BB-NCIPD. Ltd.. Solia. Bulsaria DIFTET C2119 p.l

EYJI EIIO - HU3TIE EOO.II BB - NCIPD Ltd.

1504 CoOn ,6yn.rHto Carosos 26Oarc: **359 2 943 34 55

TeleQou Vnpaaurer:**359 2 9446 t9te-mail : bulbio@bulbio.com

lnlernational name

Tradc name/commetcial name

Product licence (marketing authorization)numberCountryName and address of manulacturer

Final packing lot numberT-Ype ofcontainerNumber ofcontainers in this package lotFinal conlainer Iot numberNumber of filled containers in this final ldDatc ofnranufacture

Nature of final productPreservative and nominal conccntrationVolume ofcach single humalr dose

Number ofdoses per tinal containerNumber ol'doses pcr secondar-n. packagcs

ShelI-lilc approvedExpir] datc

Storage condition

1504 Sofia. 26 Yanko Sakazor blvd.Fd(: **359 2 9,ll 34 55

l elephone Ccncral Nlandger:**359 2 9.1.16 r9lc-ml] i I : hu I bio r-rbulbio.conl

SUMMARY PROTOCOL FOR DIFTET

DT VaccineDIPHTIIERIA AND TETAI{US VACCINE (Adsorbed)

Susp.inj.,vials- 5.0 ml - l0 doses, IM

Summary information on the firlal lot

Diphtheria and letanus Vaccioc(Adsorbcd)

Ditiet

20011158BulgariaBts - NCIPD I,td,150,1, Sofia.26 Yanko Sakazov Blvd

.,? I I9Vial,5.0 ml,16 200C2I I917 )2301.1t.20t6

adsorbedI0 9/o Ihiomersal0.5 nlll0 doses100

i6 monthsOclober 20192 -8'CNot to he frozen!Shake belorc usel

BB-NCIPD, Ltd., Sofia, Bulearia DIFTET C2119 p.2

Production strain and seed lots

Struin Corl n ebactcriunr Diphtlreriae PW,'S

Ide tily of (bry-nebaclerium Diphtheliae identicalusedJbr vtcci e pro.luctionReference .\b q/ seed lot 2

Dates oJ'reconsthution ol ampoules for 21.03.1016

Single har!ests used for preparing thc bulk purified toxoidSingle harvest CDI 195

Medium (lascin-hvdrol) sate

Dales ofinoculation 29.03.2016'I'emperature of incubation 35"uDates ofharvest 31.0i.2016Volumes 173.0 I

Yields /Lf/ l3 8.10 000Bacterial puriiy test:Method: Gram slainingDate: 31.03.1016Rcsult: passed

Method ofdetoxificatiorl: lormaldehyde 37 %;5.5 ml per 1000 mll5 da),s

Date ofstart and flnish: i1.03.2016-05.05.2016Volume of inactivation: 17i.0 1

Temperature: ,+0 "CConcentration ofdetoxitication agcnt: 3'7 %

Confi rmation of detoxifi cation ( beforepurification):Te st./ir a bsenc e of d i pht he ri o toxinMcthod Animal test in guinca pigs

Specification NoDe ol the animals shorvs abnornralreacllon

,Nfi ot'guinea-pig. injected lDate olinjection 09.05.2016

ose and route ofinjection 80 I-flmll 5 X 0.2 ml : s.c.

Date ofend ofobse lion 13.05.2016Rcsult oftest passed

Bulk purificd Diphtheria ToroklBatch Ns PDT i22Volumc and Lf/ml 6.0 l:990Date ofproduction 12.07.2016Yield /Lll 5 9'10 0001.f

BB-NCIPD. Ltd.. Sofia. Bulqaria DIFTET C2119 p.3

Method,Dateand result oftest for antigcnic purity (Lfl mgPN)

Test.lbr irrerer\ibil ityMethodSpecification

Lf/ml oltest toxoid solutionTcmperature of incubation oi tesled toxoidDates olbeginning and end ol incubalionN! ofguinea-pigs injected, route and dose,date ofiniection

Dale of end ofobscnationResult of lest

Tesl lbt abscnce ofdiphtheria toLritl

MethodSpecification

Ne of guinea-pigs injectedDale ofinjectionN ofLfpcr guirrea-pig. dose and route o1'

iniectionDate of end of observationResult of est

Steriliry- testMethod:Media and temperature of incubation:

Number of bulk (containers) tested:Volume of inooulum per bulk (containcrs):Volume ofmedium pcr bulk (containers):Date of start oftestDate of end oftestResultFree (residtral) detoxiJjing dgenl conlentMethodSpecilicationDetoxil'ying agentDate and resull oIlest

Lf/ml / Protein niirogen.t3.07.20 t6:t9l3

Animal test in 8uinca pigsNone olthe animals shows abnormalrcactioll30: 30;i7.C: 2-8 "C:11.07.2016 2i.0u.20165; 5:s.c-2x2.5m1:2i.08.20 t604.r0.20r6100 per cent survi\ ing

Aninral lest ir guinea pigsNone ol lhe aninrals !ho\\,s abnormalreaclion5

2i.08.2016990; 1.00 mlr s.c.

0.1. r0.2016passed

Dircct inoculalionsoya-bean cascin digcst mcdia with\udrunr ihro!lJcolaIc ll.r t l.: Lfluid thioglycollatc 12.5 l:2.5 rC

2

20.0 ml130.0 mlr2.07.201626.07.2016passed

QualitativcI 0.2 9,1lormaldehldet5.07.2016< 0.2 g/l

BB-NCIPD. Ltd.. Sofia. Bulearia DIFTET C2119 p.,l

Production strrin and seed lots

Strain CorYncbactcriLrnl Diphthcriac PW/8lLle tit!ofCorynebdcteriwn Diphtlleriae identicalused Ji)r |acche produclionReJbrencc Nt ol seed lot 2.

l)dtes of reconstil ut ion o/ ampoules.for 10.03.2016

Singlc hanests uscd for preparing the bulk purificd toxoidSingle haNes! CDI 196

Medium Casein hl drolysatcDates ofinoculat;on 05.0,1.2016Temperature ol incubation l5"CDales ofharvest 07.0:1-2016Volumes 171.0 I

Yields /Lf/ 17 i00 000Bacterial puritv test:Method: f;ram stainingDatc: 07.0'1.2016I{esult: Dassed

Method of detoxification: Formaldeh)de l7 o./o 15.5 ml per 1000 ml35 da)s

Datc olstart and finish: 07.01.2016- 12.0-s.l0l6Volume of inacrivation: 171.0 I

Temperature: 40 "CConcentration ofdetoxification agent: 37 %

Confi rmation of dctoxifi cation ( beforepurification):T est _fo r a bse nce of di pht heri d to.ti nMethod Animaltcst in guinea pigsSpecification None ofthe animals sho\ls abnormal

.N! ofguinea-pigs injected 2

Date of injection 16.05.2016d se and route ofinjection 100 Lllhl:5 X 0.2 nrl : s.c.Date olend ofobservarion 20.05.1016Resull oftest passed

tsulk purified Diphtheria ToxoidBatch N! PDl i23Volume and LlJml ILo l:900Date ofproduction 19.07.2016Yield /L / 9 900 0001.1

BB-NCIPD. Lt'd.. Sofia. Bulearia DIFTET C2ll9 p.5

Method, Lllml / I'rotein nitrogen.Dale 02.08.20161and result ofresr for antigcnic purit,v (LfJ mg I692PN)

Te s t.fr tr i tew rs i b i li tyMethod Animaltest in guinea-piesSpecification None ofdre aninrals shows abnornral

reaclronLlTml oftest toxoid solution 30; loiTemperature ofinoubation oftcstcd toxoid 37"Ci 2-8 "C;Dates of beginning and end of incubation 19.07.2016 10.08.2016,rVo ol'guinea-pigr inj<.ted. r'outc eld do.c. i: 5.

date of injection s-c. 2 x 2.5 nrli10.08.2016

Date ofend ofobservation 11.10.2016Result oftest 100 per cenl surliling

Test_/rtr ahsence ol dil:htherid toxinMethod Animal test in guinca piSsSpecificatiorl \one ofthe aninrals sho*s abnonral

J,l! ofguinea-pigs injcctcd 5

Date of injeorion 10.08.2016NrofLfpcrguinea-pig.doseandrouteol 900: l,0l)ml:s.c.iniectiorlDate ofend ol obser\'ation 11.10.2016Result of est passed

Steriliry testMethod: Di|ecl inooulationMedia and temperature ofincuhation: so)a-bean casein diges! media wilh

..diur'i rh'^el\cohre.'a j '.< (

fluid rhiogl)collate 12.5 t 2.5 LrC

Nurnber of bulk (containers) tcstcd: lVolume ol inoculum per bulk (containcrs): 20.0 mlVolume olmedium per bulk (containcrs): 80.0 mlDate of srart oftcst 19.07.2016Datc ofend oftest 02.08.2016Result passedFree lre\idttdl) deloxif)ing dgenl conlcnlMethod eualilali\eSpecillcation : 0.2 si I

Deloxil.\ ing agenl lo.t.:lloclt\ocDale and resulr oltest 0.1.08.2016

<02g,'l

BB-NCIPD. Ltd.. Sofia. Bulgaria DIFTET C2119 p.6

Production strain and seed lots

Strdin Clostfidium tetani Harlard .1i.ll5lde tiry oj Cl. tetdniused _lr'rdccine identical

Relbrence .Ni ofseed la! 3

l)atesofreconstituli)nofampoules.fitr 22.11.2015

Singlc hanests used for preparing the bulk purified toroid

Single ha|vest CIT ,185

Mcdiurr Casein-h'-drol)sa1eDates of inoculation 26.11.2015

Temperature of incubation 35 + l"CDates ofharvcst 02.12.2015Volumes 100.0 I

Yields /Ll7 28 500 000Bacterial purit,v test:Method: Cram stainingDate: 01.12.1015Result: pussed

Merhod ofdetoxification: forrraldehyde 37 9ri,:5ml pcr 1000 ml2l days

Date ofstart and finishr 02.12.2015 11.12.2015Volumc of inactivation: 300 I

Iemperature: 36+ I "CConcentralion ofdetoxification agcnt: 37 o./a

Confi rmation of detoxifi cation ( bet'orepurificalion):Testfot dbsence ofteta us torinNo ol guinea-pigs injected and datc ol l0: 07-01.2016injcctionDosc and route ofinjeclion 95lflm1;2 X 2.5 ml ;s.c.Date ofend ofobservation 28.01 .2016Result oltes I00 per cent sur'\'i\,ir1g

Bulk purified Tetanus Torioid

Batch ,\! PTT,108Volume and Lflml 30.0 l: 900Date ofproduction 01.03.2016Yield /Lfl 27 000 000 Lf

BB-NCIPD. Ltd.. Sofia. Bulearia DIFTET C2119 p.7

Method.Dateand result oftcsl for antigcnic purity (Lll mgPN)

Tcsl f)r irret,elsihili tyMcthodSpccificatiorl

LtTml oftest toxoid solutionIemperature of incubation oftested toxoidDates ofbeginning and cnd of incubaiionNe ofguinea-pigs inlccted. route and dose.date ofinjection

Date of end ofobservationResult oftest

Tes/-fbr absence ef tetanus toxinMethodSpecification

.Na of guinea-pigs injectedDate olinjectionNo oll.fper guinea-pig. dose and route ofiniectionDate of end of observationResult ol lest

S/eriliry^ te\tMetllod:Media and temperature of incubation:

Number ol bulk (containers) tested:Volume ofinoculum per bulk (conlainers):Volunrc olrrcdiurr per bulk (conlainers):Datc of start oftcstDate ofcnd oftcstRcsultFree (resiitral) detoxifiing uge tco lenlMethodSpecificationDetoxifying agcntDate and result ol test

Lflml / Protein nitrogen,r 0.03.2016;13 39

Animal tcst in guinea-pigsNonc ofthc anirnals sho\s abnolmalreaction20r 20;37"C: 2-8 "C:02.03.20 I 6 - I 3.0,1.20 I 6

5:s.c.2 x 2.5 nrl:1i.04.20160,+.05.2016passed

Anirral tcst in gLrinca-pigsNone ofthe anirrals shou,s abnor'rralreaclion5

Ii.0.l.l0l6LX)o; 1-00 mli s.c.

0,+.05.201 6passed

Dircct inoculationsova-bcan cascin digcst mcdia \\,ith.odLurn rhrogl!!ulirte 2].) t 2 ) (

lluid thiogl)collale 32.5 t 2.5 "C)20.0 ml80.0 ml0 t.03.20 t615.03.20 t6passed

Qualitative0.2 g,l

lb naldehtdeI 1.03.2016< 0.1g/l

BB-NCIPD. Ltd.. Sofia. Bulgaria DIFTET C2119 p.8

Final bulkvaccine

Lotnumber FBDT 119tDate ofmanufactue/ blending 01.11.2016Volurne 295.2801Lflml for Purified Tetanus Toxoid 20 +2Lflml for Purified Diphtheria Toxoid 30 +3

Tests on Iinal bulkpEMethodSpecificationDate oftestResult

Alurfliniam coLlerrtMethodSpecificationDate of testResult

Anlimicrubial prese dl e - ThiomersalMethodSpecificationDate oftestResult

Sodiut , chloride contentMethodSpecificationDate oftestResult

Polentiomelfic6.0 7.00l. t L20 t66.68

( omplexometfic litralion: 1.25 mgi0.5 nrl03.11.20160.57 mgi0.5 ml as A1* *

Colorimctric0.037- 0.050 mg,'0.5 ml03.11.20160.0.11 m8i 0.5m1

Potcntiomctric titration7.0 10.0 g/l02. r I .20168.71 pll

Identification Prcscription(SI ID')

Added

Diphtheria toxoid PDT 322PDT 323

l0+3 Lli'ml 4.465 I

3.980 I'Ietanus toxoid PTT 408 20 + 2 Lilhrl 6.000 I

Adjuvant:Aluminium hydroxidegel

Ne 389l.2l

(A1 in e/l)

280.0 + 28 I 280.555 r

PrcseNative:Thiomercal 10 per cent

K45390043 0.05 ms/0.5 ml 0.2{J0 I

Final vohrme 295.0 I 295.280 I

BB-NCIPD. Ltd.. Sofia. Bulearia DIFTET C2119 o.9

Free fomaldehydeMethodSpecificationDate of testResult

Degrce of adsorption for tetanusMethodSpecifioationDate of testResult

Degree of adsorplion for diphtheriaMethodSpecificationDate oftestResult

Specilic loxicily test for tela us andtliphlheriaNumber of guinea-pigs injectedVolume and route ofinjectionDate ofinjectionDate ofend of observation forletanusDate of efld ofobservation for diphtheriaResult of test

Potenc! testFor dip hl herid co mponent(l) Based on lethal challenge(2) Four-dilution assaySpecies and weight ofanimalsDate of immunizationRoute of injection and volume ofdilutionsadministeredDate of challengeChallenge toxin usedChallenge lethal doseDate ofend of observatioll

Qualitativc! 0.2

-1rll01.11.2016< 0.lgil

I locculationt809609.11.20t6l0(l per cent

Flocculation:800;09.11.2016100 pcr ccnt

5

2.5 rrl: s.c.;0r.r 1.201622.1t.20t6I 3. 12.t0 l6I00 per ccnt surviving

guinea-pigs (250 - 150 g)01.|.2016s.c:1 ml

29.11.20r6Ne,l: Ce(iilcate lY! I116.05.2016I ml = I00 I.D.,l01.12.2016

BB-NCIPD. Ltd.. Solia. Bulearia DIFTI,T C2119 p.10

Result:

DilutionIU

l\! ofsurvivors ,/ Nq ofaninrals inicctcd

Nicdian clfcctir.c dosc(ED .,,)

Relerencevaccine

( I00 IUi ml)

40)010

5

8/8618

2/80/8

14.14(9.4s 21.t6)

Test vaccineFBDT 1I9t

402010

5

8/85i83/8r/8

12.80(9.25- t',|.70)

Potency oflest vaccinc for diphthelia is 55.25 ILI per single human dose. Ihe conlidence inter!al(l':0.95) is 31.40 98.54 per single human dose.'lhe statistical analvsis shows no deviation liom linearil) and parallelism oI the dose-response

Fot teldnus compofient(l) Based on lethal challcnge(2) Four-dilution assalSpecies and weight olanimals guinea-pigs (250 - 350 g)Date of immunization 01.11.2016Route of injection and volume ol dilurions s.c: l mladministeredDale ofchallenge 29.11.2016Challenge toxin uscd .Ilq ,1: Certillcale N! 6/07.09.201 6Challenge lethaldose lml . 50 LDnrDate ofend ofobservation 04.12.2016

Result:Dilution

IIJ,\! ofsurvivors / Nr of

animals iniected\4cdian cffcctivc dose

(ED N)Ref'erencevaccine

(l60 IU/ml)

t68

42

8/8618

2t80/8

5.66(4.19 7.64)

Test vaccineFBDT I 1St

l68

42

8/86/83/80/8

5.22(3.92 6.94)

Potency of test vaccinc for tctanus is tt6.7,+ Itl pcr single hulnan dose. Ihe conlldence inlerlal(P:0.95) is 55.I2 I36.70 per singlc human dosc.

The statistical analysis shows no deviation l'r'om linearitl and parallclism ofthe dose-responsecurves.

BB-NCIPD. Lt'd.. Sofia. Bulgaria DIFTET C2119 p.11

Final lotLot numbcrDate offillingType ofcontainerNumber of containers after inspectionfillirrg volurre

\4cthodSpecification

c2l l90t.11.1016Vials.5 ml,+6 2005.0 ml

VisualSuspension ofuhite or gra) particlesdispersed in colorlcss or palc l,cllon liquiclsand ma\ linm a sedinlenl at lhe bottorn olthe conuiner02.r.2016l'assed

Lnmunodiilusion.Idcntit)t0 I I r0t6passed

lmmunodiffusion.Identilt10.|.20t6passed

Vlcasurc:5.0 ml (10 doscs)02.|.201610 doses

Potcnriomctric6.0 7.002.11.20166.73

Complcxolnctric titratiolr! l.l5 mgi0.5 ml0t I I 20 t60.59 mgiO.5 ml as Al+

Date of tcstResult

Idehtity of e\ch compqnentTest fbr diphtheria toxoid - methodSpecificationDate oftestResult

Test lbr telanus toxoid - methodSpecificalionDatc oftcstResult

Extrdctoble Nol fieMethodSpecification

Result

pHMcrhodSpeciticatiorlDate oltestRcsult

Alaminium co lenlMethodSpecificationDate oftestResult

BB-\-Cll>D. Ltd.. Solia, Bulearia DIFTET C2119 p.12

Test for sleriwMethodl$ of times the test had to be performedJli! of containers testedMedia and temperaturcs of incubation

Volume inoculatedVolume ofmedium per containerDate of staxt of testDate ofend oftestResult

Preservative conterrl - Thiome$alMethodSpecificationDate of testResult

Sodi am chloride co ntenlMethodSpecificationDate oftestResult

Residual fiee detoxilying agent conte tDetoxiling agentMethodSpecificationDate of testResult

Innocuity teslStrain ofanimalsNumber of animalsRoute ofinjectionVolume of injectionDate ofinjectionDate ofend of observationResultInspeclian ofjinal conta tersDate of inspection

Organoleptic chamcteristicsNumber of containers inspectedoZ of rejected containers

Direct inocula!iorlI

x20sova-bean casein digcst media uith sodiurrthiogl)colate 22.5 + 2.5 '"Cflrid thioglycotlate i2.5 t 2.5 lrc

20 x 2.5 ml130 ml01. .20t623. .2016passed

alolorimctric(1.0:17-0.050 nrg/0.5 ,11l

03. r r .20160.0:11 rng/0.5rrl

Polenliolnetric titration7.0 - 10.0 g/l02.11.20168.76 g/l

forrraldchyde

Qualitative:0.2 g/l0:l.l 1.2016< 0.2 g/l

M ice5

Guinea pigs2

intrapcritoneall,0.5 ml 0.5 ml0i. t 1.201610.11.2016passcd

12.01.:0r7Il.0l .2017Visual47 |01.98 %

BB-\CIPD. Lld., Sofia. Bulsaria DIFTET C2t tq n.tJ

Certification by the manufacturer

Head of Production Department: ........... :...\PhD

Certificalion by lhe person.fl-om the control lebor.tto\) of the no ufLtcttffing can/\tA, t.tkineoverall responsibility lbr lhe production alld control oj the fitccinc.

Head ofQC Department:Dr. J. Cenkova. MD

raccines (\\'HO IItS No.1)80. l(11.+) and Lurop.a| Phlrnracono.l.r.

IIcad of Q,\ Dcprftment:

I)atc 16.01.1017

Dr. S. T rov. MD

Dr.

I cc(i1\ lhat 1.ot I"! Clll9 Diliet (Dl Vaccine). Diphrhcril rnd tcLanus rrccinc (.\dsorbc.l).\\ho\e nunrbcr appears on the labcl oflhc lllxtl coItaijl.r\. ntcets all nalioIil rcqLtircItcn1\ eIalsatisliesParlAol_rhc\\'llOReconrlrcndalionstorssL[.lhcqua]it\.sllil\aIJ.t]lcac\o1 l)l-l)urc(l

(

6erexrn

Ne na cepruSurara:

Crpana [r3HocureJl(cepmQraquparqa crpaua) :

Crpana BHocI4TeJI

(crpana saxerzter):

9039

EbJIIAPI,Ifl

KAHAAA

No. of Certficate:

Exporting (certifzing)country:

Importing (requesting)country:

oe0

9039

BULGARIA

CANADA

,ffi, PEnYSrl l,l KA Et rIfAPnf,l,l3nrrnnrarenHa a reH qnf, no reKa pcrBaraREPUBLIC OF BULGARIABulgarian Drug Agency

rr rrpoAyKTl

H CbruracHo MoAeJra,

opraHr43arlu_rr

us.uo6gcuwrentu

Certificate of a Pharmaceutical Productr

This certificate conforms to the format recommended bythe World Health Organization (general instructions andexplanatory notes attached)

t.2

1.3

1 TrproBcKo Har4MeHoBaHLIe I{ neKapcrBeHa QoprraaHa npoAyKra:Diftet susp. inj. amp. 0.5 ml (1 dose) x 10, x 50;susp. inj. vial 5 ml (10 doses) x 10;susp. inj vial 10 mt (20 doses) x 10

1.1 ArrusHu ueruecrra2 Ir KoJII{qecrBo Ha aKTI4BHo

BerrlecTBo 3a Ao3oBa eArtrqa:3

Diphtheria Toxoid > 30IUTetanus toxoid > 40 IU

3a rrcmtuyi xarlecrBeH cbcraB, BKn. rIoMoIrIHI,ITe BellrecrBa,

nux flpurox"rr.ro.4

Paspenreu Jtu e 3a ynorpe6a JIeKapcrBeHI4-,Ir

rpoAyKr B crpaHara ueHocurer?5

XAu nn.flycHar Jrrr e neKapcrBeHllf,T rlpoAyxr Ha rla3apa B

crpaHara rasHocurel?

XAu En.Aro orronop'sr sa 1.2. e.{a, upo4uxere cac cexquz,s.2Au

[porrycHere cexqus 28.

Aro orronop'l'n sa 1.2. e He, rporrycuere cerqru 2,{ n[poAbnxere crc cerqnx 28.6

2A.1 Nr Ha pa:peureHrrero sa yuorpe6aT na

iIeKapCTBeHI{rI IIpOAyKT V [aTa Ha ITBAaBaH€TO My:

I Name and dosage form of product:

Diftet susp. inj. amp. 0.5 ml (1 dose) x 10, x50; susp. inj. vial 5 ml (10 doses) x 10;susp. inj vial 10 ml (20 doses) x 10

1.1 Active ingredient(s) 2 and amount(s) per unit

dose: 3

Diphtheria Toxoid > 30 IUTetanus toxoid > 40 IU

For complete qualitative composition including excipients,

see attached. 4

Is this product licenced to be placed on the

market for use in the exporting country?s

Xves f]NoIs this product actually on the market in thisexporting country?

XYes [NoIf the answer to 1.2 is yes, continue with section 2A andomit section 28.

If the answer to 1.2 is no, omit section 2A and continue

with section 2B.6

2A.l Number of product licenceT and date of issue:

t.2

1.3

[*-k]

II-15235/ll.l0.20ll II-15235/tt.t0.20tl

6yr. t'.fluro Ca

,t)

- f \=-.--i/3a rareropnn 6 H BltrMeio ta alpec'br Ha

[polr3BoArrTeJrfl Ha neKapcTBeHI,I{ npoAyKT

2A.2 llpnrexarer Ha pa3perrreHrrero 3a yuorpe6a(rrue u agpec):

EyrBuo-HI{3IIB EOOA

24.3

2A.3.1

21..4 llpl,rrtoxeno lu e Pesrovre Ha ocHoBaHrrrra 3a

rr3AaBaHe Ha piBperueHue sa ynotpe6a?10

XAu nn"2A.5 fl:rnna nr{ e npunoxeuara o$uquamro ogo6pena

un<[oprraauux 3a neKapcrBeHl,Ir npoAyrr I.r B

cboTBeTcTBt4e JIpI e c pa3pelueHl.reTo 3a

yuorpe6a?rl

XAa nn" I rr. e npr{JroxeHa

2A.6 3arnurer Ha cepruSuxata, a cryrafi ue epa3nHqeH oT flplrTexaTeJrf, Ha pa3pelueHl,IeTo 3a

ynorpe6a (rnae r.r a4pec):12

2B.l 3asnurer na ceprutfuxara (uue u a.qpec):

28.2 Craryr ra garrrrerr:8

na Eo ns28.2.1 3a rareropuu 6 lr n nuero r{ aApecbr Ha

[por{3BoAr{TeJlfl Ha roToBr,r, JIeKapcTBeH rIpoAyKT

ca:9

28.3 3aulo se e r,BAaAeHo PaspeureHue :a ynorpe6a?

He ce ugucxsaHe e gaqseHo

B npoqegypaOrras

Product-licence holder(name and address):

BulBio-National Center of Infectious andParasitic Diseases LTD26 Yanko Sakazov Blvd.1504 SofiaBulgariaStatus of product-licence holder:8

24.2

24.3

Xa Eu nc2A.3.1 For categories b and c the name and address of

the manufacturer producing the dosage form

ar",9

2A.4 Is Summary Basis of Approval appended?1o

XYes EN,2A5 Is the attached, officially approved product

information complete and consonant with the

licence?11

X Yes n No n Not provided

2A.6 Applicant for certificate, if different from

licence holder (name and address):12

28.1 Applicant for certificate (name and address):

28.2 Status of applicant:8

na Eu nc28.2.1 For categories b and c the name and address of

the manufacturer producing the dosage form

ure:9

28.3 Why is marketing authorization lacking?

n Not requiredE Not requestedn Under considerationn Refused

28.4 3a6erexxa:13 28.4 Remarks:l3

3.2

-1_ .)

3.2

-)-,

floMerqenusra 3a npol{3BoAcrBo Ha neKapcrBenl,If,

lpoAyKT noAnexaT nlr Ha nepuoAl{rIHI,I [poBepKLI

or peryJraTopHr,rf, opfaH, H3AaBaIII Hacro.flIul{llcepru$urat?

XAa nH" I Henpuno*r*ol4

Axo orronopbr e He I{,JII{ HenpuJroxlrMo ce [peMI4HaBa

xru nrnpoc 4.3.1 Ileprao,4rvnocr Ha pyrl{HHl4re flpoBepxu (ro4unu) :

3 roAuHu

I{:nrpurena Jrr4 e npoBepKa Ha [polr3BoAcrBoro Ha

ro3rr BrrA neKapcrBeHa ([opua?

XAu In"floueulenusra u [poI,I3BoAcrBeHI,ITe Aefi nocrucborBercrBar nlr Ha craHAap:rure :a 4o6panporr3BoAcTBeHa IrpaKT?IKa, IlpenopbrlaHl,I oT

c30?ls

XAu En" I Henpruro*rrol4

4. flocramuna tu e 3a peryJlaropHlrfl opraH,r.BAaBarrI cepruQuxara, [peAocraBeHara or3af,BI4TeJI{ I,rnrpoprr,raqu.a, rro orHorueHl{e Ha BcLrqKI{

acrreKTr,r oT rrpor,r3BoAcrsoro?16

XA, ns.Axo otronopbr e He, MoJIf, rlof,cHere:

Does the certifuing authority arrange forperiodic inspection of the manufacturing plant inwhich the dosage form is produced?

X yes n No I Not appticablel4

Ifno or not applicable proceed to question 4.

3.1 Periodicity of routine inspections (years):

3 years

Has the manufacture of this type of dosage formbeen inspected?

[Yes ENo

Do the facilities and operations conform to GMPas recommended by the World Health

Organization?15

X Yes E No E Not appticablel4

4. Does the information submitted by the applicantsatisff the certifuing authority on all aspects ofthe manufacture of the product?16

[Yes nNoIf no, explain:

LIv.e sa y[]JrHoMorrleHoro Jrr4ue:

Ceprefi .{apangarueecT.eKcIIepTorger ,rPalpeuraBaHe Ir perrrcrpr.rpaHe Ha rbproBl{flTau perrarrara"

Name of authorized person:

Sergey Darandashevexpert,,Autho of trading and

lloAnuc:Si

fle.rar zStamp and08.01.2015

1

8.

1

8.

O6acuumenuu 6eaecrcrcu

1" Hacro.qul,rsrcepru(pnxar, LI3rorBeH cbrJracHo MoAeJIa,

lpe[optqaH or CBeroBHara 3ApaBHa opraHl{3alltlfl,onpeAeJr{ cTaTyTa Ha neKapcTBeHI4rI npoAyxr a Ha

3aflBvfferfl, B crpaHara I,I3HocI4TeJI. Cepru$uxarur ce

v3raBa caMo 3a eAI{H neKapcrBeH [poAyKT, ttft ratoycnoBr{rrra 3a rlpol,I3BoAcrno u IaHt[opMau[sra 3a

orAenHr,ITe JIeKapcrBeH[ $opruu I{ Ao3I{poBKa Moxe Aa

ca pa3n[qHu.2. I,I:uorssafire MexAyHapoAHlrre HerIareHrHIr

HAIIMEHOBAHII'I I{JII{ HAIII{OHZUIHI{TE HEIIATEHTHII

HaITMeHOBaHI,ITI npl{ HUUII{[II{eTO Ha TaKI4Ba.

3. fluHrur KoJII{qecrBeH rr KarlecrBeH c:bcraB (arrunuu ra

[oMorrrHrr neulec, aa) Ha neKapcrBeHI.IrI npoAyKr rptlnaAa 6rAe rlocoqeH n ceprraSlrrara.

4. llpe4oc'raaruero Ha EaHHr4 3a KarIecrBeHI,Ifl cbcraB Ha

neKapcTBeHIUI npOAyKT e [IpenopbtluTeJlHo, Ho 3a ToBa e

neo6xoAutllo cbrJlacllero Ha nplITexareJlf, Ha

pa3perlleHl4ero sa ynorpe6a.5. flocoqere no4po6nocrlt 3a HaroxeHllre orpaHttqeHlr.,I

rro orHorueHrre upo4aN6ara, puBnpocrpaHeHl,Iero I4

lpunoxeHr{ero Ha neKapcrBeHl{{ npoAyKT, rlpuHulJrr{q}rero Ha raKlIBa, B pEBpelxeHl{e:ro sa ynorpe6a.

6. Cerquu 2Au2B B3aIrMHo ce I{3KrIoqBar.

floco.rere AaJru pa3peueHuero sa ynorpe6a e I{3AaAeHo

rroA ycnoBlre u Eanv neKapcTBeHI{rT rIpoAyKT Bce olueHe e pa3peueu sa ynorpe6a.Yrounere, Aiurlr Jrrluero orroBopHo 3a rrycxaHe Ha

neKapcTBeHr,rrr npoAyKT Ha rla3apa:

a) npousneN4a JleKapcrBeHlr.fl npoAyKr;6) onaroaa uJutru eruxerrrpa neKapcrBeH [poAyKr,

qpol{3BeAeHa or Apyr qpoI43BoAnreJI;

n) ue nsnrpuBa Hr{To eAHa or lrocorleHlrre

Aefinocrn.Ta:n nHQoprr,rarlr{Jr Moxe Aa 6rAe rlpeAocraBeHa caMo

cbc cbrJracr4ero Ha npr,rrexarers Ha Pasperuenuero :aynorpe6a, a r clyrafi Ha JIeKapcrBeH npoAyKr, xoftro ue

e pa3perrreH sa ynorpe6a, cbc ctruIacuero Ha 3a.,IBI4TeJIf,.

B ra:u cexrIr{-,r He ce npeAocmnr unQopuaql4fl, axo

cborBeTHara 3ar,rHTepecoBaHa crpaHa He e AanacbrJracrrero crr 3a roBa. Tpx6ra 4a ce or6erexu,uerauQopuaqurra 3a o6eKra Ha rrpolr3BoAcrBo e qacr orpa3peruenr{ero sa yuorpe6a.3a la e BanIrAHo eAHo

pa3perneHr{e sa yuorpe6a, Bcsxa upoMrHa na o6exra ga

npor{3BoAcrBo rpa6aa \a 6'sg.e orpa3eHa.

Tosa ce orHacfl 3a AoKyMeHTa, r,BrorBflH or H.f,KoLI

HarlrroHzrJrHrr perynaropHrr opraHrr, xofiro o6o6rqanaTEXHI{TIECKIITE LAHHV! Bb3 OCHOBA HA KOITTO

nexapcrBeHlrfr [poAyxr e pa3perxeH :a ynorpe6a.

11. Toaa orupaula mrr,r nnQopMawflTa 3a rerapcrBeHl{srrpoAyKT, o4o6peua or KoMlereHTHrIrI HaIIIrIoHzlneH

peryJraropeH opraH, raro Kparxa xaparrepl{cruna Ha

nexapcrBeHl4, [poAyKr.

Explanatory notes:

l. This cerlificate, which is in the formatrecommended by WHO, establishes the status ofthe pharmaceutical product and ofthe applicantfor the certificate in the exporting country. It is fora single product only since manufacturingarrangements and approved information fordifferent dosage forms and different strengths can

vary.2. Use, whenever possible, International

Nonproprietary Names (INNs) or nationalnonproprietary names.

3. The formula (complete composition) of thedosage form should be given on the certificate orbe appended.

4. Details of quantitative composition are preferredbut their provision is subject to the agreement ofthe product-licence holder.

5. When applicable, append details of any restrictionapplied to the sale, distribution or administrationofthe product that is specified in the productlicence.

6. Sections 2A and2B are mutually exclusive.

Indicate, when applicable, if the licence isprovisional, or the product has not yet been

approved.Specifu whether the person responsible forplacing the product on the market:

a) manufactures the dosage form;b) packages and/or labels a dosage form

manufactured by an independentcompany; or

c) is involved in none ofthe above.This information can only be provided with theconsent ofthe product-licence holder or, in thecase of non-registered products, the applicant.Non-completion of this section indicates that theparty concerned has not agreed to inclusion ofthisinformation. It should be noted that informationconcerning the site ofproduction is part oftheproduct licence. Ifthe production site is changed,

the licence has to be updated or it is no longervalid.

This refers to the document, prepared by some

national regulatory authorities, that summarizesthe technical basis on which the product has been

licensed.

This refers to product information approved bythe competent national regulatory authority, such

as Summary Product Characteristics (SPC)

9.9.

10.10.

1.t.

12.12.

13.13.

14.14.

15.15.

B rosu cryrafi 3a r,BAaBaHero Ha cepul$uKara ce

rr3rrcKBa csDracr4ero Ha rrpr{Texaren{ Ha pa3pe[]eHlrerosa yuorpe6a. flucueuoro cbrJracue rpr6na Aa ce

rrpeAcTaBrr Ha perynaTopHlu opraH or 3tuIBIrreJIfl.

Molt, nocouere rIpFIIrHara, [opaAlt Kof,To 3aflBIlTeJIrr

He e rroAzrn AoKyMeHTLI 3a perl4cTpaul{f,.

1. JreKapcrBeHurrr rrpoAyKr e paapa6oreHIr3KJIrotIrITeJIHo 3a JleqeHrre ua za6olrnarur,Kor{ro He ca eHAeMrrrHV3acTpaHaTar43HocrrreJl (Hanp. aa za6orsnaHus, xapaKrepHll3a rporrrFlecKlrre pafi onra);

2. nerapcrBeHl{flT npoAyKr e c npoMeHeH cbcraBaa noAo6pxnane cra6ursocrra My B

Tpo[FrecKlt ycnoBlrfl;3. JreKapcrBeHrrrrr npoAyKT e c rIpoMeHeH cbcraB,

3a Aa ce ug6erne Ir3[oJI3BaHero Ha [oMoIqHI{BerrlecTBa, KoI{To He ca pa3pellreHl{ 3a

lpon3BoAcTBoro Ha JreKapcTBeHIa npoAyxrl{ B

cTpaHara BHocI{Ten;

4. ireKapcrBeHrrrr npoAyKT e c [poMeHeH cbcraBnopaAu pa3Jrttl{ufl. B MaKcI{MiuIHorocbAbpxaHl{e Ha aKTI,IBHOTO BeIIIeCTBO;

5. ,{pyru, MoJrfl rrocoqere.Heupuloxrzuo o3xaqaBa, qe [pol43BoAcrBoro ce

r,r3BbprxBa Ha Tepr{TopruTa Ha cTpaHa, pil3JII{qHa orTzr3r{, Korro r43l.aBa cepruQlrxara u [poBepKara e

npoBeAeHa or perynaropHrrfl opraH Ha cTpaHara

IIpor,r3BoAIrTeJr.

l4zucxsauuxra sa go6pu flparrlrKu rlplrnporl3BoAcTBOTO r{ Kat{eCTBeHI{-'I KOHTpOn Ha

neKapcrBeHr{ rrpoAyKTI,I, nocoqeHlr n cepruSuxara, ca e

cboTBeTcTBr.re c Te3I,I, 3€IJIeTHaJII{ B TpI.IAeCeT I,I BTOpI{s

AoKnaA na Expert Committee on Specifications forPharmaceutical Preparations, WHO Technical ReportSeries No. 823, 1992, Annex I . Ilpenoptxllre roorHorrreHrre ua 6uororrqHr{ neKapcrBeHla npoAyKTIr ca

rocorreHr{ or WHO Expert Committee on BiologicalStandardization (WHO Technical Report Series, No.822,l99z,Annex l).B raslt ceKrrr{, cJreABa la 6r,.e rrpeAocraBeHa

uH$opuaqua, axo nprrrexareJrflT Ha pa3perxeHr{ero 3a

yuorpe6a wJru3aflBrTeJrflT ca c'bc craryr 6 lru s,cbrnacHo roqxa 8 [o-rope. Cueuuaruro BHI,rMaHr,re

rpri6vaAa ce o6rpue B cJIyqaI{Te, B KolrroqyxAecrpaHHlr qpor{3BoArrTeJrra } {acTBaT B

nporr3BoAcTBoro Ha neKapcTBeHr{{ [poAyKT, Bb3

ocHoBa Ha Bb3JrarareJleH AoroBop. B tesu cJr1yl,avr

3aflr'rrerflr rpa6ra Aa npeAocraBr,r Ha perynaropHr.rrr

opraH, ra3AaBarq ceprurfuxara, un(lopu aws. 3a

cTpaHr,rTe no Bb3JraraTelHr.rq .{oroBop, oTroBopHr,r 3a

r{3BbprrrBaHeTo Ha BceKr4 eTa[ oT rlporr3BoAcTBoTo Ha

roroB?r, JreKapcrBeH [poAyKT, KaKTo r{ un$opruaqux aa

Br4ilau o6xnara Ha KaqecrBeHr,r, KoHTpoJr, [poBexAaHoT BCflKa OT C',rpaHr{Te.

In this circumstance, permission for issuing thecertificate is required from the product-licenceholder. This permission has to be provided to theauthority by the applicant.Please indicate the reason that the applicant hasprovided for not requesting registration.

1. the product has been developedexclusively for the treatment ofconditions - particularly tropical diseases- not endemic in the country of export;

2. the product has been reformulated with aview to improving its stability undertropical conditions;

3. the product has been reformulated toexclude excipients not approved for usein pharmaceutical products in the countryof import;

4. the product has been reformulated tomeet a different maximum dosage limitfor an active ingredient;

5. any other reason, please speciff.

Not applicable means the manufacture is takingplace in a country other than that issuing theproduct certificate and inspection is conductedunder the aegis of the country of manufacture.

The requirements for good practices in themanufacture and quality control of drugs referredto in the certificate are those included in thethirfy-second report of the Expert Committee onSpecifications for Pharmaceutical Preparations,WHO Technical Report Series No. 823,1992,Annex 1. Recommendations specificallyapplicable to biological products have beenformulated by the WHO Expert Committee onBiological Standardization (WHO TechnicalReport Series, No. 822, 1992, Annex 1).

This section is to be completed when the product-licence holder or applicant conforms to status b orc as described in note 8 above. It is ofparticularimportance when foreign contractors are involvedin the manufacture of the product. In thesecircumstances the applicant should supply thecertiffing authority with information to identiffthe contracting parties responsible for each stageof manufacture of the finished dosage form, andthe extent and nature ofany controls exercisedover each ofthese parties.

16.16.

CoSrn 1303, yn.,QaunH l-pyea Ne B,ren.: (02) 8903 555, Saxc: (02) 8903434B, Damyan Gruev Str., 1303, Sofia, Bulgaria, tel: + 359 2 8903555, fax: + 35928903434,

e-mail: bda@bda.bg

Certificate of pharmaceutical product Xb 9039/08.01.2015 Appendix Nb 1

ITpu.nocrceuue JW I rcum cepmuSuxam 3a reKapcmeeu npodyrcm Nb 9039/08.01.2015

1. Name and dosage form of product:Tupzoecxo HauMeHoBaHue u reKapcm*eHa Qopua ua npodyxma:

Diftet susp. inj.amp. 0.5 ml (1 dose)xl0, x 50; susp. inj. vial5ml (10 doses)x 10; susp. injvial 10ml (20 doses)x 10

2. Content:Cztcmae:

Active substances and strength

Axmueuu seu4ecmsa u Kottuqecmlo Ha aKmu*Hume 6eulecm6a sa dosoea eduuuqa

flolrou{uz BerqecrBa H KoJII{uecrBo Ha [oMorrIHHTe BerqecrBa 3a Ao3oBa eAulyr'\aExcipients and strength

LIve ua ynbJrHoMorrleHoro Jrrzue:

Ceprefi .{apangauencT.eKcrrepTorAeJr,rPaspeuranane rr perficrprrpaHe HaTbproBrrfl Ta u per.natrara"

Name of authorized person:Sergey Darandashevexpert,rAuthorisations andtrading and adve

flognzc:Signature:

Ieqar v Aara:Stamp and date:08.01.2014

Active substancesAxmueuu seu4ecmsa

StrengthKonurtecmeo sa dosoea eduuuqa

Diphtheria ToxoidTetanus toxoid

>30ru>40ru

Pellet excipientsIf e rc mu/If onot4Hu s e up c me a

StrengthRonuraecmao sa dosoea eduuutla

ThiomersalTuorrrepcar

0.045 mg

Natrii chlorideHarpues x;roprr.rl

4.25 mg

Aluminium hydroxide a maximum ofAryNruHrEesrr.f,T xrlApoKcuA He rloBeqe or

1.25 mg

Water for inj to the required volumeBo.qa sa rimreKur{, 4o neo6xoA[MrEq o6eN,r

0.5 mg

+\\oFCI