W O R LD H E A L TH ORGANIZATION

W O R L D H E A L T H ORGANIZATION

EXECUTIVE BOARD Thirty-third Session

Provisional agenda item 2.^.2

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ORGANISATION MONDIALE DE LA SANTÉ

ЕВЗЗ/17 ^ 27 November 1963 ORIGINAL:• ENGLISH

C L I N I C A L AND PHARMACOLOGICAL EVALUATION OF D R U G S :

‘ STANDARDS OF D R U G S1

Report by the Director-General

1 . T w o resolutions concerning drugs were passed at the Sixteenth W o r l d Health A s s e m b l y . W h e r e a s resolution WHAI6.36 "Clinical and Pharmacological Evaluation of D r u g s " deals with adverse drug r e a c t i o n s , resolution W H A l 6 , 3 8 , with which this paper is c o n c e r n e d , refers t o t h e conformity of pharmaceutical preparations t o "drug control requirements" which apply in the exporting c o u n t r y , in the case of imported d r u g s .

F o r the purposes of this r e p o r t , "drugs" include pharmaceutical chemicals as raw m a t e r i a l for the preparation of pharmaceutical p r e p a r a t i o n s , preparations in bulk t o b e packed in the Importing c o u n t r y , a n d pharmaceutical specialities packed r e a d y for u s e , including t a b l e t s , injectable s o l u t i o n s , d r a g e e s , ointments, suppositories, ophthalmic p r e p a r a t i o n s , e t c ,f which m a y include preparations

containing a single drug or a mixture of m a n y active p r i n c i p l e s , for instance isoniazid w i t h para-aminosalicylic a c i d , and mixtures of a n t i b i o t i c s , s t e r o i d s , v i t a m i n s , a n a l g e s i c s , e t c .

W h i l e it is n a t u r a l that countries should wish to obtain assurance that the pharmac eut i с als imported into t h e i r countries are of satisfactory q u a l i t y , such assurances cannot in m o s t cases be obtained simply b y requesting certificates of quality from the exporting country or the exporting firm or agent • The

reasons are m a n i f o l d , as explained below»

1 Resolution W H A l 6 . ) 8 , Handbook of Resolutions and D e c i s i o n s , 7 t h e d . , p . 19

2. The control of the identity, purity, potency, sterility, etc. of these preparations, covered by the expression "pharmaceutical quality control", can be effected by:

(a) the manufacturer at the time of manufacture of the basic pharmaceutical chemical, and also later on,:when the phámiaceutical preparation is made ready for u s e , including one or more active principles with added excipients, colouring material, buffering a g e n t s , stabilizers, preserving agents, etc. A difficulty arises from the fact that the pharmaceutical preparation made in an exporting country will often have as the active drug or drugs pharmaceutical chemicals produced in another country without the manufacturer of the pharmaceutical preparation - for instance tablets or

injections - having sufficient knowledge of what testing has been made of the quality of these chemicals. It so happens that a pharmaceutical speciality of an exporting country may include only drugs which have actually been produced in a number of other countries, which may exercise no official quality control over pharmaceutical

chemicals made in their countries. It is well to remember that all batches of

manufactured pharmaceutical chemicals and preparations have to be examined. Evidence establishing the safety and effectiveness of one or more batches of a drug has no

significance with respect to the safety of subsequent batches of the drug unless they can be shown to be the same as to identity, strength, quality and purity as the

batches studiedj

(b) .the national control authority.• This .control of the work done at the manufacturers to check the quality of their products can thus be effected through

inspection by the national or a provincial administration, with the taking of samples to be analysed in a.national laboratory for quality control. A number of countries have regulations for this purpose; however, in many cases the preparations are actually checked in the national laboratories only at the time of their first

introduction onto the market of the country, if at a l l . Other exporting countries may have only regulations a n d , in practice, effect little or no official quality- control whatsoever of the preparations sold in their own and in other countries•

EB33/JL7 page 3

S t i l l other c o u n t r i e s , doing a large export of d r u g s , do n o t h a v e regulations

- - - . ' • " ' • . . . . • . . . . . .

requiring pharmaceutical quality control b y a n a t i o n a l or provincial a u t h o r i t y , even for the drugs and pharmaceutical specialities used in their countries. F o r these c o u n t r i e s , although the drugs exported comply fully with their r e q u i r e m e n t s , it does not m e a n that they have undergone any pharmaceutical quality c o n t r o l .

2.1 T h e problem o f finding ways and m e a n s t o ensure that exported drugs comply with requirements of ：the exporting country for these drugs is further complicated b y the fact that manufacturers and agents m a y produce and export drugs which conform to the requirements of "their c o u n t r y , but w h i c h , h o w e v e r , are used only to a v e r y limited extent in t h e i r c o u n t r y , or not A t a l l . In this c a s e , there m a y b e n o quality control effected on these p r e p a r a t i o n s , even in countries where a certain amount of quality control exists for the preparations in regular u s e in the c o u n t r y .

2 . 3 The number of manufacturers of pharmac eut i cal preparations is growing s t e a d i l y . There are u p t o a few hundred pharmac eut i cal manufacturers in certain c o u n t r i e s , and t h e i r number is g r o w i n g , m a n y of them exporting part or a l l of their production.

T h e number of countries exporting pharmaceutical preparations is increasing y e a r after y e a r , as private or nationalized manufacturers are endeavouring t o export their

preparations also t o m o r e c o u n t r i e s .

2.4 Inspection of the plants of the pharmaceutical m a n u f a c t u r e r s , including a n examination of the qualifications of their staff and of their equipment for quality c o n t r o l , c o u l d , t o a certain e x t e n t , ensure the quality of the drugs produced in a . country» T h i s , h o w e v e r , does not apply t o drugs imported into a c o u n t r y , unless

the importing country is satisfied that the pharmaceutical quality control of the drugs they import h a s b e e n effected adequately in the exporting c o u n t r y , or unless they

arrange t o send inspectors t o ensure that the quality control of the manufacture in the exporting country is a d e q u a t e . Certain countries have now introduced legislation t o m a k e it possible t o send, inspectors to inspect plants and t h e i r quality control in the country from which they believe that the drug o r i g i n a t e s . H o w e v e r , the

possibility that t h e exporting country would allow such inspection of its manufacturing plants is an open question•

Mention of the quality of the packing material should also be m a d e , since chemical changes will take place if proper packing and storage conditions are not observed, particularly for products going to tropical countries, with the formation of

disintegration products, thus increasing the toxicity of the drug or decreasing or nullifying its'strength• Packaging providing sufficient protection in one country may be wholly insufficient for export purposes to certain climates and under poor•

transport and storage conditions. In such cases even expiry dates may not afford sufficient protection, and it may happen that shipments o f , for instance, an

antibiotic, which was of the required quality at the time of export, have lost much of their strength when used in the importing country.

4 . It should be stressed that the analysis of pharmaceutical preparations is

difficult, especially for many of the new drugs and when the pharmaceutical preparation contains many chemicals therapeutically active. It cannot be undertaken successfully in a national control laboratory without a well-trained staff and adequate equipment.

Reference to the problems involved can be found in the report of a Study Group which met in Geneva from 4-8 December 1956 to discuss the "Use of Specifications for

Pharmaceutical Preparations"

产 under Item 8 ,

2

29 May to 2 June 1961 on "The Quality Control of Pharmaceutical Preparations"9 under Item k , "Methods for the Examination and Analysis of Pharmaceutical Preparations",

From what has been said, it can be seen, however, that no other effective and practical way of controlling the quality of drugs imported exists than by checking it in an official control laboratory of the importing country. The issuance of a

certificate of analysis from the exporting country will not solve the problem, since the appropriate control officials in some of the important exporting countries have no authority to issue such certificates a n d , moreover, such certificates may not have value or may be unacceptable in some of the importing countries. However, it may happen that a number of countries will undertake to make arrangements to accept each other1 s certificates, and this would indeed require further study.

1 Wld Hlth Org, techn. Rep. Ser,, 1957, 158 p

Wld Hlth Org, techn. Rep. Ser,, 1962, 249

EB53/17 page 5

5 * 1 T h e difficulties and expense of installing and staffing a n adequate national control laboratory will be amply compensated by^the assurance it can give t h a t imported drugs are of the right q u a l i t y , and b y enabling good decisions t o be taken on which drugs ought t o be i m p o r t e d , vñien drugs and pharmaceutical preparations are offered at varying prices b y exporters from different countries. W H O provides assistance for the establishment of the n a t i o n a l laboratories for pharmaceutical and biological c o n t r o l , particularly b y assisting within its fellowship programme in the training of pharmaceutical analysts and biologists• Courses in pharmaceutical quality

control have b e e n established in certain pharmaceutical institutes a t t h e instigation of W H O . In a d d i t i o n , W H O can supply lists of laboratory equipment necessary for pharmaceutical quality c o n t r o l .

5 . 2 In certain c a s e s , two or m o r e countries can agree t o h e l p each other in

establishing common laboratories for phamiaceutical quality c o n t r o l . T h i s is already in effect in certain countries or is being p l a n n e d , and W H O could offer advice on the s u b j e c t . On the other h a n d , at the beginning s t a g e s , effective assistance can be provided within a country by the staff of the pharmaceutical, m e d i c a l and other faculties, schools and i n s t i t u t e s , using their facilities and e q u i p m e n t . Quality- control should also b e instituted regularly h o s p i t a l p h a r m a c i e s , where a larger part of the drugs is dispensed in m a n y of the developing countries.

5 . 3 Other h e l p is provided b y W H O by sending consultants t o requesting countries t o h e l p health administrations t o p l a n for proper quality control of pharmaceutical p r e p a r a t i o n s , either imported or locally produced•

5.4 Great assistance is also provided b y W H O in supplying proposed specifications for the quality control of the m o r e important pharmaceuticals, as published in the International Pharmacopoeia,^ and requirements for a number of biological substaxices,

Volumes 工 and II of the first edition of the International Pharmacopoeia and the Supplement (WHO, G e n e v a , 1959); V o l u m e of Specifications for Reagents m e n t i o n e d in the International Pharmacopoeia (WHO, G e n e v a , 1 9 6 3 ) . T h e text of the second edition of the International P h a r m a c o p o e i a , including specifications for m a n y

additional pharmaceutical s u b s t a n c e s , w i l l be sent early in 1964 t o M e m b e r States as a mimeographed document (VfflO/Pharm/4o8)•

as published in the W H O T e c h n i c a l Report Series^ M o r e o v e r , the international non-proprietary names proposed by W H O for pharmaceutical substances are of help to n a t i o n a l administrations for the labelling of drugs and for regulatory and control p u r p o s e s . International biological standards are also supplied through W H O , as well as authentic chemical substances for pharmaceutical quality c o n t r o l . 2

6 . In c o n c l u s i o n , it should be stated that in order to ensure the quality of all pharmaceutical preparations used in therapeutics in a country, it is essential for this country t o organize a laboratory for pharmaceutical quality c o n t r o l , including the required technical s t a f f , equipment and facilities needed for a n adequate quality control of d r u g s , either produced w i t h i n the country for home consumption or for export f or imported•

1 International Non-proprietary N a m e s , Cumulative List (WHO, G e n e v a , 19б2) and Lists 12 and 13 (Chron> W l d H l t h O r g ” 1 9 6 2 , 16, N o , 10 and C h r o n . W l d H l t h Org* 會

1 9 6 ) , 1 7 , N o . 10)^ ~ ~ — — - — — 一— —一 一— — … 2

International Laboratory for B i o l o g i c a l S t a n d a r d s , Statens S e r u m i n s t i t u t , Copenhagen； International Laboratory for B i o l o g i c a l S t a n d a r d s , National Institute for M e d i c a l R e s e a r c h , London； International Centre for Authentic C h e m i c a l S u b s t a n c e s , Apotekens K o n t r o l l a b o r a t o r i u m , Stockholm.