Press Release WHO/44
29 May 1998
STARTING MATERIALS FOR MANUFACTURING OF PHARMACEUTICALS MUST COMPLY WITH INTERNATIONAL STANDARDS
The active and inactive starting materials used in the manufacture of pharmaceutical products often change hands many times before reaching the manufacturer of a pharmaceutical product. Along the distribution and trade chain, there are many opportunities for the type and quality of material to change. As a result, chemicals required for production of pharmaceuticals can become contaminated, resulting in unsafe pharmaceutical products with grave dangers for the patients who use them.
The most often documented example of the above happening is the incorporation of diethylene glycol (DEG) into pharmaceutical preparations. Ingestion of DEG may affect the central nervous system, liver and kidneys, and can lead to death through kidney failure. The latest large-scale, well-documented instance of this happening was in Haiti in 1996, where some one hundred children died after taking contaminated cough syrup, but similar accidents have occurred previously in many countries, resulting in a total of at least 500 unnecessary deaths during the last ten years.
International action is consequently needed urgently to prevent such accidents in the future and the World Health Organization (WHO) convened a meeting of experts at WHO headquarters in Geneva from 25 to 27 May 1998 to address this issue. The experts came from 15 countries and represented national drug regulatory authorities, pharmacists' associations, traders, chemical and pharmaceutical manufacturers' associations, international nongovernmental organizations, major pharmacopoeias, consumer organizations and world customs organizations. The meeting formulated several concrete recommendations.
In addressing the experts, WHO Assistant Director-General, Dr Fernando Antezana, underlined that"the risk is not limited to diethylene glycol, similar incidents may happen at any time with other starting materials if quality assurance is not in place".
As contamination is most likely to occur either during manufacture of the starting material itself or during its trading, transportation and distribution to the pharmaceutical manufacturer of the final drug product, the group's major recommendations addressed these areas. Manufacturing activities with starting materials for pharmaceutical products should be covered by an authorization, from the competent health authority, requiring adherence to Good Manufacturing Practice (GMP). Governmental inspectorates should also be able to conduct inspections of manufacturing facilities at any time and place and be able to inspect containers of starting material produced.
Perhaps the major problem is in the transhipment of starting materials. Starting materials often pass through several agents or traders and can be repacked and relabelled at any stage, so that there can be an inaccurate indication of what a container holds by the time it has reached its final destination. To combat this, the group of experts insisted that a system of Good Distribution Practice be installed. Traders and agents should preferably hold an authorization from the local government. Moreover, national inspectorates should have access to free ports, areas which are exempt from many regulations.
It was recommended that WHO itself should actively develop a list of critical excipients (inactive starting materials) and their nomenclature. This would aid manufacturers, traders, inspectorates and other officials in recognizing and checking the quality of starting materials for pharmaceutical products. Furthermore, the group recommended that each manufacturer or country should have testing facilities for analysis of starting materials and final pharmaceutical products. Where no such analysis is possible, WHO should also advise developing countries to use formulations in essential drugs with ingredients for which they have appropriate testing facilities. Whereas every party in the chain has his own responsibilities, the final responsibility remains with the manufacturer of the final product.
"We have to have safe trading in all starting materials for pharmaceutical manufacturing. There have been repeated catastrophes with diethylene glycol, and now WHO will help develop activities to prevent this happening again," said Dr Juhana Idänpään-Heikkilä, Director of WHO's Division of Drug Management and Policies (DMP).
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