Several months ago this blog discussed the potential for clinical use of expired drugs, citing interesting shelf-life data for drugs evaluated by FDA/DOD’s SLEP, the Shelf Life Extension Program. More recently the issue of wasted, expired drugs has reached the public press in a recent Reuters article and in medical literature (Cantrell L, Suchard JR, et al. 2012.). The drugs tested in this recently published study were a whopping 28-40 years past expiration, with re-analysis showing that 86% of the 14 tested drugs (12 drugs, multiple batches of each) had at least 90% of their labeled potency, thus falling within an acceptable range of potency for drug batches that are still within their expiration period. As pointed out in our earlier blog, FDA’s Division of Quality Research has itself published evidence that most (88%) of 3,005 tested lots of expired drugs had documented stability at least one year beyond the original expiration date and many drugs were shown to have much longer demonstrable stability. This is not particularly unexpected since expiration is a procedural concept, based solely on the extent to which stability data have been generated and no consideration is given to the properties of the drug past this point.
It has gradually become clear that at least some drugs are extremely stable over long periods of time, and it seems a shame to simply toss them out upon expiry. Dr. Cantrell and the other authors of the recently published study are careful to acknowledge that their retained potency data do not address whether the drugs’ safety profiles may have become altered over time. Theoretically, small levels of degradation products could gradually accumulate, including some degradants which had been either undetected or quantified within acceptance criteria during the time of shorter-term (e.g., 2-4 years) stability analyses following original production of the drug product. However, whereas a decrease in potency of the active component may result in an increase in an impurity/degradant, if some old expired drugs have retained most of their original potency, it is reasonable to expect that they may also have an essentially unchanged impurity/degradant profile. In addition, conformance to pre-expiry in vitro release testing would assure acceptable bioavailability.
One could pose the following argument loosely based on the precedent of the presumed safety of generic drug products, which are formulations that can be marketed without long-term human safety testing:
- A generic drug, if chemically and pharmacokinetically identical to the innovator, is assumed to have the innovator’s safety profile without any additional safety testing.
- Chemical comparability means that the generic and innovator products have similar active ingredient potencies and similar minor components of impurities and degradation products.
- Pharmacokinetic comparability for the generic is defined by the 90% confidence interval around the ratio of the generic to innovator being within 80-125% for critical blood level parameters. This concept of bioequivalence usually is equated to sameness of the active pharmaceutical ingredient between the generic and innovator products. However, it also implies that it is acceptable for innovator and generic formulations to have some demonstrable differences in blood levels of the active ingredient and, by extrapolation, also of degradants in the formulations.
- Therefore, if an expired drug product was subsequently found to have near-labeled potency, acceptable in vitro release, and a profile of degradants/contaminants similar to product within expiration, it should be possible to conclude that the expired drug would have the expected efficacy and safety profile of that formulation within expiration.
It seems reasonable to postulate that re-analyses of expired drugs could identify some for which expiration could be re-established and thus qualify for recycling into clinical use. Criteria of sameness between expired and unexpired lots would need to be codified, and a method would need to be established for determining a new expiration date for such products. However, if a process of re-qualifying an expired drug could be established that was cost effective, drug wastage due to expiration might be decreased. This would not only benefit the overall cost of medications in the US, but would also help address the problem of drug shortages all too common these days.
Posted by Bob Roth, Vice President and Worldwide Medical Director and Nick Fleischer, Vice President. For more information, please contact Bob at email@example.com or Nick at firstname.lastname@example.org.