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WORLD HE LTB ORGA IZATIO

ORGANlSATlO MONDI LE DE LA SA T
LG /~ No p/77_ 2 R J.

E?'GLI SH 0 Lr

lA AL FOR TIU: PRODUCTI ON AND

CONTROL OF VACCI NES

TET#'US TOXO I D

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1 pr p re d b y th folio l n Con u lt a nt s
t h WHO See r t a rLat :

Wlll da l ,

Or nl a tl on ,

C n

Labo . t o

Corp. ,

f , B 010 l eal , a,

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Please click inside the blue boxes below to access the Appendices
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T6. SnJ. 1NS Of CL. Tt TANI
n. I NnODUCT\ON , . . .. . , T6. 1
n . 1 1l.. l plton o f , h ~ . ecc lne , t6 . 2 ''' In '.n .n , ~ 0 1 ,h. .. r ein
T l. 2 H U oao f o f .he ve ocl ne , T6 . ) P p. . . . I "" f o r pr od ucti on "
TI , 3 S.gge"~ d ... hod o f pr oduo .l on
-n, /'IlODUCn ON OF VACCI N[
"
T I .4 WHO R ~ qu l r ~ n
"
T L. ' Cl o' ' ' r y f to ... . , T1 . I P.oduc tl on
"
. od n
"
T2, /'IlI'IIS! S . .. . n
Tl 2 H. . u . tl ng
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D. . l go o f p TO. to . .
Q.all .y 0 1 ma'erle l .
u
T7 . )
T1. 4
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S. p. .. ti " n
Produ< ti "n
"I n proc ..... " ..
.ool n

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T1 . S( U ) p .o<e .... . e ... . o . old
r r, I;'.QUI I'!'lNT F01\ TOXIK PRODUCTION Tl . 6 r . rl f1 ea Uon t oooid ....
"rz
"
Tl .I Equ I~o , f or pr od , <. l on I n a ' a ' l, n. POO LIHC, , =~ .~ tE STI NG er WU
'ut h.. TOXOID
T) . 2 F ~ ..... n.er p .odu<t l on " "
STAFf .. ... , " 18 . 1 P"o li nl
"
.' " TB. 2 S<or e ge
"
....
T4 , I TB. ) T. . U ng o f bu l~ . o> ol d
T4 .2
Que U f1 , . . t on . end o_ be ..
" " ., Po tenc y . ... . "
T4 . 3
br OTh n,e
Hu l ' b . T9. Il lUlT1 NC AND FI LLI I<C
"
Or la oh .. l"" o f a " h ttf "
!' IlI A .. '" . .. .." T9 . 1

n .2
Pre p. .. . l o, . nd . ... l ng 0 1 fl u i d
'o .old
Ad Ju.. nt. "
"
BI.C!UNDP! n 2 Rev . 1
f1 1J,;/ t1 ffi P/77 . 2 R'v .l
p il g ~ 6 pa ge 1

Pa e TETAN S TOXO iD

T9. 3 Pr epara tion and te sting of ndsorbed ( Rcqvi r m nl s f or Bi o l o&i ~l Subs t a nc es ~ o .

toxoid . 26 r~ vl sc d I ; 8) ) Se e Append ix T. 2 7
T9.4 Fil ling in to f inal contain r s 28
T9. 5 I ns pec ti on <10 ..
30
' 1, INTRODUCTION

TI O. TE STS ON FINAL PRODUCTS . 31

of the va c ci ne ( Pa r t A, S ec t l ~ n 1. 2 . page 4 1)
r to. r Tests 31
TI O.2 Report ing o f datn 31 Tetanus toxoid Is pre p red fr om the t oxin pr oduce d by the
g rowth of 8 hIghly t oxIgenIc s t r a i n of Clos t r i dIu tet nI In
TI1. LABELLING ASD PACKAClNG 32 su i t a b l medium. The su pe rn at an t f l ui d, wh i c h cont ai ns t he
t oxin. i $ s e pa r a t ed f r om the o rg an Isms, the t oxi n so separat d
TIl.I Labe lling 32 f ro m t he organiSMS is d ~t o x i f i d and purfl~d .
TIl. 2 PackagIng 32
Tl. 2 Ef f i ca cy of t he va ccine
T12. RELEASE . . 33
Tetanus toxoi d 1s the i lJQuni.:d ng a n t i gen pr otect ing
11 3. RETAI, EO ~AMPLES aga i ns t the adve r s e e f fects of In ( ect ion by t et anus o r g a~ i $ ms.
33
Although the toxoid induces t he product i on o f te tanus a n t i t ox I n
T14. SURVE I LLANCE OF VACCINES a nd wi il t he r eby protect ge ins t the l e t ha l f fe ets of t e t nus
34
toxin, it d oe s not n ~e s sa ril y prevent t he gr owth o f the or gan-
T14 . 1 Sa f e t y . i sms .
34
T14. 2 Efficacy. 34 The toxoi d 1s a v~ry good a nt igen a nd even plai n t o~ o ld
. ( a toxoid wi t hou t the a dd i t i on of 8n ad J u v nt ) given in adequa t e
r i.s . WHO REQ UIREMENTS 3~ dosa ge can be relLed upon t o protect whe n used for pri mary
immun Lz c i O!l. I t l s conmon. howev r , for the t oxof d to be
T 16. SUHW.RY PROTOCOLS ad s or bcd on to n adjuva nt ( us ua l ly a l um i ni um hydroxide or
phosphate ) . Te t anus toxoi d, ei ther ptain ~ r ads or bed , i s
LI ST OF APPENDI CES . . .. ... ~ . .. .. .. ... .. 36 r.rely gi ven al one 1n chi ldren for wh om i t is much mor e
common l y i nc lu de d i n combin d va cc i ne t ogethe r with d iph -
t her i a t o x ~ id and pe r t us si s vacc in e.

Tet anus t oxoid 1 use d al one t n pregna nt women In ord~ r to

pr event nc ona t d\ tc t a nuE ( t c t nnu$ noonot oru ). I t i s LV n 150
Continuation of appendices to be found here t o casua l t ies an d is used pr o phy l e c t Lcn l Ly in ' t"cups in wh i ch
tetanu 5 is B 1 occ upst i ona1 ha za rd, e . g . th os . wDr kl n wt Lh
mach ines.
 BU;/U KD P!77 . 2 vsI
Bte! / 77 . v. l
P
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(l la 293 )

1. )

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r
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o f 0 in
1 Inter-
s n

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the

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r
LG/ U P/17 .2 Rev . l LG/ U P/ 77.2 ev. l
p 10 p 11
L
5

L / 10

d
e t
LT e a un 0 toxin w i h h n
co b n d th fix ed a unt of a nt i - na l
toxi n (ulIuMl ly 0 . 002 1. U. of an t i t ox n)
in t h vo lum of 0. 2 ml ~AU 8e 5 a 10 1
ak in J;" ac ti on eh. t l s J us t vis b I Tb Unal toxoid pr I nt 1n a
( On ly for diph t h r1 ) con ta in r fr wbich b_ f in 1 con-

o
. The ou nt of t oxln th a t kill
f i l l ed ei ther di rec t l y or
o more i nte dia t co nta in r
g r oup o f a n i I II th n fo ur d
LD dH r. o r d iff rent n1
50 -L
.L.D.

o. . asur e of
on
cl y
1 h h I nt
a.
.I
r pa r a tion oC Opa c i ty.
T.e. . Tot 1 co T , the r ecl pr oc 1 of
b pr oduc d i n ep ar a t b c au s @
t he vol um of t o oi d which wh n dl lu t d 11 a po r ng organ1
nt fo r h pr8m1see In whi ch oxi n o be
is f ound to b qu l v lent to 1 t n t r -
nationa l Uni t. th!!y Ih ou ld be cl ean, cmafor tabl to var l n ,
per t ur a nd humidi t y, i nclud .11 t he
 LC/ U p/n .2 v. l
p. e 13
ic/u 177. 2 R v. l
e 12

d
a c
.n,~rhe: r e and und r
th t s uIt
unde r con di ti o
ln
not b ubj c t ed to c r o

Tb r equ lr :
c l e an livi n cond it i ons
oo d vent i l a t i on . Ani
od he at a s v 11
can be di s.' r u
T2 . J Cha n i n f acl l iti es
ood ba 1.nc d dl t
ortant t t c t
i c us . n y i
be pr eat d ;
d i Y
(c) 1
ad
 BLC/U P!77.2 R v.1
pe 1 U:;/ UNDP/77 .2 Rmt.l
t~

o 11 tr
e

OD

ca

J. EQUIP FOR X . PR eTI 1.

( p rt S ctlon 2 pa 42 S th Y
App ndlx T. 27 are
1 f ea r e -
ra.r
Th n e used for th producti on of oxln
upon th ne u ed f or the produCt i on 0
i chole n fo r cultivat i on oC t h OX1n III d P nd prate t al l t l Ir all 0 h r quip nt.
pr neip l no xp ns lv qui be l bu t 1n
out I n id _ d bottl nt la ne d d . I c n b e r r l ed
pro d uct1 0n. I n s ta l n l es a _ t all b a k rill or . f or!ar r se 1
e l v e ss 1
T f

.1 era
(~ .
die P u cl DC t [
l nv o l '1 0 1 o t o d 0
et
ul r
 LG/U / 77. 2 R v . l
pa I
wl u P/71 .2 v.l
17

f loo 1
d 111 0

tory f or
r hould b
T . In v nt , a ccura t e Dd r cords 51 ned
1 l bl y and dated st b kept, vallable a t
a ll tl I t o th co nt ro l I t l e as well
Th t ff hcu l d hav
t c hn c a I
no 1 -c h 0 Un h d to h 1 I h alth authorltie
In fu rth r ed uc t lon ond x pi l uch r cor d a r e s hown
n OppOrtunlty of t Udyl n had
knowI d of rl 1 mlc ro 10 10 y ln productlon f ac l it l es
The sc le ntlf ic -taff t cchnl q ue s and th h nu f actu r e of other
mont h I n a pr oduc ion hau Id have spen t at I n t he pr oduc-
t ur nd co n r ol 0 unl t c tl ve ly en It c n be u cd
ct rlal v ccln s . nu pr oduc-
Tt.. 3 If al t con t ro l s t a ff
vaccine .

o od h
ra l
qu rl!d to
s a nd not e
al s ea se .
no t ent r
 BLG/ UNDP/ 77 . 2 Rev.l
page 18
BLG/UND P! 77 . 2 Rev. 1
page 19
n. MEDIA
T6.2 Mainten nce of the train
Tb edium OSt c
t e t ni is t h only use d
( J . -I rmmJ no l.. e (1medium or1 1 11 f or t he Cult i vati on The stock cu1tur a prepar d from the or i gi na l t r ai n ha ve
947) S6 g na y d c r i b d by Huell of _Cl.
_ , 143). e r ..r Hi I Le r t o be intained in the free~e-dri d form to preserve Vi Abi l i ty.
The orking seed culture pr pared from this can b main tai n d by
h Some IlIOd1 fi ca tL on8 in th daily s ubcu l t u r e in glu cos br ot h un til th e cu lture s hows a fall
.llve been made nd t h e fO~ l ti on of the or ln toxin pr oduction . The dally sub cu l tur e! are gr own i n an
ese ar 1 0 descri bed I 181n.l medium
n Appendix T I anaerob ic jar .
The in COn titu t f .
ca sein. This ma b n 0 the medium is t
c erclally. Y Cl prepared in t he l ab or ryptl c digest of T6.3 Pro?!r tion for product i on
t ory or bought
The contain T 8 of t he culture medi um tha t ha ve be en a u t o-
cl Bved and rap idly cool ed In r un ning t pwater Or in lee cold
wat er ore tran ferred to t he inocu la t io n room where the 24-h ou-r-
ol d se ed c ul t ur e s and the r e quired nu ber of ste r i l e syr 1nges or
T6 .
STRAI NS OF _CL. TE Pasteur p.ipe t te s are kept. The pur i t y of each aeed cu l tu r e 1-
T6.1 - rAm.
Obt a in ing the a t r a ln che cke d by the exami nat ion of Gr am Iltained smears a nd only th os e
cu l tu r es f ound t o be pur r e u ed or th e i nocu l a t ion of t he
In the producti on of f res hly pr epared a nd coo l ed medi um .
importa nt r ole . t et. nu toxi n t h
In eo blna t! The s train \/'hi ch hA
on with the d
b e st r a i n plays an
een ~Ost c 1
York S t ate Dep. me ia described o r i i On Y used
1 b rUn n t o f fie 1 h g oat s fr h
a o r atory which 1 t a nd hou ld be t e Ne\/'
; t r4il1 i s 8 hlghly St::r:;~~;Cedt I n t oxin produ:~:~nfd f r OUl 8
T7 . PRODUCTION OF VACCI
rom no rmal Cl a raLn and diff The
te ta.!!!. s t r a l na . r s consi de r ab ly
In orde r to follow mo r e ea s I l y the product ion 0 pur1f t d
Although all teta . t an us t oxoid suggested fl ow charts a r e ah 'n i n App ndt x T. 26.
t oxigeni c stra ins nus toxoid are mad fro t r La I ar
Thes e indi ca te at ea ch s tep I n t h produc ti on vh re
o f t oxi n by a tr~i~ ti ~ s not Pos si bl e t o obtain :h:
ew
hI hI y ndde d as \/' 11 8 S \/'her s amp les are t a ken f or t s ti ng . The te st !
in its compO!i t io A t he growth medium is k B me yie lds
a pp l ie d are 41 0 s pec ifi ed.
wUl ne d t o Obt~ ' ne\/' prOdUCti on 1 b mar ed ly cha nge d
t Lon of t he a n a strain and under oratory , therefore
. or ga nistll t o e h go a peri od of d ' T7. 1 Pr ~ u cti o n of toxin
maximum yi el ds e medi um s el c ted f apta -
Y be expected. o r grewth be fo re
Th e con t al n rs o f the dium re l.nocu la t ed
pt l ca lly
e !l
I
Ne\/' manufacture Ith a t1 ass sy r i nge or Pas eur pipe t t e s u ing one eed culture
s~rn l " fr o the WH rB y obt n da ta t ube or the i noculation of a slng l cont si ner. The contain rs
o S cr@tarlll t ( conce rning a uitabl a re t h n in cuba ted a t 35C: l OC o Suc h cul tiva ti on canno t be
Chi ef, 81olog ica l s) .
co ns l de r ed to be p r fo rtlled in lti a Uy under anaerob t c ci rcum-
stance s , but t he hi gh ly red uc i ng proper t ies of the ced i um -re
suffici n t t o promot good r ow t h a nd t oxi n product i on. The
t oxin I s h rve s ted [ter f i ve to s eve n day s ' Incub t ion ; th e
av erage yie l d of toxin va rie between 60 and 80 Le ml .
 Le/ r/ n. R v. I
p 20
Le/ iDP/17. 2 v .I
onn P e 11

a
to

l~

1 l e t o 1e It dd t o t h
and I ncu b te f or
Hhlneh t l rete t f or
When t oxold l ng 15
d e ntrol
t , t !It a In T7 .5 ( U )

T7.S " I n p r oe !I " t e s ts o r produ ctl o

T7. 4 l a t o xoId d b o r purU Le t l 0 8

d to I l ea e t en f or th
o h o t her
t I . Aft r d t oxi! ca -
10 la pp ll cabI
o f th
 LC/u 177 .2 R v.1
p :2 5 LGI p/n. 2 v. l
pa 23
d

to t "1 procea "

11 car r d ou

t S
Ap n.db T.
r
of Lt eo t: n
p n e!
tu
of .L.D . (q ~Q l:=m
1
App nd x T. 7
IV D !.nftt l on o f . .V. ( xl
o 1n v l u
App ndb T. 9
V D tn t on 0 Lf/lo do e
App ndh T.8
T7.} (U .. t ests f o r oxaM
Toxoi d r eco vered by t hi pra c dur v i iI co n t a I n abou t
Sp e fi e toxLe t t y
t es t 707. of th orlgl nal t o~ oid cont n v i h Rn a v r age pur i t y
App ndlx T. 14 v yIn b t ween 10 nd 12 Lt / m prot In N. Su c h 11 t oxot d
tI St rl1 ity
1 on i d r ed acce p t ab l .
App nd lc08 T.20
and T.28
ItI D t e n~ t r~tton af L[~ 1
App nd x T. 6
IV Tot al e blnin p er T . TEsn . OF 8U
App ndb .10
T.
on o f t Oxol

of t 0 d
P .y
 BLG/ UNDP/ 77. 2 R v .l
p4 2 u;/ u / 77 . 2 ev , l
p 25
500 1 tr
th
ra tion o t nc, t es t

St ~

.3
o f te a
a ft r r lea I D
fo 11 d t o the

e t ne t t
"pp nd i T.l3
11 s c U ic t o i et t y T9. DIWTI NG It. IL L!
App ndx T.14
III S riU y
App ndh r .20 In om c ountr ies , t t enu s oxo d u both . p I in
IV T I t fo r an e ni c concentrat ion : nd a n ad orbed toxoid; it i s adv i b l t o us the ad sor bed
( ) t oxoid beau e of i t s s uperior 1 n08 n c i t y.
tion of Lf! 1
(b
App ndix T.6
D rm! n U n o f total
co ~ L n n po r ( TCP)
App n dh T. IO

" p nd le a T.
a nd T. IS

. 14
Append l T. I

. 11
 e .1
BLG/U P/ 77
P 27
v.l
I nto a c: cOU
rtblolate t e a r ou
101are le e

e
1.

: . In
.2

nlua pbo apliUll:e nl

pr e p. at l 0 toxoid
a e r eial
s oure nl th n 20
hyd rodd I para tl ons p r t uss1 st co n in not or ne 0 not
3.
su ch a o t ho d Opaci t y Uni t s (O.U. ) wI th. po
n doa
f o r h pr (lU n 1n I B than 4 1. P r 1n I hu
App nd1x T.20. n ad o rba nt . ata ar c r r1 d out at t h i s
'l1l
jor1ty of control t of h v ce l n , t ~ o l d s
Tb co ne nt ra t l on of alumd nl sh al l not xc d 1, 25 per at a \ofh
n all t he 1n 1" dl nt 1 auap na lon , ad juvant
In I h n do. (diphth a and t e t a nue , P r t u v b n hi nd d . Tb e
( r
pp l l ea l e) and d1 1u nt,
T9.3 a nd t e a t ing of adaorb oid ar
~

t
.D
1 Po enc! t e st
p
11 1 nOCU Y t ea

11
. 0
1 St r t 1 re
 B LG/U N1'~ .;' ... 1
P ~
'l> flLG/ mDP/ n .z Rl!v.1
....." pll e 2
.on t ne ( fo r fluid
vacc ine )
App ndb T.6 Th fil l ln of biolog ic a ls mu t be carr ied ou und r tr l et
,i OlDe r sa l content a s ep tic condit ions a s the p rod uc t once contaminated e ll n nl th r
Appendix T. t 6 be recovere d nor ter na l ly r e s t ril i zed. I t la. th e r e f or ,
VII pH pr e f e r bl e th at fi l ling s hou l d be carried out by s complete ly
Appendix T. 17 au t omat ed pr oce s s wi t h least t.n t e r I rence by the fil ling s taf( .
VIII Aluminium content Such comple t l y automa t ic (i l1 1ng , s t oppering and s ealing
Appendix T. 19 equi pment for mu Lt Ldo se co n td ne rs is c rc l a 11y a va Lla " le
IX Fre ( e Appendix T.24). Simi l rly, au t t ic amp oul f ill i n a nd
( r es i dua l) forma ldehyde
Appendix T.IS s ea li ng equi p ent 15 a l s o va l labl e ( s ee Appendi X T.2 4 ) for
x Tell t for adsorption f111 i ng s ing l e dose ampoule s . Semi- au tomat ic machi nes for
Appendix T. 6 f i l l i ng vial s fo l lowed by nua l s top pering a nd cap pi ng or manual
T9 . 4 Fill ing in to fin I s t opper ing an d mechan ical capping can a l s o be use d . It ls
pr fer ble , howeve r, to use co pI tel y t tic equ i~en t s o s
The requirement for filIi to in t ain eptlc co ndi t ions t h roughout the ope r a ti on. Suc h
a d scr ibed in t he Cene r 1 R ng I:h final Containers shall be machines n ce s 8~L ly r equire th use of vi a l prop er ly st nda rd -
E t ab li hmen ts and C equireqents f or Manufa tU !zed with r e pect to body dia ter, height nd di m n ion of
Seri s ( 1966) 323) ( on trol Labor tories (WHO Techni c 1ring
a si n l e --- lI~e Append! T 29 ) ca port th mouth so s t o b compatib le wi t h stand rd rubb r cl oaur s,
s i ze g "bUl k COn t a i ne r a t any tlm~ ah~ll ~e vol presenC-in Simi lar p recautions are al s o required for the d imensions of
. ever, t he size of h etermine the b tch ampoul es [0 be us ed in aut omat i c f i l l 1n
by the ca pa c i ty of t he f1111n t fUling lot i U be governed
procedur ad opted in f i l I i g eqUip nt to be used and tb The qua Lity of g l ss containe rs influences the keep i"
di s tribu ted i n c on t a i ne r a ~8f' tl f th parent i nal bUl k i: qua lity of t he fi n I pr oduc t. It 1s nec 66ary, ther fo re, to
s ha ll fo Ei l a ler size h
a 11ng l o t an d b ,eac s uch contain r us e ne utral boro9 i lic t e U.S. P. type I co nt ainers in the intere st
If , howeve r, the f U lln i individually labe lIed aa h of qu al ity a nd s afety of t he p r od uc t t hou gh U.S.P. type 2 gl ss
uC
final bu l k con tainer t~e s ca;r ied OUt dir etly from t h: . may be permiss ible in some coun t r i es .
in one s es s i on Wl tho~t a s~:um er of final containera fil led
as a fLna 1 lot or t11 Hng l:~a:e or br ak s ha ll be deemed The quali ty of rubbe r clo ur el is al a o i mpor t a nt. Ru bbe r
con t a i ne r a . Or all t he te a t a on fi nal i kn own t o a bs orb ph nol& and ercu r i a l pr es r vatives nd
ood quality or co ted rubb r ia needed t o preve nt t h is .
C ple tely au toma tic e i Sou rc e s of r ubbe s hould b ch ecked , t he re o re, fo r co mpa ti-
qu pment f o r f:1ll1n~ It
and aealLng lIlUl t id
oae con taine
nufacturera uch aa those
i &.
Opperlng
ra a available f r om repu ta ble
.
bility lIi.t h t he va ccine and i t preaerv ti v But yl r u bbe r
Il t opp ers tre at ed wi th s uch pre se rva t i ve s . t hiomers a l or phe no l
Wher s uc h facilitie s n tioned 1n Appendix T 24 1
p i or t o us e i n t he fi na l pr oduc t a r e found to a bs orb a inimum
f11U ng equip nt COlllpr~el no t available lie -auto ~ l c te 9.
j
S quan ti t y of pres erva tive dud n s to r ag e of the v cc1.ne . The
nua l stoppe r i ng od t ng aut t ic f ill ing f o ll owed b
u Outi c se 11n y use of buty l or othe r rubber stopp r s whi c h ha v be n shown t o
y al s o be Ob ta ined . b s o t i f actory i s r ec oma nd d.
Fhor 1n l e dose Con taine r s
city s oul d be u ed. ampoule s of ppropr ia te capa-
 RLG/U P/ 77. R v. l
P 11
B Il P/ 71 . Rt'.1
.... .....1IIrT'S
n o. s

c t lon
aw/ ND / 17 . 2 v. 1
pa )
BLC/U / 71. 2 Rev. l
pa J)
TU. LA ELLI A PAC Cl
T12 .
TU .l

p rl ov c-
a phy at c Lan i

Tl3. RELAI ED SA LE S

At t h of release 0 a l ot th nufac t uc-er

t a s i de nd re fr l g ra nou h 11 rv t 0
pur poll a :
t
( 1) to out i n
the
to s et
st
 LC/U mp/n .l R v. l
p jS
u;1 / 77 . v.r
ody r sp n e 1n
and titra t ed t o of th a e e l t l on
i dea 0 In b l ood sa 1
i'u r t ermore , 1 d t ne
I dr e 0 lnt 1
d t ere Y

Tl.
15.

r . lipolu l-

.1

t la d l n th I bo r atory t o
aa f e by ubj c tln a l l l otl t o It
a bno 1 toxi c l t y, a co It n t a t ch Ihould
pt fo r adve r l reac ti on. in ch l l dr n .

Tb r co nt r a i nd i ca t i ona t o t he ua of a ll va ccinea,
a nd a n inv a t i on of a l l a dve r s e r a c tionl Ihould b d
particularl th Y a ppe a r t o b 10 - r 1 t d .
Tl su y

T14.2
ponl
nity
of t

an