It has been the last six months; the use of expired medicines in Tamil Nadu becomes a big issue. It started with alleged death of a child due to use of expired medicine. Almost all the newspapers have been covering how the expired medicines are being recycled and the stockists are desperate to dispose such stock throwing as garbage. The drugs control administration seems to have awakened and joined hand with state police to curb the menace of use of expired medicines in the state. This has caused undue panic among the public and the drug retailers as well.
Medicines or medicinal products are required to be physically, chemically, therapeutically, toxicologically and microbiologically stable. The physical stability refers to the retention of original physical properties of medicinal product like appearance, palatability, uniformity, suspendability etc. In chemical stability, the active pharmaceutical ingredient retains its chemical integrity and labelled potency. Therapeutic stability ensures that the therapeutic effect remains unchanged. Toxicological stability ensures that there is no significant increase in toxicity of the product. The microbiological stability ensures that the sterility is maintained or resistance to microbial growth is retained.
Physical instability
The physical instability refers to mottling of tablets, creaming of emulsions, caking of suspension etc. It may not cause a loss of potency. But the patient is likely to loose confidence in the product. The chemical instability is normally the big issue in stability and is the single most factors considered predicting the shelf life. The chemical instability causes decomposition of the active pharmaceutical substance(s) leading to the formation of a new chemical entity in the product. Hydrolysis and oxidation are the major degradation pathways which cause loss of therapeutic activity, thus loss of potency. Often the physical and/or chemical change in the diluents (or, additives) used in the formulation causes lowering of bioavailability leading to lowering of therapeutic efficacy. This may be independent of changes in API. The toxicological instability is concerned with toxicity of decomposed medicinal product.
In order to ensure that the stable medicinal products are made available for use by the patients, the drug regulation (The D&C Act and Rules) requires that the product must bear a label indicating the date of manufacture and the date of expiry of the potency. The time period between the date of manufacture and the date of expiry is known as shelf life. The shelf life of the various drugs and medicinal products is specified in Schedule P of Drugs Rules. But the shelf life is linked to the condition of the storage. The rule also specifies that the shelf life shall not exceed 60 months unless the manufacturer produces satisfactory evidence to the Licensing Authority.
Data on stability testing
Data on stability testing is necessary for approval of new drugs. The stability testing is intended to generate evidence on how the quality of the drug or the drug product varies with time under the influence of various environmental factors such as temperature, humidity and light. The stability testing is necessary to determine the shelf life of the product and to recommend the desired storage requirement. The approval of new drugs requires that data on stability from both long term and accelerated stability testing. The minimum study period specified are 6 months for accelerated stability testing and 12 months for long term stability testing. The shelf life determination is based on the principle that during this period the product retains its potency as per standard specified in recognised pharmacopoeia. That means during this period the product is expected to retain 90-95 per cent of the labelled potency depending on the product standard.
The storage conditions specified in Schedule P includes: cool place, temperature not exceeding 5°C, well closed container with temperature not exceeding 30°C, temperature not exceeding 20°C, temperature between 2°C and 8°C but must not be freezed, cold place, temperature between 2°C and 5°C, between 2°C and 10°C preferably at the lower limit. Even there is different shelf life for different storage conditions. To cite an example, the polio vaccine shelf life is specified as 24 months if stored at -20°C, 6 months at 0°C and 3 months at 4°C. The cold place (a place having temperature not exceeding 8°C) can be easily maintained using a cold chain during distribution system and using a refrigerator in a retail medical store. The maintenance of cool place condition (a temperature between 10°C and 25°C) is not an easy task. It requires air conditioning of the logistic system and the retail medical store. There are very few air conditioned retail drug store in the whole country. This issue is relevant only to tropical countries like India. As the temperature is the most significant contributing factor to drug degradation, the drug products stored in ordinary condition in retail drug store where often temperature goes beyond 45°C, in all probability loose their potency and get expired well before the expiry date. As a general rule the drug degradation rate doubles for every 10°C rise in environmental temperature.
The expiry date is printed on the label of the product indicating month and the year like March 2010. This indicates that the drug can be used till 31 of the March 2010. After this date (meaning April 01, 2010 onwards), the product is legally not permitted to be sold. Here often an obvious question arises, how can the product which was useful on March 31, 2010 becomes useless (not suitable for use) on next day (April 01, 2010)? There is no biological death in the product and the loss of potency is also not instantaneous. The loss of potency is a gradual process. Rationally speaking the drug product is suitable for use even after the expiry date if properly stored. But it is an ethical dilemma whether to use the expired product or not. But when the fresh stock of the product is not available, perhaps it is rational to use the expired product.
Looking from safety point of view, there are very few reports of human toxicity due to ingestion, injection or topical application of presently available medicinal products after their expiration date. There are very few examples where the products of degradation are significantly more toxic than the original active pharmaceutical ingredient. Tetracycline gets decomposed to epianhydrotetracycline and the decomposed product is shown to cause renal tubular damage. Chloroquine can produce toxic reactions attribute to photochemical degradation. Phototoxicity has also been reported following administration chlordiazepoxide and nitrazepam. Infusion of degraded Penicillin G is known to cause sensitization of lymphocytes and formation of antipenicilloyl antibodies.
When the storage requirements of medicinal products are complied through out the logistic system including in the retail drug store, the products are likely to retain the labelled potency as per standard specified in the pharmacopoeia. The majority of the drug products will retain this potency beyond the expiry date too. Barring few examples the majority of the products would be safe too like during their shelf life. When no suitable alternative is available, the expired drugs may be considered useful. However the ethical and legal concerns remain!
(The authors are with Division of Pharmacy Practice, Department of Pharmacy, Annamalai University, Annamalai Nagar - 608 002)