WHO 1999: Guidelines to Combat and Test Counterfeit Medicines
In many countries, the quality of industrially manufactured pharmaceutical products is assured primarily through appropriate licensing and inspection systems and by the application of good manufacturing practice (GMP) by manufacturers. Until recently, analytical controls in the drug distribution system were regarded merely as supplemental. Quality surveillance following licensing/authorization was considered as a mean of detecting: any unintentional errors in the manufacture of drugs by legitimate producers; and/or any degradation which might occur in the course of normal distribution. Since such events were considered to occur infrequently, heavy sampling was seldom recommended.
Today, owing to the widespread danger of trade in counterfeit drugs, quality control in the distribution system has acquired new dimensions. When unlicensed/unauthorized products are suspected of being in circulation and adherence to GMP cannot be assumed, a greater number of samples had to be tested in order to maintain an appropriate assurance of drug quality. At the same time, however, pharmacopoeial analyses have become more expensive. The use of simple test should facilitate a balance between the need to increase the frequency and extent of testing on the one hand, and the need to contain costs on the other. Such first-line simple tests or screening methods would not replace pharmacopoeial, compendial or legally accepted test methods but would identify those products requiring further investigation. No regulatory action could be initiated on the basis of their results, and all samples considered to be potentially counterfeit or substandard would need to be referred for testing according to the pharmacopoeial, compendial or legally accepted reference method(s) to validate the findings of the initial screenings.
The principal requirement for a suitable screening procedure in the identification of the active drug substance. Depending on the capabilities and resources available, this can be achieved through test-tube colour reactions, melting-point determination or thin-layer chromatography (TLC). However, such tests provide only an estimation of the amount of drug substance; any other ingredients, which may be harmful, would not necessarily be detected and quantified. Practical considerations suggest that screening procedures should be performed according to a consistent method, and should have sufficient sensitivity and specificity to permit accurate testing of a large number of products.
Test methods for the detection of counterfeit products will be affective only within the framework of a national DRA with overall responsibility for control of importation and manufacturing procedures for drugs, and the inspection of drug distribution channels.
Methods based on thin-layer chromatography
TLC screening procedures are recommended for the detection of counterfeit drugs. Numerous studies have demonstrated the multiple uses of these methods. They can be employed for the identification of drug substances, the estimation of drug substance content and the detection of related substances which could be regarded as impurities. TLC procedures are more specific and selective as WHO basic tests for the identification of drug substances and are also subject to less interference by excipients.
A counterfeit product may contain the correct active ingredients but in amounts other than declared. In response to effective anticounterfeit measures, counterfeiters have often introduced small quantities of the genuine pharmaceutically active substances into the dosage forms. This gives positive identification results and in this way counterfeiters attempt to foil or confound the process of detection. In such cases, the basic tests are inadequate; TLC procedures are therefore preferred, as they are capable of giving semi-quantitative information on the active ingredient and also on the related substances in the dosage forms.
Other simple methods
The WHO basic tests have provided the basic for the preparation of the testing kits used in the field by various countries.
The basic tests are complementary to TLC methods, and it may be desirable to make use the form in certain cases and the latter in others. The testing laboratory should decide on the method(s) to be used on a case-by-case basis.
Where sophisticated counterfeits are present, testing will require the use of advanced analytical techniques such as mass spectrometry, nuclear magnetic resonance, ect. Hightechnology techniques , such as those using an near-infrared spectrophotometer, are also useful. The apparatus is simple to operate and can be used for the identification and semi-quantification of active ingredients in dosage forms. It is available as a portable unit requiring a very small amount of sample and little sample preparation, and gives results in a matter of minutes with the help of computerized controls. While the initial cost of such technologies may be an inhibiting factor, this should be weighed against the advantages they provide in terms of quick and accurate detection of counterfeit drugs. It should also be considered against the costs of training personal in other methods and of acquiring and maintaining the supplies of reagents and other special materials required for those methods.
Irrespective of the analytical method used, the first step in identifying potential counterfeit drugs is the careful visual inspection of the product, and its packaging and labelling. A comparison with the authentic drug product is always preferred. Differences in labelling, packaging and the physical appearance of dosage form, e.g. shape, colour, ect., indicate a potential counterfeit.
Even in the absence of knowledge of the physical characteristics of the authentic drug, a visual inspection may indicate that there has been tampering, that there is non-uniform colouration of the drug product under investigation, ect. Again such observations signal the possibility of a counterfeit.
Legitimate drug manufacturers should be encouraged to collaborate with national DRAs and with WHO by providing information and materials on the physical attributes of their products; this would also be to their own benefit.
Successful implementation of simple tests
The following points should be taken into consideration:
- the costs of performing simple and other tests for the detection of counterfeits should be weighed against the larger costs of drug injury, ineffective therapy and possible patient deaths.
- Guidelines for official organoleptic detection procedures should be widely available to all relevant persons. Pharmaceutical manufacturers should be encouraged to collaborate with national DRAs in the provision of information and appropriate materials dealing with the physical attributes of their products.
- All available technical documents should be translated into the official/national language(s).
- Consideration should be given to the application of rapid quantification procedures when counterfeit products have been positively identified.
- The type of systems to be used should be carefully considered before anyone is selected for training in counterfeit testing. Some methods, e.g. high-performance TLC, are sophisticated and have proven too difficult for less qualified personnel in previous training programmes.
Counterfeit Drugs – Guidelines for the development of measures to combat counterfeit drugs, WHO/EDM/QSM/99.1, 1999, pages 35 - 37