase,beaccompanied bya
briefindicationofthemethodofsyntheticpreparation .I!heresubstances
canonlybedescribedbytheirmethodofpreparation ,,thedescriptionwill
havetobesufficiently detailedtocharacterize asubstancewhichis
constantbothinitscomposition andinitseffects;
(c)Methodsofidentification maybedividedintocompletetechniquesas
usedfortheformulationofthemedicinalproduct,andtestswhichoughtto
becarriedoutasaroutinematter.

-12-1
(d) Purity tests shall bedescribed inrelation tothe stuntotal of
predictable impurities ,especially those which mayhave aharmful effect ,
and ,ifnecessary ,thoss tdaibfc ,having regard tothemedicinal association
towhich theapplication refers ,might adversely affect thestability of
themedicinal product ordistort analytical results ,
(e) Theassay technicrue(s )must bedescribed insufficiently precise
detail soastobereproducible inchecking tests carried out attherequest
ofthecompetent authority ^ar$special apparatus andequipment which maybe
used shall bedescribed inadequate detail ,possibly accompanied bya
diagram .Theformulae ofthelaboratory reagents shall besupplemented ,if
necessary ,bythemethod ofpreparation .
Thestandard deviation ofthemethod ,itsreliability andthe accept­
ability limits oftheresults shall bespecified and,ifnecessary ,justified
inthelight offeasibility andtheprogress ofscientific knowledge .
With regard tocomplex substances ofplant oranimal origin ,a
distinction must bemade between thecase where multiple pharmacological
effects render achemical ,physical orbiological check oftheprincipal
components necessary ,andthecase ofsubstances containing oneormore
groups ofprinciples exerting similar action ,inrespect ofwhich anoverall
method ofdetermination maybeaocepted .
(f)^v w.tions that may>enecessary during storage
v>.iosubstance and,ifnecessary ,itsstorage lifeshall begiven .
««--tuChecks during manufacture
Theparticulars anddocuments which mustaccompany anapplication f»r -
marketing authorization ,pursuant toArticle 4,second paragraph ,points 9
and10,ofCouncil Directive of shall more
especially include particulars relating to-theproduct checks thatmaybe
carried outatanintermediate stage ofthemanufacturing process ,witha
view toensuring consistency ofthetechnical characteristics andthe
production prooess .

-13.-
These-testsaxeessentialtoverifytheconformityofthemedicinal
productwiththeformulawhen,exceptionally,anapplicln^proposesan
analyticaltechniquefortestingthefinishedproductwhichdoesnotinclude
theassayofalltheactivesubstances(orofallthecomponentsofthe
excipientsubjecttothesamerequirements astheactivesubstances).
•(
Thesameapplieswherequalitycontrolofthefinished?*productdepends
onin–processchecks,particularly A#"the ^^essentially
definedbyitsmethodofpréparation.
E.Chacksonthefinishedproduct
Theparticularsanddocumentswhichmuertaccompanythe^plication
formarketingauthorizationpursuanttoArticle4,second,paxa^p^points
9and10,ofCouncilDirective of include
particularsrelatingtochecksonthefinishedproduct.Theysl^tesub_
mittedinaccordancewiththefollowingrequirements./
-^ffifinera.!eristicsofthe|variousp^m^eu^cal^f 03^
.Certainchecksonthegeneralcharacteristics ofaproductwhichcan
becarriedoutinthecourseofthemanufacturing processshalibeincluded
amongthetestsonthefinishedproduct.
Asaguideline,andsubjecttotherequirements oftfc©European
Pharmacopoeia orthenationalpharmacopoeias ofMemberStates,thegeneral
characteristics whicharetobeverifiedforvariouspharmaceutical forms
aregivenatpoint5below.
Thesechecksshall,whereverapplicable,relatetotheverification
ofaverageweightsandmaximumdeviations,tomechanical,physicalor
microbiological testsjorganolepticcharacteristics suchasclarity,colour
andtaste,andphysicalcharacteristics suchasdensity,pH,refractive
index,etc.Foreachofthesecharacteristics ,standardsandlimitsmust
bespecifiedbytheapplicantineachparticularcase.

-14-
2.Identificationandassayofactivesnbstance(s)
Thedescriptionofthetechniquesforanalysingthefinishedproduct
shallsetout,insuchprecisedetailthattheyoanbereproducedreadily,
themethodsusedforidentification andassayoftheactivesubstance(s)
eitherinarepresentative averagesamplefromtheproductionbatchorina
numberofdosage-units consideredindividually .
Ineverycase,themethodsmustcorrespondtothestateofscientific
progressatthetimeandgivedetailsandexplanations concerningthestandard
deviations,thereliabilityoftheanalyticalmethodandthemaximumaccept­
abledeviations.
Incertainexceptionalcasesofparticularly complexmixtures,where
theassayofactivesubstanceswhichareeitherverynumerousorpresentin
verysmallamountswouldnecessitate anintricateinvestigation difficult
tocarryoutinrespectofeachmanufacturing batch,theassayofoneor
moreactivesubstancesinthefinishedproductmaybeomitted,ontheexpress
conditionthatsuchassaysaremadeatintermediate stagesintheproduction
process?thisrelaxation maynotbeextendedtocoverthecharacterization
ofthesubstancesconcerned.Thissimplifiedtechniqueshallthenbesupple­
mentedbyamethodofquantitative evaluation,enablingthecompetendauthori­
tytohavetheconformityofthemedicinalproduotwithitsformulaverified
afterithasbeenplacedonthemarket.
Anassayofbiologicalactivityshallbeobligatory whenphysico­
chemicalmethodscannotprovideadequateinformation onthequalityoftheo
product.
WheretheparticularsgiveninparagraphBshowthatasignificant
overageofanactivesubstancewasemployedinthemanufactureofthe
medicinalproduct,thedescriptionofthemethodsforcheckingthefinished
productshall,include,whereappropriate ,thechemicalandeventhetoxico-
pharmacological investigation ofthechangesthatthissubstancehasunder­
gone,andthecharacterization ordetermination ofthedegradationproducts,
ifany.
./■

-15-
3.Identification andassay ofcomponents ofexcipients '""
Anupper-limit test shall bemandatory inrespect ofexcipient compo­
nents which aresubject torules relating totoxic substances orwhich are
used aspreservatives ;furthermore ,components liable toaffect physiological
functions shall besubjected toanassay .
Themethod proposed foridentifying colouring agents must enable a
verification tobemade that such agents appear inthe list tobeappended
toafuture Council Directive ontheapproximation ofthe laws oftheMember
States concerning thecolouring agents authorized foruse inproprietary
medicinal products .
Insofarasisnecessary ,thecomponents oftheexcipient shall be
subjected atleast tocharacterization tests .
4.Safety tests
Apart from thetoxico-pharmaco logical tests submitted with theappli­
cation formarketing authorization ,particulars ofsafety tests (abnormal
toxicity )orlocal tolerance inanimals shall beincluded intheanalytical
dossier wherever such tests must beundertaken asamatter ofroutine in
order toverify thequality ofthemedicinal product .
5.General characteristics ofmedicinal products tobeverified systematically ,
depending onthepharmaceutical form ofeach product
Thefollowing requirements aregiven forguidance andwithout pre­
judice toanyrequirements ofthe3uropean Pharmacopoeia ornational
pharmacopoeias ofMember States ;forexample ,microbiological testing of
preparations tobeingested orally shall beperformed inaccordance with
therequirements oftheEuropean Pharmacopoeia .
-Tablets andpills :colour ,weight andacceptable variations inunit weight ;
ifnecessary ,disintegration time with themethod used todetermine this .
-Coated tablets ?colour ,disintegration time with themethod used todetermine
this ;weight offinished tablet ;weight ofcore andacceptable variations
munit weight .

-16-
–Hardgelatinecapsulesandsoftgelatinecapsules:colour,disintegration
timewiththemethodusedtodeterminerthis5appearanceandweightof
content,"withacceptablevariationsinunitweight.•
–Enterio-coatcd preparations (tablets,hardandsoftgelatinecapsules,
granules):inadditiontotherequirementsoftheparticularpharmaceutical
form,resistancetimeinanartificialgastricfluid,withthemethodused
todeterminethis;disintegration timeinanartificialintestinalfluid,
withthemethodusedtodeterminethis.
–Preparations withspecialprotectivecoating(tablets,hardandsoft
gelatinecapsules,granules);inadditiontotherequirementspeculiar
toeachpharmaceutical form,verification oftheeffectiveness ofthe
coatingforthedesiredpurpose.
–Preparations ensuringgradualreleaseoftheactivesubstance:inaddition
totherequirements peculiartoeachpharmaceutical form,requirements
relatingtogradualrelease,withthemethodusedtodeterminethis.
–Cachets',packetsandsachets:natureandweightofcontentsandacceptable
variationsinunitweight.
–Parenteralpreparations ?colour,volumeofcontentsandacceptablevariations
inthisvolume;pH,clarityofsolutes,sizelimitofparticulatematter
inthecaseofsuspensions 5sterilitytests,withdescriptionoftest
methodsand,ifnecessary,apyrogentestwithdescription -ofmethod.
–Ampouleswithsolidcontent:quantityofmedicinalproductperampouleand
permittedvariationsinweight;sterilityrequirements andtests.
–Drinkableampoules:colour,appearance,volume6fcontentandacceptable
variations.
–Ointments,creams,etc.:colourandconsistency ;weightandacceptable
marginofvariation;natureofcontainer;incertaincases,microbiological
tests.
–Suspensions :colour;wheresettlementoccurs,theeaseofre-suspendability .
-Enulsions:colour;type;stability.

-Suppositories,"bougiesandpreparationsforintra-uterine administration:
oolour,weightandacceptablevariationsinyfanitweight;meltingtemperature
ordisintegration time,anddescriptionofthemethod.
-Aerosols:descriptionofcontainerandvalvewithdetails/ofoutput;
particlesize-limit,wheretheproductisintendedto"beinhaled.
-Eyedrops,ophthalmicointments,eyelotions?colour;appearojioe 5sterility
tests,withdescriptionofthemethodused;whereappropriate,clarityand
size-limitofparticulatematterinthecaseofsuspensions ;pHdetermination .
–Syrups,solutés,etc.:colour,appearance
–Pre-mixformulationsformedicatedfeeds:inadditiontotherequirements
peculiartoeachpharmaceutical form,allusefulinformation onthe
characteristics ofthepre-mixformulationenablingasufficiently homo­
geneousmedicatedfeedto"beprepared.
-Preparations foradministration withintheudderviatheteatcanal:colour,
consistency ;weightofcontentand,inthecaseofproductspresentedin
singleslow-release doseformulations ,usableweightwithacceptable
deviation;sterilitytest;pHdetermination . .
P.Stabilitytests
Theparticulars anddocumentswhichmustaccompanytheapplicationfor
marketingauthorization pursuanttoArticle4»secondparagraph,points6
and9,ofCounoilDirective of•••.••••••••shallbesubmitted
inaccordancewiththefollowingrequirements .
Adescriptionshallbegivenoftheinvestigations bywhichtheshelf
lifeproposedbytheapplicanthasbeendetermined.
Whereafinishedproductisliabletogiverisetotoxicdegradation
productstheapplicantmustreporttheseandindicatecharacterization or
assaymethods.

-18-
Theconclusionsshallcontaintheresultsofanalyses,justifying
theproposedshelflifeundernormal,or,whereappropriate ,underspecial
storageconditions.
Astudyoftheinteraction "betweenthemedicinalproductandthe
containershallhesubmittedwherevertheriskofsuchinteraction is
regardedaspossible,especiallywhereparenteralpreparations oraerosols
forinternaluseareconcerned.

-19
• Part2
TOXICOLOGICAL AITDPHARi'IACOLOGICAL TSSTS
Theparticulars anddocumentswhichmustaccompanytheapplication
formarketingauthorization pursuanttoArticle4,secondparagraph,
point10,ofCouncilDirective.••••••••••of••••••••••••• shalltoesubmitted
inaccordancewiththerequirements ofChaptersIandIIbelow.
ChapterI;Performance oftests
A.Introduction
Thetoxicological andpharmacological testsmustshow:
1.thepotentialtoxicityofthemedicinalproductandanydangerousor
.undesirabletoxiceffectsthatmayoccurundertheproposedconditions
ofuseinanimalsjtheseeffectsshouldbeevaluatedinrelationtothe
gravityofthepathologioal conditionconcerned }
2.itspharmacological properties,inbothqualitative andquantitative
relationshiptotheproposeduseinanimals;
3.towhatextentandforhowlongafteruseofthismedicinalproductin
animalsthereexistresiduesinfoodproductsobtainedfromtheanimals,
whataretheirpossibleharmfuleffectsonISanandwhataretheirdraw­
backsfortheindustrialprocessingoffood.
Allresultsmustbereliableandofgeneralapplicability .Whenever
appropriate ,mathematical andstatisticalproceduresshallbeusedinworking
outtheexperimental methodsandinevaluatingtheresults.Furthermore,it
isnecessaryforclinioianstobegiveninformationaboutthetherapeutic
potentialoftheproductandaboutthehazardsconnectedwithitsuse.

-20-
B.Toxicitystudy
1.Single-dosetonicity
Singlc-dosetoxicitytestmeansaqualitative andquantitative study
ofthetoxicreactionswhichmayresultfromasingleadministration ofthe
activesubstancescontainedinthemedicinalproduct,intheproportionsin
whichtheyarepresentintheactualmedicinalproduct.
Whereverpracticable ,theproductinitsactualpharmaceutical form
shall "besubjectedtoanacutetoxicitytest.
Thesingle-dosetoxicitytestmustbecarriedoutinatleasttwo
mammalianspeciesofknownstrain,andatleasttwodifferentroutesof
administration shallnormallybeused.Thestudywithtwomammalianspecies
canbereplacedbystudywithonemammalianspeciesandanajaimalspecies
ofanotherclassforwhichthemedicinalproductisintended.Oneofthe
formsofadministration mustbeidenticalwithorsimilartothatproposed
foruseintheanimalforwhichthemedicinalproductisintendedandthe
othermust.bearouteensuringsystemicabsorptionoftheproduct.Thestudy
mustbecarriedoutonequalnumbersofmaleandfemaleanimals.
Thisstudywilldescribethesymptomsobserved,includinglocal
reactions.Where.possible,theLD^valuewithitsconfidencelimits(95f°)
willbenoted.Theperiodduringwhichthetestanimalsareobservedshall
befixedbytheinvestigator andshallnotbelessthanoneweek.
Inthecaseofactivesubstancesinassociation ,thestudymustbe
carriedoutinsuchawayastocheckwhetherornotpotentiation phenomena
ornewtoxiceffectsoccur.
2.Repeated-dose toxicity
Repeated-dose toxicitytestsareintendedtorevealanyphysiological
and/ormorbidanatomicalchangesinducedbyrepeatedadministration ofthe
activesubstanceorassociationofactivesubstancesunderexamination,and
todeterminehowsuchchangesarerelatedtodosage.

Generally,itisdesirabletoperformatleastonetesttheduration
ofwhichshalldependontheconditionsofclinicaluse5itspurposeshall
hetodetermine "byexperimentthenon–toxicdoserangeoftheproduct
examinedduringthetrial.Theinvestigator mustgivereasonsfortheextent
anddurationofthetrialsandthedosageschosen.
If,however,havingregardinparticulartothedirectionsforuse
ofthemedicinalproduct,theresponsibleinvestigator seesfitnotto
carryoutthisexamination hemustgiveadequatereasonsforhisdecision.
Repeated-dose toxicitytestsmustbecarriedoutontwospeciesof
mammalsoneofwhichmustbeanon-rodent.Whereveritisfeasible,the
studywithtwomammalianspeoiesshallbereplacedbyastudywithone
speciesandanotheranimalspeciesforwhichthemedicinalproductisin­
tended.Thechoiceoftheroute(s)ofadministration mustdependonthose
envisagedfortherapeutiouseandonthepossibilities ofsystemicabsorption.
Themethodandfrequencyofadministration andthelengthofthetrials
shallbeclearlystated.
Themaximumdoseshouldbechosen,soastobringharmfuleffects
tolight.Thelowerdoseswillthenenabletheanimal'stoleranceofthe
newproducttobedetermined.
Theevaluationofthetoxiceffectsshallbebasedonobservation of
behaviour,growth,bloodpictureandphysiological tests,especiallythose
relatingtotheexoretoryorgans,andalsoonautopsyreportsandaccompanying
histological data.Thechoiceandrangeofeachgroupoftestswilldepend
onthespeciesofanimalusedandthestateofscientificknowledgeatthe
time.

21a
Inthe case ofnew combinations ofknown substances that have been
investigated inaccordance with theprovisions ofthis Directive ,the
long–term tests may ,except where acute andsubacute toxicity tests have
demonstrated potentiation ornovel toxic effects ,besuitably modified by
theinvestigator whoshall submit hisreasons forsuch modifications#
Substances that have been shown tobesafe bywide usagg ";over atleast
three years inclinical treatment ofhuman beings ,andbytheresult of
controlled trials shall betreated inthesame wayasknown substances which
have already been investigated inaccordance with these standards and
protocols ,
•xoipient Heed forthefirst tine inthepbazmoettiQal field <shall be
treated like anactive ingredient ,
3.Tolerance inthe intended species ofaninal
This study must becarried outwith allanimal species forwhich the
medicinal product isintended .Itspurpose istocarry outinallthe
animal species forwhich themedicinal product isintended local and
general tolerance assays toestablish themaximum does tolerated andthe
olinical symptoms ofintolerance using therecommended route orroutes ,insofaras

-22-
itispossibletoattainthisaimbyincreasingthetherapeutic dose.The
reportonthetrialsmustcontainasmanydetailsaspossibleontheexpected
pharmacological effectsandtheadverseside-effects $thelattermustbe
assessedwithdueregardtothefactthattheexperimental animalsmaybe
ofveryhighvalue.
Themedicinalproductshallbeadministered viatherouteslikelyto
producetheappearanceofthepharmacological effectssought.
Wherethetrialsmustbecarriedoutwithanimalsofhighunitprice
thesequentialmethodmaybeused.
Thismethodconsistsincalculating anon-lethaltheoretical dosefor
theanimalconcernedonthebasisofthepharmacologically effective
dosesdeterminedduringtheexperimentaltrialswiththemedicinal
product,bearinginmindthemaximumtolerateddosesobservedduring
thesingle-dosetoxicitystudy,inaccordancewithpointB.l.This
doseshsllthen1ba^dminieterdd toananimalwhichshallbewatched
verycarefullyinordertoobtainasmuchinformation aspossible
regardingtheeffectsofthemedicinalproduct.Iftheanimalpresents
nosymptomsofintolerancethetestshallberecommenced withanother
animalusingahigherdosethestrengthofwhichshallbelefttothe
investigator 'sdiscretion.Iftheanimaleasilytoleratesthisnew
dosethetestshallbecontinuedwithayethigherdose.Thedose
whichmustnotbeexceededwillbefoundwhensymptomsoftoxicity
appear.Iftheanimaldies,thetestshallberecommencedwitha
lowerdoseandsoon.Ineverycasetheaimistodetermineasingle
dosagewhichenablesafavourablepharmacological effecttobeobtained
withoutharmingtheanimal.
Anyexoipientemployedforthefirsttimeinthepharmaceutical field
shallbetreatedasanactivesubstance.
/.

-23-
4.Foetaltexicit.y
Thisstudyconsistsinexaminingthetoxicandabortifacient effects
observedintheprogenywhenthemedicinalproductunderinvestigation is
alsointendedtobeadministered tothefemaleduringpregnancy.Thetests
inquestionmay"becarriedoutaspartoftheclinicaltrials.
5.Examinationofreproductive function
Iftheresultsoftheclinicaltrialsrevealanythingsuggesting
impairmentofmaleorfemalereproductive functionorharmfuleffectson
progeny,thereproductive functionmust"beinvestigated byappropriate
tests.
I
C.Studyofpharmacological properties
1.Pharmacodynamics
Pharmacodynamics meansthestudyofthevariationscausedbythe
medicinalproductinthefunctionsoftheorganism,irrespective ofwhether
thesefunctionsarenormalorexperimentally modified.
Thisstudymustfollowtwodistinctlinesofapproach.
First,theactionsonwhichtherecommendedapplicationinpractice
isbasedshallbeadequatelydescribed.Theresultsshallbeexpressedin
quantitativeterms(dose-effectcurves,time-effectcurvesetc.)and,
whereverpossible,tocomparisonwithaproductwhoseactivityiswell
known.Whereahighertherapeuticcoefficientisclaimedforaproduct,
thedifferenceshallbedemonstrated byreferencetotheconfidencelimits.
Secondly,theinvestigator shallgiveageneralpharmacological
assessmentofthesubstance,referringinparticulartothepossibility
ofside-effects.Ingeneral,themainfunctionsofthephysiological
systemsshouldbeinvestigated ;themorecloselythedosesliabletoproduce
sideeffectsapproximatetothoseproducingthetherapeutioeffectsforwhich
theproductisbeingproposed,themorethoroughthisinvestigation mustbe.
./•

-24
Theexperimental techniques,unlesstheyarestandardprocedures,
mustbedescribedinsuchdetailastoallowthemtobereproduced,and
theinvestigator mustestablishtheirheuristicvalue.Theexperimental
resultsshallbesetoutclearlyandforoertaintypesofteststheir
statisticalsignificance shallbequoted.
Unlessgoodreasonsaregiventotheoontrary,anyquantitative
modification ofeffectsresultingfromrepeatedadministration ofthedoses
shallalsobeinvestigated .
Medicinalassociations mayresulteitherfrompharmacological premisses
orfromclinicalindications.Inthefirstcase,thepharmacodynamic study
shalldemonstratethoseinteractions whichmightmaketheassociationitself
recommendable inclinicaluse.Inthesecondcase,wherescientificjusti­
ficationforthemedicinalassociationissoughtthroughclinicalexperiment­
ation,theinvestigation mustdeterminewhethertheeffectsexpectedfrom
theassociation canbedemonstrated inanimals,andatleasttheimportance
ofanyside-effects shallbeinvestigated .Ifanassociationincludesa
newactivesubstance,thelattermustpreviouslyhavebeenstudiedindepth.
2.Pharmacokinetics
Pharmacokinetics meansthestudyofthefateofmedicinalproducts
withintheorganism,andcoversthestudyoftheabsorption ,distribution ,
biotransformation (ormetabolism)andeliminationoftheproducts.
Thestudyofthesedifferentphasesmaybecarriedoutbymeansof
physical,chemicalorbiologicalmethodsandbyobservationoftheactual
pharmacodynamic activityofthemedicine.
Dataconcerningdistribution findeliminationshallbenecessaryin
respectofchemotherapeutic products(antibiotics,etc.)andproductswhose
usedependsontheirnon-pharmacjrdynamio effects,andinallcaseswhere
suchdataareindispensable todeterminethedosageforanimals.
/•

-25-
Inthecaseofnewassociations ofknown substances whichha*,been
invested inaccordance withtheprovision ,ofthisDirective ,pharmaco .
kinetic studies .hallnotberetired ifthetoxicity tests andclinical
rials justify their emission .Thesameapplies tosubstances thathave
beenshowntoboeffective andsafebyverywideusageoveraperiod ofat
leastthree years inhuman oranimal therapy andbycontrolled trials
D.Study ofresidues
For theimplementation ofthis Directive "residues' shall mean all
active ingredients ormetabolites thereof which remain jlnmeats orother
food produced from theanimal towhich themedicinal product inquestion
has been administered inaccordance with the recommended directions for use .
Thepurpose ofstudying residues istodetermine whether ,andifso,
under what conditions andtowhat extent ,residues persist infood produced
from treated animals ,and "Eoascertain -thewaiting periods tobeadhered to
inorder toobviate anyhazard tohuman health arid/or-sny -drawbacks for -the ,
industrial processing offood .
Assessment -ofthehazard duetoresidues entails ascertaining the
presence ofresidues ,ifanytandtheinvestigation oftheeffects ofthese ^
r^rddues inthe treat~"3nt .ofanimals under normal conditi ™*«? ofuse ."
1. in-V :->Tr-TMu.cs ;
Thedetermination ofresidues shall becarried outwith .dueregard
fortheresults ofthepharmacokinetic tests .Atvarying times after the
test animal .-'hasreceived thefinal dose ofthemedicinal product thequantities
ofresidues present shall bedetermined byappropriate physical ,chemical
orbiological methods ;thetechnical procedures andthereliability and
sensitivity ofthemethods employed must bespecified .Theresults must be
checked asfaraspossible ,andattheleast ,bysampling .,in .the .sick
animals forv:hich themedicinal product isrecommended .
./■

-26
2.Investip;ationoftheeffectsofresidues
a)^dHsioic(severalmonths)toxicityoforallyadministeredresidues.
Thestudyofthechronic(severalmonths)toxicityoforallyad­
ministeredresiduesshallheperformeddifferentlyaccordingtowhetherit
isamedicinalproductthatiseliminatedwithouttransformation orone
thatismetabolized.Inthefirstcasetheresearchercanworkdirectly
onthemedicinalproduct.Inthesecondcasehemustworksimilarlyonthe
principalmetabolites whicharefoundchieflyinfood.Ifthemetabolites
cannotbeisolatedorsynthesized ,recourseshallbehodtothestudyof
"relayedtoxicity"whichconsistsofoperatingwithtissuesinwhichthe
greatestquantityofresidueshasbeentracedorwithproductsfromtrcatsd
animals.
;Thetrialsmustbecarriedout,usingtheoralroute,intwomammalian
speciesoneofwhichmustbenon-rodent.Theusualdurationofthetrials
shallbe3-6months.Ifoneworksdirectlyonthemedicinalproductora
i
metabolite,thedosesmustbefixedwithdueregardfortheresiduesactually
presentandmustbeselectedinsuchawaythatthehighestdosecauses
harmfuleffectstoappearasfaraspossible,whilethelowerdosesthen
enablethelimitoftoleranceinanimalstobefound.Ifthestudyof
"relayedtoxicity"isadopted,theupwardgradationofthedosesislimited
bythequantityofresiduesactuallypresent.
*
Theevaluationofthetoxiceffectsshallbob~Ee&onrbncrvr.tion of
behaviour,growth,bloodpictureandphysiological tests,especiallythose
relatingtotheexcretoryorgans,andalsoonautopsyreportsandaccompanying
histological data.Thechoiceandrangeofeachgroupoftestswilldepend
onthespeciesofanimalusedandthestateofscientificknowledgeattho
time.
b)Othereffectsoforallyadministeredresidues
5heeffectsofresiduesonreproductive functionsmustbetestedin
rodents.

-27-
Teststorevealcarcinogenic effectsareindispensable :
1.inrespectofsubsrt^cea-faaving ,aclosechemicalanalogywithknown
carcinogenic orcocarcinogenic compounds 3
2.inrespectofsubstaEflXBorhichhavegivenrisetosuspiciouschangesduring
therepea.ted-dose toxicitystudy.
Teststorevealteratogeniceffectsareindispensable :
1.inrespectofettfeetaaawwi .basringaclosechemicalanalogywithknown
teratogenic productsj
2.inrespectofsubstanceswhichhavegivenrisetoeSiapiciOUB-ciyingeaDURINGthestudj
ofeffectsonthereproductive functions.
Thestud;'-ofteratogeniceffectsshallbecarriedoutwithatleast
twoanimalspecies:abreedofrabbitsensitivetoknownteratogenic substances,
andratsormice(specifyingthestrain).Thedetailsofthetest(numberof
animals,amountsadministered andcriteriaforevaluationofresults)shall
dependonthestateofscientificknowledgeatthetimewhentheapplication
islodged,andthelevelofstatisticalsignificancethattheresultsmust
attain.
Furthermore ,thestudyofmutageniceffectsandallergicphenomena
isalsodesirable.
Testsontheoriginationofresistantpathogenicgermsarenecessary
inthecaseofresiduesofthemedicinalproductsusedtopreventortreat
contagiousdiseasesinLlanoranimals. ''
c)Disadvantages fortheindustrialprocessingoffood
Incertaincasesitmaybenecessarytocarryoutteststodetermine
whetherresiduesconstitutedisadvantages fortechnological proceduresinthe
industrialprocessingoffood.

-28-
Thestudyoftheeffectsofresiduesinaccordancevxithpointsa)
toc)shallnotherequiredifithasbeenestablishedthatthemedicinal
producthasbeenrapidlyandcompletelyeliminatedorifitisonlyused
occasionally .Insuchcasesthewaitingperiodshallbedeterminedinsuch
awaythatmeasurableresiduesarenotincludedinthefood.
ÎM. E.Medicinalproductsfortopicaluse
Whereimedicinalproductisintendedfortopicaluse,systemic
absorptionmustbeinvestigated intheintendedspeciesofanimal.Ifit
isprovedthatSystemicabsorptionisnegligible,therepeated-dosetoxicity
tests,thefoetalVtoxicity testsandthestudiesofreproductivefunction
referredtoatpau.ntsB.2,B.4andB.5maybeomitted,
Ifithemedicinalproductisabsorbedsystemically inasignificant
quantityfromthestandpointofviewofresiduesorfromthatofpharmaco-
dynamics(concentration )orifsuchsystemicabsorptionhastobeexpected
inthecaseofaccidentaloralingestionofthemedicinalproductbythe
animal,themediciitalproductmustbeinvestigatedinaccordancewiththe
requirementsofgoijitsBtoD.
Inallcasesltestsoflocaltoleranceafterrepeatedadministration
shallbecarriedovaandshallincludehistological examinations .Wherea
medicinalproductwkichisnotsystemicallyabsorbedmayenterafoodproduct
obtainedfromthetreatedanimal(mammaryimplants,etc.),theassayof
residuesinaccordeftoewithpointDshallbecarriedouteachtime.
ChapterII:Presentation ofparticulars anddocuments
Asinanyscientificwork,thedossieroftoxicological andpharma­
cologicaltestsshallincludethefollowing:
/
a)anintroductiondefiningthesubject,accompaniedbyanyusefulbiblio­
graphicalreferences,particularly wherethemedicinehasbeenusedon
humanbeings.

-29-
t>)adetailedexperimentalprotocolgivingthereasonsforanyomissionof
certaintestslistedabove,adescriptionofthemethods,apparatusand
materialsused,detailsofthespecies,"breedorstrainofanimals,
wheretheywereobtained,theirnumberandtheconditionsunderwhich
theywerehousedandfed,stating,interalia,whethertheywerespecific
pathogen-free(SPP)ornot\
c)alltheimportantresultsobtained,whetherfavourableorunfavourable.
Theoriginaldatashouldbedescribedinsufficientdetailtoallowthe
resultstobecriticallyevaluatedindependently oftheirinterpretation
bytheauthor#Bywayofexplanation andillustration ,theresultsmay
beaccompanied byreproductions ofkymograms,photomicrographs ,etc.5
d)astatisticalanalysisoftheresults,wheresuchiscalledforbythe
testprogramme,andvariancewithinthedata5
e)anobjectivediscussionoftheresultsobtained,leasingtoconclusions
onthetorcicological andpharmacological propertiesofthesubstance,
onitssafetymarginsintheintendedanimalanditspossibleside-effects ,
onitsfieldsofapplication ,onitsactivedoselevelsandanypossible
incompatibilities 5
f)informationshowingwhetherthecomponentsofthemedicinalproductare
usedasmedicinalproductsinhumcntherapy;ifthisisso,areport
shouldbemadeonalltheeffectsobserved(includingside-effects )in
Hanandontheircause,whereappropriateinthelightoftrialresults
orbibliographical documents }wherecomponentsofthemedicinalproduct
arethemselvesnotusedasmedicinalproductsinhumantherapythe
reasonsshouldbestated?
g)adetaileddescriptionandathoroughdiscussionoftheresultsofthe
studyonthepresenceofresiduesinfoodandanassessmentofthehazards
theyconstituteforMan.Accountshouldbetakenofallthefactorswhich
maybeofimportance,particularly withregardtocustomarydietandlevels
ofcontamination byforeignmatterpresentintheenvironment.Inthe
caseofeachrecommendeduse,thisdescriptionshallbefollowedbypro­
posalsconcerningthewaitingperiodswhich,allowingforanadequate
/.

-30-
safetymargin,mustbesoestablished astoensurethatnofarther
residueremainsinfoodor,ifthisisimpossible,toensurethatany
dangertoIlaniseliminatedbyapplyinginternationally recognized
assessmentcriteria(dosedevoidofeffectinanimals,acceptabledaily
dose,safetymarginof..l:100or1:100accordingtoavailable
information,etc.);
h)allinformationnecessarytoacquainttheclinicianasfullyaspossible
withtheutilityoftheproposedproduct.Thediscussionshallbe
supplemented bysuggestions astopossibletreatmentforacutetoxic
reactionsinanimalstowhichtheproductistobeadministered and
forside-effects ,
i)asummarytogetherwithpreoisebibliographical references.
/.

Part3
CLUÏICALTRIALS
Theparticulars anddocumentswhichmustaccompanyapplications for
marketingauthorizations puraaanttoArticle4»point10,secondparagraph,
ofCouncilDirective of shalltoesubmittedin
accordancewiththeprovisionsofChaptersIandIIbelow.
ChapiferI:Conductoftrials
Thepurposeofclinicaltrialsistodemonstrateortoascertainthe
therapeuticeffectofthemedicinalproduct,tospecifyitsindications and
contrar-indicationsaccordingtospecies,itsdirectionsforuse,anyside-
effectsitmayhaveanditsharmlessness undernormalconditionsofuse.
Clinicaltrialsmustbeprecededbyadequatepharmacological and
toxicitytestscarriedoutinaccordancewiththeprovisionsofthis
Directiveand,wheretheyarepracticable ,bytestscarriedoutpreferably
ontheoneormoreanimalspeciesforwhichthemedicinalproductisintended.
Theinvestigator mustacquainthimselfwiththeconclusionsofthese
preliminarytrials.
Asfaraspossible,clinicaltrialsmustbecarriedoutwithcontrol
animals(controlledclinicaltrials)?ifitiseconomicallyjustifiable,the
therapeuticeffectobtainedshouldbecomparedbothwithaplaceboandwith
absenceoftreatmentand/orwiththeeffectofamedioinalproductofknown
therapeuticvaluethathasalreaclybeenused.Alltheresultsobtained,
whetherpositiveornegative,mustbereported.
Themethodsusedtomakethediagnosismastbespecified.Theresults
mustbesetoutbymakinguseofquantitativecriteriaorcriteriarepresented
bysymbols(crosses,etc.).
/.

k ■
\
f*32-
Chapter II:Particulars and documents
Particulars concerning clinical trials must besufficiently detailed
toenable anobjective judgement tobemade .
1.Records ofclinical observations
Alltheparticulars must besupplied byeach oftheinvestigators on
individual record-sheets ofclinical observations inthe ease ofcollective
treatment .
Theparticulars supplied shall beclassified asfollows :
..a)name ,address ,function anduniversity qualifications ofinvestigator ;
b)place anddate oftreatment }name andaddress ofowner oftheanimals ;
c)inthecase ofindividual treatment andcollective treatment ,ifthe
latter has tjeen given ,full identification ofthetrial animals ,names
orregistered numbers ,species ,breeds orstrains ,age ,weight ,sex
(inthecase offemales ,specify whether pregnant orinmilk and,in
thecase ofbirds ,inlay,etc.)}
d)method ,ofrearing andfeeding ,stating thenature andquantity ofany
additives contained inthe feed }
e)case history (asfull aspossible )}occurrence andcourse ofanyinter -
current diseases }
f)diagnosis andmeans used tomake it;
g)symptoms andseverity ofthedisease ,ifpossible giving criteria represen –
1tedbysymbols (crosses ,etc.);
h)dosage ofthemedicinal product ,method ,route andfrequency ofadministra­
tion andprecautions ,ifany,taken during administration (duration of
injection ,etc.)}
i)duration oftreatment andperiod ofsubsequent observation }

-33-
j)alldetailsconcerningmedicinalproducts(otherthanthat"beingassayed)
whichhavebeenadministered duringtheperiodofexamination ,either
priortoorconcurrently withthetestproductand,inthelattercase,
detailsoftheinteractions observed;
k)allresultsoftheclinicaltrials(includingunfavourableornegative
results)withafullstatementoftheclinicalobservations andthe
resultsoftheobjectivetestsofactivity(laboratoryanalyses,physio­
logicaltests),requiredtoevaluatetheapplication ;thetechniques
usedmustbespecified,andthesignificance ofanyvariationsinthe
resultsexplained(forexample,varianceinmethod,variancebetween
,individualsortheeffectsofthemedication);demonstration ofthe
pharmacodynamic effectinanimalsshallnotalonesufficetojustify
conclusions concerninganytherapeutioeffect;
l)allparticularsoftheobservedside-effects ,whetherharmfulornot,
andofanymeasurestakeninconsequence ;relationofcauseandeffectmust
beinvestigated withthesamecarenormallyaccordedtoidentifying a
therapeuticeffect;
m)effectonanimals1performances (egg–laying,milkproductionandreproduc­
tivefunction);
n)anopinionconcerningeachindividualcaseor,whereseveralseriesof
collectivetreatmentareconcerned,anopiniononeachcollectivecase.
Omissionofoneormoreofitemsa)ton)mustbeexplained.
When,inrespectofparticulartherapeuticindications,theapplicant
canshowthatheisunabletoprovidecomprehensive dataontherapeutic
effectbecause:
a)theindicationsforwhichthemedicinalproductinquestionisintended
areencountered sorarelythattheapplicantcannotreasonablybe
expectedtoprovidecomprehensive evidence;
b)inthepresentstateofscientificknowledge,comprehensive information
cannotbeprovided,

-34
marketingauthorization maybegrantedsubjecttothefollowingconditions:
a)themedicinalproductinquestionshall"besuppliedonveterinaryprescrip­
tiononlyandshall,incertaincases,"beadministered onlyunderstrict
veterinarysupervision ;
b)thepackageinsertandanyotherinformationshalldrawtheattentionof
theveterinarypractitionertothefactthat,incertainspecifiedrespects,
theparticularsavailableconcerningthemedicinalproductinquestion
axeasyetinadequate.
Thepersonresponsibleforplacingtheveterinarymedicinalproduct
onthemarketshallmakeallnecessaryarrangements toensurethatthe
originaldocuments,whichformedthebasisofthedatasupplied,arekept
foratleastfiveyearsasfromthedateoftransmission ofthedossierto
thecompetentauthority.
2.Sùmmaryandconclusions
Theclinicalobservations referredtoinparagraph1aboveshallbe
summarisedinasynopsisofthetrialsandtheirresults,indicating:
a)thenumberofanimalstreatedeitherindividuallyorcollectively ,witha
breakdownaccordingtospecies,breedorstrain,ageandsex;
b)thenumberofanimalswithdrawnprematurelyfromthetrialsandthereasons
forsuchwithdrawal ?
c)inthecaseofcontrolanimals,whethertheyhave:
–receivednotreatment;
-receivedaplacebos
–receivedanothermedicinalproductofknowneffectj
d)thefrequencyofobservedside–effects;
/.

-35-
e)details concerning test animals which mayheatincreased risk owing to
their age ,their mode ofrearing orfeeding ,orthepurpose forwhich
they areintended ,oranimals whose physiological orpathological condition
requires special consideration ;
f^astatistical evaluation oftheresults ,when this isentailed "bythe
programming ofthetrials andthevariability ofthefactors involved .
Finally ,theinvestigator shall draw general conclusions from the
experimental evidence ,expressing hisopinion onthefcarsleeenese -cftheno&icinr.l
product ,under normal conditions ofuse ,itstherapeutic effect andanyuse­
fulinformation relating toindications and contrar-indi cations ,dosage and
average duration oftreatment and ,where appropriate ,anyinteractions
observed with other medicinal products orfeed additives aswell asany
special precautions tobetaken during treatment andtheclinical symptoms
ofoverdosage .
...000OOO000 ...