WORLD
HEALTH
ORGANISATION MONDIALE D E L A SANTÉ iQ/wp/67.5 ORIGINAL: ENGLISH
ORGANIZATION COMMITTEE ON INTERNATIONAL QUARANTINE Geneva, 28 November - 7 December I967 Item 6
ÏROCEDURE FOR THE APPROVAL OF YELLOV/ FEVER VACCINE AND NOTES ON OTHER VACCINES by B i o l o g i c a l S t a n d a r d i z a t i o n Unit World Health Organization, Geneva
Tlie Executive Board o f the World Health Organization, i n a s e r i e s of r e s o l u t i o n s , approved f o r the i s s u e o f i n t e r n a t i o n a l c e r t i f i c a t e s the y e l l o w fever vaccine produced by the f o l l o w i n g i n s t i t u t e s and l a b o r a t o r i e s : Commonwealth Serum L a b o r a t o r i e s , Melboiorne Yellow Fever Laboratory, I n s t i t u t o Oswaldo Cruz, R i o de Janeiro I n s t i t u t o de Estudios E s p e c i a l e s C a r l o s P i n l a y , Bogota I n s t i t u t Pasteur, P a r i s K o n i n k l i j k I n s t i t u u t voor de Tropen (Royal I n s t i t u t e f o r the T r o p i c s ) , Amsterdam Wellcome Research L a b o r a t o r i e s , Beckenham, Kent, United Kingdom N a t i o n a l Drug Company, Swiftwater, Pa., United States of America Since 1954, however, by v i r t u e o f r e s o l u t i o n EB13.R52, the Director-General was authorized t o grant approval f o r yellow fever vaccine.
Handbook o f Resolutions and D e c i s i o n s . 8th ed., p. 15.
Tho Issue of this document does not constitute format publication. It should not be reviewed, abstracted or quoted without the agreement of the World Health Organization. Auth.:>rs alone are responsible for views expressed in signed articles.
Ce document ne constitue pas une publication. Il ne dolt faire l'objet d'aucun compte rendu ou résumé ni d'aucune citation sans l'autorisation de l'Organisation Mondiale do la Santé, Los opinions exprimées dans les articles signés n'engagent que lours auteurs.
IQ/WP /67.5
page 2
"Tlie yellow fever vaccine produced by the following i n s t i t u t e s and laboratories was approved for the issue of international c e r t i f i c a t e s i n accordance with t h i s resolution; Robert Koch Institute, B e r l i n ; Central Research Institute, Kasauli, India; Yellow Fever Laboratory, Federal Laboratory Service, Yaba, Lagos; I n s t i t u t Pasteur, Dakar; South African Institute for lytedical Research, Johannesburg." The following i s the text of the resolution: The Executive Board "AUTHORIZES the Director-General, subject i n each case to the satisfactory completion of the tecimical procedure now e s t a b l i s h e d to grant approval to yellow fever vaccines for the issue of i n t e r n a t i o n a l ' c e r t i f i c a t e s of vaccination and revaccination. l-Jhen such approval i s requested, the practice v;laich has been applied f o r some time i s substantially that given i n V / H O Monograph No. 30 (I956), page 196-197, with some modifications introdviced as a result of the p u b l i c a t i o n of Requirements for Yellow Fever Vaccine (V/ld Hlth Org, teclin. Rep. Ser., 1 7 9 ) It i s indicated that the following conditions w i l l be followed i f approval"~ls to be granted, (a) (b) (c ) The premises and equipment must not be used for any other purpose Tae requirements published i n IJld Hlth Org, teclm. Rep. Ser.. 179 (Requirements for Yellow Fever Vaccine) must be f u l f i l l e d , and ' * The results of potency tests on the vaccine done by three independent laboratories must give satisfactory r e s i i l t s . "
Tlie attached aide-memoire gives the various steps i n carrying out the procedures mentioned above. I t w i l l thus be seen that the main basis for approval of yellow fever vaccine i s related to a particular period of time and i n r e l a t i o n to one batch of vaccine Proposals for improved control internationally of yellow fever vaccine have been made on a number of occasions. connexion. Bonnel, P. H. (1956) Wld Hlth Org. Monogr. Ser., 30, 202-203 Second Report of the Expert Committee on Yellow Fever, Off. Rec. Vad H l t h Org; 56, Annex 6, 83 Study Group on Requirements, V/ld l i l t h Org, teclm. Rep. Ser., 179> 6-8. Tne following are important references i n t h i s
IQ/WP/67.5 page 3
. V/ithout repeating the text i n the above references, i t may
b r i e f l y be stated:
"The Study Group pointed out that, while approval f o r yellow fever vaccines has i n the past been given by WHO a f t e r a s i n g l e exhaustive i n v e s t i g a t i o n of the nianufacturing establishment and of the product, t h i s approval applies i n d e f i n i t e l y . Tlie Study Group suggested that there was a need to devise some nioans whereby ^ . J H O could assure i t s e l f of the continued s u i t a b i l i t y of vaccines prepared by these l a b o r a t o r i e s . I t was a l s o suggested that a c e n t r a l advisory service could act as an agency f o r the c o l l e c t i o n of such information as would assure V , H O of the continued high q u a l i t y of the approved vaccines." In a d d i t i o n to the above, i t was considered u s e f u l i f i n s t i t u t i o n s which and
produce WHO-approved yellow fever vaccine could send protocols of production
t e s t i n g of a l l primary and secondary seed l o t s as w e l l as seed l o t s of f i n i s h e d vaccine to Geneva. Δie f u r n i s h i n g of protocols i n t h i s way has been requested from
as f a r back as December 1952.
IMfortunately, i t has not been possible to trace made. I t was proposed, therefore,
the o r i g i n a l l e t t e r s i n which t h i s request was
to write to each of the i n s t i t u t i o n s which produce approved yellow fever vaccine which lias not been i n the habit of submitting protocols and to request tliat such protocols be submitted i n future. Letters were addressed to a l l the manufacturing i n s t i t u t i o n s producing yellow fever vaccine, e i t h e r thanking the manufacturing establishment approved
f o r regular and
submission of protocols or pointing out that protocols have not been received
requesting a c t i o n commencing with batches i n current use and continuing t h e r e a f t e r . A number of r e p l i e s were received but i t i s pertinent to point out the following: (a) Manufacturing establishments so. which were w r i t t e n to i n September to do so. Others which have r e g u l a r l y submitted protocols
are continuing to do (b)
Some manufacturing establishments
1964 responded with protocols. have not.
Some of these have continued
page 4 (c) A s t u d y o f t h e p r o t o c o l s shows t h a t i n s e v e r a l i n s t a n c e s , there the establishments to are
c e r t a i n shortcomings i n c o n f o r m i t y of yellow f e v e r vaccine w i t h published requirements. I n some i n s t a n c e s , the i n a n u f a c t u r i n g
t h e m s e l v e s have g r a t u i t o u s l y i n d i c a t e d t h a t t h e y i n t e n d t o talce a c t i o n Improve n : £ t t e r s . (d) I t has been d e f i n i t e l y a s c e r t a i n e d t h a t i n many o f t h e
manufacturing yellow
establishments,
t h e o r i g i n a l s t a f f c o n c e r n e d w i t h the p r o d u c t i o n o f and o t h e r s t a f f , Secretariat,
f e v e r v a c c i n e have l o n g s i n c e d e p a r t e d , be l i t t l e o r no i n f o r m a t i o n a t t;ie \Mj I n one i n s t a n c e ,
o f w h i c h t h e r e may work.
are c o n t i n u i n g the
the e n t i r e r e s p o n s i b i l i t y f o r y e l l o w f e v e r v a c c i n e p r o d u c t i o n technologist. staTf
i s i n t h e hands o f a s i n g l e l a b o r a t o r y (e)
l^hatever may be t h e q u a l i f i c a t i o n s and e x p e r i e n c e o f t h e p r e s e n t
engaged i n y e l l o w f e v e r v a c c i n e p r o d u c t i o n , t h e f a c t r e m a i n s t h a t no I n f o r m a t i o n i s on r e c o r d a t t h e WAO S e c r e t a r i a t , n o r have e x p e r t s b e e n i n v i t e d
t o g i v e any o p i n i o n on the p r e s e n t p r o d u c t i o n s i n c e the o r i g i n a l a p p r o v a l w a s granted. (f) A t t e m p t s a r e b e i n g made t o i n v i t e the s u b m i s s i o n o f p r o t o c o l s f r o m t h o s e considered of
I n s t i t u t i o n s w h i c h a r e n o t s u b m i t t i n g them r e g u l a r l y , b u t i t i s n o t
l i k e l y t h a t t h i s measure a l o n e v ; i l l be s u f f i c i e n t f o r t h e c o n t i n u e d c o n t r o l t h e q u a l i t y o f y e l l o w f e v e r v a c c i n e produced i n t h e i n s t i t u t i o n s f o r w h i c h . a p p r o v a l was g i v e n . (g) \M0 has a s t a t u t o r y . r e s p o n s i b i l i t y f o r ensuring the q u a l i t y o f y e l l o w
f e v e r v a c c i n e used f o r I n t e r n a t i o n a l c e r t i f i c a t e s o f v a c c i n a t i o n o r revaccination. It seems i l l o g i c a l , therefore, t h a t a new r e q u e s t f o r
a p p r o v a l f r o m a c o u n t r y v â l l have t o be s u b m i t t e d t o t h e e x i i a u s t i v e and c o m p r e h e n s i v e p r o c e d u r e l a i d down, w i i i l e c o u n t r i e s w h i c h have obtained and
a p p r o v a l , p e r î i a p s many y e a r s ago, may have c e a s e d t o a c h i e v e t h e s t a n d a r d s c r i t e r i a s p e c i f i e d and may p e r h a p s t o d a y , i n obtaining i t .
i f s e e k i n g a p p r o v a l , be u n s u c c e s s f u l ' •*
The Committee on I n t e r n a t i o n a l Q u a r a n t i n e a g r e e d t h a t p e r i o d i c c o n t r o l o f y e l l o w f e v e r v a c c i n e s a p p r o v e d by t h e O r g a n i z a t i o n s h o u l d be c a r r i e d out.''"
O f f . R e c . V\fld H l t h O r g . , 95,
S t h R e p o r t o f IQ. Committee, s e c t i o n
92.
IQ/I/P/67.5 page 5
IJith regard to c e r t a i n other vaccines, there are two wliich may s p e c i f i c a l l y mentioned - smallpox vaccine and c h o l e r a v a c c i n e . r e s o l u t i o n EE22.R12, paragraph 4, the Executive Board:
perhaps be
Under the terms of
"PîEQUESTS the Director-General to ensure, i n accordance w i t h the normal p r a c t i c e of the Organization, t h a t an^ vaccine accepted f o r the antismallpox programme i s of acceptable q u a l i t y . " I n order to implement t h i s , i t has been customary f o r the WHO s a t i s f y i t s e l f on the b a s i s of information a v a i l a b l e regarding the Secretariat to producing
l a b o r a t o r y and by t e s t s of potency, s t a b i l i t y and s t e r i l i t y t h a t the vaccine o f f e r e d as a g i f t f o r the Smallpox E r a d i c a t i o n Programme i s acceptable. An arrangement has
been made betvreen MiO and the Statens S e r u m i n s t i t u t , Copenliagen, arvi the R i j k s I n s t i t u u t voor de Volksgezondheid, tests. Utrecht, Netherlands, t o c a r r y out the r e q u i r e d
In a d d i t i o n , c e r t a i n amendments were made t o the I n t e r n a t i o n a l S a n i t a r y By v i r t u e of r e s o l u t i o n l/lIAlO,5,
R e g i i l a t i o n s , p a r t i c u l a r l y i n regard to Appendix 4.
the World Health Assembly r e q u i r e s t h a t the i n t e r n a t i o n a l c e r t i f i c a t e of v a c c i n a t i o n or r e v a c c i n a t i o n against smallpox s h a l l s t a t e t h a t the vaccine used i s c e r t i f i e d t o f u l f i l the recommended requirements of VJHO. V/lth regard to c h o l e r a vaccine, i t may be pointed out t h a t s i m i l a r p r o v i s i o n s do not e x i s t . Tne e x i s t i n g Requirements f o r Cholera Vaccine, published i n T e c l u d c a l were formulated i n 1950 and are i n process of r e v i s i o n at
Report S e r i e s No. 179, present.
I t i s p o s s i b l e that c e r t a i n complications i n regard t o i n t e r n a t i o n a l these
c e r t i f i c a t e s of v a c c i n a t i o n or r e v a c c i n a t i o n against c h o l e r a may a r i s e and may be talcen up i n due course.
On c e r t a i n occasions when t e s t s have had t o be c a r r i e d out on some other vaccines, f o r exacple, p o l i o m y e l i t i s vaccine, measles vaccine, ad hoc arrangements have been made by l i a i s o n between the V i r u s and B i o l o g i c a l S t a n d a r d i z a t i o n I M i t s f o r these vaccines to be t e s t e d f o r s p e c i f i c piirposes. No r e g u l a r arrangement, how-
ever, e x i s t s or i s envisaged at present f o r c o n t i n u i n g t h i s .
^ Handbook of Resolutions and Decisions, 8th ed., p. 49.
IQ/VJP/67.5 page 6
AIEE-MEf'Dirvi P r o c e d u r e A d o p t e d f o r O b t a i n i n g MEC A p p r o v a l o f Y e l l o w lifever V a c c i n e f o r t h e I s s u e o f I n t e r n a t i o n a l C e r t i f i c a t e s o f V a c c i n a t i o n and R e v a c c i n a t i o n 1. to Formal a p p l i c a t i o n from the t h e D L r e c t o r - O e n e r a l o f V/IIO. Government oi* M i n i s t r y of Health of the Governinenl:
In s u c h an a p p l i c a t i o n i t i s advisable f o r a s t a t e m e n t t o b e made t h a t the l a b o r a t o r y i n q u e s t i o n i s e i t h e r a n offic-{_Q_ Government l a b o r a t o r y o r a l a b o r a t o r y a p p o i n t e d b y t h e G o v e r n m e n t fcr prodviclrxg yellow fever vaccine f o r the purpose f o r w h i c h V/HO a p p r o v a l i s b e i n g r e q u e s t e d . 2. D e t a i l e d i n f o r m a t i o n c o n c e r n i n g personnel, premises, equipment and p r o p o s e d p r e p a r a t i o n t e c l i n i q u e s s h o u l d be p r o v i d e d . T h i s i n f o r m a t i o n s h o u l d a l s o be f o r w a r d e d t l i r o u g h t h e M i n i s t r y o f H e a l t h o r , i f s e n t d i r e c t t o vJEO, s h o u l d b e a r a Government c e r t i f i c a t e f r o m the Ministry'- o f H e a l t h . Tlie p r e m i s e s a n d f a c i l i t i e s n e e d t o be f i i l l y d e s c r i b e d as w e l l as equipment a v a i l a b l e and the v i r u s s t r a i n a n d t e c h n i q u e t h a t w i l l be u s e d , t o g e t h e r w i t h information concerning the p e r s o n n e l w h o w i l l be a t t a c h e d t o t l i i s p a r t i c u l a r unit and t h e i r q u a l i f i c a t i o n s . O n l y a f t e r tlT-.- ^ i n f o r m a t i o n has been r e c e i v e d c a n the' p r o c e d u r e s be s e t i n m o t i o n t o a s k o t h e r approved l a b o r a t o r i e s to p a r t i c i p a t e i n ~ control testing. ' 3. An e s s e n t i a l r e q u i s i t e t o V/HO a p p r o v a l f o r t h e u s e o f y e l l o w f e v e r v a c c i n e f o r the i s s u e o f i n t e r n a t i o n a l c e r t i f i c a t e s o f v a c c i n a t i o n and r e v a c c i n a t i o n i s the p e r f o r m a n c e o f t e s t s o n a b a t c h o f v a c c i n e p r o d u c e d a t t h e i n s t i t u t e , made i n t l i r e © l a b o r a t o r i e s a p p r o v e d f o r t h i s p u r p o s e b y VJHO. Tne r e p o r t s o n t h e r e s u l t s o b t a i n e d i n the three t e s t i n g l a b o r a t o r i e s are c o l l e c t e d b y IfilO a j i d w i l l b e t h e b a s i s o n whic/: the D i r e c t o r - G e n e r a l w i l l d e c i d e whether to grant a p p r o v a l , p r o v i d e d t h e ota< c o n d i t i o n s f o r p r o d u c t i o n a n d c o n t r o l ai>e satisfactory.
Ioywp/67.5 page 7
4. A number o f e x p e r t s on t h e V/HC E x p e r t A d v i s o r y fvimished w i t h the informiation a v a i l a b l e concerning p e r s o n n e l , p r o d u c t i o n , e t c . , as w e l l as t h e r e s u l t s b y t h e t h r e e e x p e r t l a b o r a t o r i e s . The e x p e r t s a r e b a s e d on t h e i n f o r m a t i o n s u p p l i e d t o them, a p p r o v a l granted. 5. WHO
P a n e l on V i r u s D i s e a s e s a r e the manufacturing establishment, o f examination o f the product asked whether, i n t h e i r o p i n i o n , o f t h e v a c c i n e s h o u l d be
I t h a s been t h e p r a c t i c e t h a t t h e f o l l o w i n g c o n d i t i o n s must be f u l f i l l e d i f a p p r o v a l o f y e l l o w f e v e r v a c c i n e i s t o be g r a n t e d : (a) Tlie
p r e m i s e s and equipment must n o t be used f o r any o t h e r p u r p o s e .
(b) Tne r e q u i r e m e n t s p u b l i s h e d i n WIO T e c h a i i c a l R e p o r t S e r i e s No. 179, R e q u i r e m e n t s f o r B i o l o g i c a l S u b s t a n c e s No. 3 ( R e q u i r e m e n t s f o r Y e l l o v ; F e v e r V a c c i n e ) must be f u l f i l l e d . The r e q u i r e m e n t s cover the f o l l o w i n g :
source m a t e r i a l s ( t h e v i r u s s t r a i n s , seed l o t s and t h e i r t e s t i n g , t i s s u e s f o r v i r u s production); produc t i on p r e c aut 1 ons; h a r v e s t i n g and t r e a t m e n t f i l l i n g and c o n t a i n e r s ; c o n t r o l t e s t s on f i n a l product. of bulk product;
Tliese r e q u i r e m e n t s a l s o r e l a t e t o a number o f g e n e r a l f a c t o r s i n c l u d i n g : p r e m i s e s ( c o n s t r u c t i o n and m a i n t e n a n c e ) ; staff ( q u a l i f i c a t i o n s and e x p e r i e n c e ) ; f o r yellow fever
equipment ( s u i t a b i l i t y vaccine production);
r e c o r d s ( h i s t o l o g i c a l , r e l a t i n g t o seed l o t s and c o m p l e t e p r o t o c o l s o f p r o d u c t i o n and t e s t i n g ) s t a b i l i t y ( p a r t i c u l a r l y f o r determination of e x p i r y date o f the p r o d u c t ) .