WHO Drug Information Vol. 12, No. 3, 1998
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WHO DRUG INFORMATION VOLUME 12 NUMBER 3 • 1998 RECOMMENDED INN LIST 40 INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES WORLD HEALTH ORGANIZATION • GENEVA Volume 12, Number 3, 1998 World Health Organization, Geneva WHO Drug Information Contents Seratrodast and hepatic dysfunction 146 Meloxicam safety similar to other NSAIDs 147 Proxibarbal withdrawn from the market 147 General Policy Issues Cholestin an unapproved drug 147 Vigabatrin and visual defects 147 Starting materials for pharmaceutical products: safety concerns 129 Glycerol contaminated with diethylene glycol 129 ATC/DDD Classification (final) 148 Pharmaceutical excipients: certificates of analysis and vendor qualification 130 ATC/DDD Classification Quality assurance and supply of starting (temporary) 150 materials 132 Implementation of vendor certification 134 Control and safe trade in starting materials Essential Drugs for pharmaceuticals: recommendations 134 WHO Model Formulary: Immunosuppressives, antineoplastics and drugs used in palliative care Reports on Individual Drugs Immunosuppresive drugs 153 Tamoxifen in the prevention and treatment Azathioprine 153 of breast cancer 136 Ciclosporin 154 Selective serotonin re-uptake inhibitors and Cytotoxic drugs 154 withdrawal reactions 136 Asparaginase 157 Triclabendazole and fascioliasis 138 Bleomycin 157 Calcium folinate 157 Chlormethine 158 Current Topics Cisplatin 158 Reverse transcriptase activity in vaccines 140 Cyclophosphamide 158 Consumer protection and herbal remedies 141 Cytarabine 159 Indiscriminate antibiotic use in animals — Dacarbazine 159 public health implications 142 Dactinomycin 159 Future trends in biological standardization 143 Doxorubicin 159 Etoposide 160 Fluorouracil 160 Regulatory Matters Levamisole 160 Mibefradil: harmful interactions 145 Mercaptopurine 160 HIV vaccine trial approved 145 Methotrexate 161 Counterfeiting: halothane replaced by Procarbazine 161 chloroform 145 Vinblastine 161 Warfarin interaction with miconazole oral gel 145 Vincristine 162 Nandrolone-containing products withdrawn 146 Hormones and antihormones 161 Sibutramine scheduled as a controlled Prednisolone 162 substance 146 Tamoxifen 163 Bromfenac withdrawal 146 Drugs used in palliative care 163 Discontinuation of international antibiotic reference preparations 146 .../... i World Health Organization, Geneva WHO Drug Information Vol. 12, No. 3, 1998 Contents (continued) Recent Publications and Documents Guidance for industry: active pharmaceutical ingredients 165 Guidance for industry: human plasma-derived biological products 165 WHO Expert Committee on drug dependence 165 WHO Expert Committee on Biological Standardization: Forty-sixth report 166 Use of antimicrobials in food-producing animals 166 Recommended International 167 Nonproprietary Names: List 40 ii40 WHO Drug Information Vol. 12, No. 3, 1998 General Policy Issues Starting materials for may no longer have an accurate description of its contents either on the labelling or the certificate of pharmaceutical products: analysis which accompanies it. Substitution of a safety concerns cheaper, substandard, more easily available prod- uct is, of course, of financial benefit to the supplier Many developing countries are wholly dependent — but it can have a tragic effect on the health of the on the importation of starting materials for use in consumer. the local production of essential and generic medi- cines. Starting materials are defined as those Given the need for immediate action, a meeting materials which are used in the manufacture of a was recently convened by the Division of Drug pharmaceutical product or those which come into Management and Policies of the World Health contact with the product during its manufacture. Organization on the control and safe trade in start- They may include raw materials, active and inactive ing materials for pharmaceuticals. Participants from ingredients, excipients, propellants, containers and regulatory authorities, nongovernmental organiza- packaging material. tions, consumer organizations and representatives of the major pharmacopoeias as well as inspectors, Starting materials often change hands many times pharmacists, traders, customs officials and chemi- before reaching the manufacturer or assembler of cal and pharmaceutical manufacturers, were in- the final marketed product and there are many vited. The meeting formulated several recommen- opportunities for the material to undergo relabelling dations which are set out on page 134. along the distribution and trade chain. As a result, chemicals and materials required for production of pharmaceutical products can become contaminated Glycerol contaminated with or undergo a change in identity, either accidentally diethylene glycol or as a result of negligence, and sometimes fraud. For these reasons, it is important for the manufac- G. Pierce, Director turer to implement good manufacturing practices Division of Emergency and Investigational (GMP) and carry out analytical testing on all starting Operations materials used in the production of pharmaceuti- Food and Drug Administration cals. United States of America The most documented incidents of contamination In Haiti, between November 1995 and June 1996, involve diethylene glycol, which is now held respon- 88 children died of acute renal failure after taking sible for hundreds of unnecessary deaths through- locally manufactured paracetamol (acetaminophen) out the world. Ingestion of diethylene glycol often elixir, an anti-fever syrup. A major component of the leads to death through kidney failure. In Haiti in syrup is glycerol (USAN: glycerin), which was later 1996, some 100 children died after taking paediatric found to have been contaminated with approxi- syrup containing glycerol contaminated with diethy- mately 20% diethylene glycol (DEG). DEG is an lene glycol. International action is urgently needed industrial chemical not intended for pharmaceutical to prevent similar incidents and tighten controls on or food use which can cause severe kidney dam- the distribution, trade and manufacture of starting age when ingested. materials. In June 1996, the US Food and Drug Administration Perhaps the single, most important handicap to (FDA) and the US Centers for Disease Control and controlling starting materials stems from the prac- Prevention (CDC) in collaboration with the Pan tice of transshipment and multiple trading. Starting American Health Organization (PAHO) and the materials invariably pass through the hands of Haitian Ministry of Health, identified DEG in two agents or traders, and can be repackaged and re- brands of paracetamol syrup available in Haiti. The labelled at any stage of the distribution chain. By FDA was requested to assist in the investigation of the time a container has reached its destination, it this product and its manufacture. 129 General Policy Issues WHO Drug Information Vol. 12, No. 3, 1998 The two brands of paracetamol syrup in question The carbon source of the fermentation media was were available in either 4-ounce bottles or as oral cane sugar and DEG was not used for the produc- drops for neonates in 2-ounce bottles; both had tion of glycerol. Purification would bring the concen- identical formulations. The syrup was found to tration to 95, 96 or 98% depending on the grade of contain 12–17% DEG and the oral drops contained glycerol being made. The glycerol was tested to 3–5% DEG. One shipment of glycerol was used in meet USP 21 by both the company and the distribu- five lots of the paracetamol. Later FDA analysis of tor, but the original certificate of analysis of these residue left in two drums suspected to originate tests was not available. from the glycerol shipment showed 16–24% DEG, It is hoped that the informal consultation recently 32% water, 23% sugar and 1–4% of the labelled held by WHO on the control and safe trade in glycerol in one drum and 26% DEG in the second starting materials will emphasize the importance of drum. the safety and quality of pharmaceutical starting materials such as glycerol and will provide the Further investigation revealed that the manufacturer approach and exposure necessary to prevent future of the finished dosage form did not test the raw incidents such as the Haiti tragedy. materials upon delivery, had no in-process quality control, and no finished product testing other than pH. Because of inadequate recording and lack of Pharmaceutical excipients: manufacturing controls, it was impossible to estab- lish which lots of the finished product were manu- certificates of analysis and factured from the contaminated glycerol shipment. vendor qualification The company recalled all products which contained glycerol. A.J. Falk Vice Chairman The FDA investigators traced the glycerol by visit- International Pharmaceuticals Excipient ing the shipper in the Netherlands. This disclosed Council (Americas) that the glycerol was shipped from the Netherlands, but the shipping record showed that the product Before purchasing or trading in excipients or other was billed through a company in Germany. Records starting materials takes place, it is common practice of the German company disclosed that the glycerol within the pharmaceutical industry to request a originated in China. A sample of the glycerol held certificate of analysis (COA). A COA relates specifi- by the company in the Netherlands was collected cally to the results of tests carried out on a repre- by FDA officials and analysed. The analysis dis- sentative sample drawn from the material to be closed 11%