A survey published on September 19 by the Federal Consumers’ Union (UFC)-Que Choisir has revived the debate. Of around thirty drugs (paracetamol and ibuprofen) tested, 80% had an active ingredient content greater than 90%, despite an expiry date sometimes several years past. These results raise the question: could the expiration dates be extended?
Active ingredient content and effectiveness
These two notions cannot be considered completely equivalent. A medication that “retains 90% of its active substance” is not necessarily “90% effective”. The National Agency for the Safety of Medicines and Health Products (ANSM) clarifies: “Measuring the active ingredient content is not sufficient to certify the quality, effectiveness and safety of the medicine. The quality attributes of a medicine include not only the content of active principle but also those of degradation products, microbiological quality, attributes linked to the pharmaceutical form such as dissolution for tablets, the sterility and the particulate contamination for injectable forms, etc. “.
“It would be interesting to explore the idea that solid forms, such as tablets, can be used beyond their expiry date, which corresponds to the limit of the stability studies submitted to the authorities. »develops Odile○Chambin, professor of galenic pharmacy at the faculty of pharmacy of Dijon, in Côte-d’Or (see box). Beyond the active substance contents which may remain high, the specialist expresses doubts about the rest of the formulation: “For a tablet to be effective, its release must also remain consistent, the active substance can be properly dissolved, pass through the intestinal mucous membranes and be absorbed systemically without the appearance of impurities. » So many steps which require knowing how the other components of the drug behave once it has expired, in particular the excipients. This point calls for vigilance, particularly for specialties with a low therapeutic margin, such as, for example, synthetic thyroid hormones.
Impurities and degradation products
Another source of question∘: if a medicine has 90∘% of active substance after its expiry date, what happened to the 10∘% that disappeared∘? “The degradation products can be of several types, analysis Philip○Chennell, pharmacist, university lecturer, hospital practitioner, head of the functional unit of the control and development laboratory at the Clermont-Ferrand university hospital center (Puy-de-Dôme). They can be inert and therefore pose no problem, or pharmacologically active. In this second situation, it is possible that their activity remains close to that of the active principle or that it is completely modified, with toxicities that may affect targets different from those of the initial drug. »
As such, certain molecules are known to degrade quite easily. Their consumption after the limits of stability tests therefore presents a risk of ineffectiveness at best, and of undesirable effects at worst. A study published in 2014 in the PDA Journal of Pharmaceutical Science and Technology* lists some examples of degradation products from very common active ingredients. Ibuprofen in particular, following oxidation and photosensitization reactions, can lead to the formation of a substance exerting cytotoxicity on fibroblasts. Another example: lidocaine, in the event of hydrolytic degradation, generates a substance causing anoxia and damage to the hematopoietic system. The potential toxicity of these degradation products is, of course, dose-dependent.
“Whether or not to take a medication after its expiry date must be considered based on the benefit-risk balance, adds Philip Chennell. A healthcare professional cannot be held responsible by advising to continue taking them once they have expired. On the other hand, if a patient presents to a pharmacy having consumed a tablet for which the use date has passed, we can indicate that the data in our possession remains reassuring if the product has been stored under the recommended conditions. » Temperature and humidity conditions represent a major factor in the physicochemical and microbiological stability of the product.
There are no statistics regarding the actual consumption of expired medicines. Who hasn’t already kept a few boxes in their medicine cabinet for several years before using them? However, the incidents linked to this phenomenon remain anecdotal, as indicated by the ANSM: “To date, since 2011, the regional pharmacovigilance centers or the anti-poison and toxicovigilance centers have reported 810 cases mentioning the taking of medication. expired, deteriorated or poorly preserved. Among these 810 cases, 177 presented one or more adverse effects, including 17 cases mentioning a risk of ineffectiveness or suspicion of ineffectiveness. »
How are medicine expiry dates defined?
They are based on stability studies submitted by pharmaceutical companies to the National Agency for the Safety of Medicines and Health Products (ANSM) at the time of the marketing authorization application. Philippe○Maincent, former expert with the ANSM, deciphers∘: “These studies are very calibrated, the conditions under which they must be carried out depend on international standards which result from the consensus of the International Council for Harmonization (ICH). » For the Europe zone, the ICH determines three types of conditions for these stability tests:
– long-term conditions: at + 25°C and 60% relative humidity;
– intermediate: at + 30°C and 65% relative humidity;
– accelerated: at +40°C and 75% relative humidity.
“The laboratory must submit its finished product to these three conditions and report numerous factors in its study. In particular, the active ingredient content must remain within a range of between 95 and 105% over the duration tested. When impurities represent more than 1% of the total product, a toxicological verification of their safety is essential,” warns Philippe Maincent. “If the product remains stable for six months under accelerated conditions, the laboratory can already request a doubled expiry date, lasting one year. At the same time, studies continue. If the product maintains its stability for one year in long-term conditions, it is still possible to request a double expiry date, i.e. two years. » For any shelf life greater than 24 months, studies must be conducted in real time, with stability results presented over three or five years.
Extending deadlines∘: multiple challenges
Are the expiry dates of certain solid medications too restrictive? Most likely. But, to be able to ensure this, new stability studies would have to be carried out, over longer periods. A national program, Slip (for Safe Life Extension Program), was launched with this in mind by the American Food and Drug Administration in 1986. In France, this approach has just been launched as part of the ecological planning of the health system. . “The ANSM is committed to encouraging the extension of the shelf life of certain medications. Work with industrial representatives has begun,” specifies the agency. The interests are numerous∘: reducing waste, making savings for health insurance and hospital services, fighting shortages, etc.
“To date, we have little data at our disposal concerning the stability of our drugs, after the regulatory three or five years”recognizes Laure○Lechertier, director of market access and sustainable development at the Upsa laboratory. “We would be ready to continue these studies and possibly extend the expiry date of our medicines, when possible, to move in the direction of an approach responsible for our ecological impact. » This involves launching new stability studies, with results that would therefore be usable in just several years.
* « Advice on degradation products in pharmaceuticals : a toxicological evaluation », Sâmia Rocha de Oliveira Melo, Maurício Homem-de-Mello, Dâmaris Silveira, Luiz Alberto Simeoni, PDA Journal of Pharmaceutical Science and Technology, 2014;68(3):221 -238.
To remember
- The expiry dates of medicines are validated by the ANSM.
- Current stability studies generally do not exceed three to five years.
- A program has been launched to encourage pharmaceutical companies to extend these expiry dates on the basis of new stability studies.
