Evaluation of epinephrine's expiration date: A US Food and Drug Administration's perspective

Abstract

Kassel et al1Kassel L. Jones C. Mengesha A. Epinephrine drug degradation in autoinjector products.J Allergy Clin Immunol Pract. 2019; 7: 2491-2494Google Scholar report results for epinephrine drug degradation in 46 random epinephrine autoinjectors (EAIs) from 1 to 168 months (median of 24 months) after the labeled expiration date. They found that EAIs up to 30 months beyond labeled expiration dates showed 90% epinephrine concentration. Because of the high percentage of epinephrine beyond the expiration date, they question the true expiration dates of these EAIs.1Kassel L. Jones C. Mengesha A. Epinephrine drug degradation in autoinjector products.J Allergy Clin Immunol Pract. 2019; 7: 2491-2494Google Scholar We agree with the authors that the expiry of EAIs is an important issue as it is recommended for patients who are at risk for anaphylaxis to carry an epinephrine product.2Lieberman P. Nicklas R. Randolph C. Oppenheimer J. Bernstein D. Bernstein J. et al.Anaphylaxis—a practice parameter update 2015.Ann Allergy Asthma Immunol. 2015; 115: 341-384Google Scholar US Food and Drug Administration (FDA) is aware of the implications of the expiry of EAIs, given the price the manufacturers charge and epinephrine shortage issues. However, we are concerned that the report from Kassel et al may encourage the use of EAIs beyond the expiration date. We believe it is important to provide some additional perspective from FDA on determination of expiry dates for EAIs. FDA regulations require drug applicants to provide stability testing data with a proposed expiration date and storage conditions when they submit an application for FDA approval of their drug.3US Food and Drug AdministrationGuidance for Industry Q1A(R2) Stability Testing of New Drug Substances and Products. 2003.https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q1ar2-stability-testing-new-drug-substances-and-productsDate accessed: July 29, 2019Google Scholar This testing is designed to provide confidence that the product will meet the applicable standards of strength, quality, and purity throughout its shelf-life. The FDA verifies that the proposed expiration date is supported by the submitted data. FDA and manufacturers evaluate multiple parameters to ensure that the quality of the drug product is maintained throughout its shelf-life. For EAIs, the concentration of the active ingredient (epinephrine) is important, but it is not the only parameter of concern for these products. Epinephrine is a chiral molecule with the l-(−)-enantiomer having greater activity than the d-(+)-enantiomer. Epinephrine is readily oxidized, and this oxidation process leads to impurities or degradants, including change from the l to d enantiomer.4Hoellein L. Holzgrabe U. Ficts and facts of epinephrine and norepinephrine stability in injectable solutions.Int J Pharm. 2012; 434: 468-480Google Scholar Change from the l to d enantiomer over time could impact the efficacy of the product. Measurement of total epinephrine concentration may not reflect the concentration of the active l-(−)-enantiomer. Storage conditions can impact oxidation and degradation. In the case of epinephrine products, impurities and antioxidant content can limit the shelf-life because we need to ensure the safety of these impurities and degradants. Given the stability and oxidation issues with epinephrine, extending the shelf-life of EAIs has been a challenge. FDA sets an expiry date based on the data provided by the manufacturer. Manufacturers can support an extension in the expiry date by submitting additional stability data, so the current shelf-life of EAIs could be updated in the future. We appreciate the efforts of Kessel et al to raise awareness of this issue and raise questions regarding the expiry of EAIs. We hope our perspective provides some insights into the challenges of extending the shelf-life of EAI. However, we caution against the use of EAIs beyond the expiry date because we cannot ensure the pharmaceutical quality of the product. For additional information regarding pharmaceutical quality and expiration dates, visit: https://www.fda.gov/drugs/pharmaceutical-quality-resources/expiration-dates-questions-and-answers. ReplyThe Journal of Allergy and Clinical Immunology: In PracticeVol. 7Issue 8PreviewLan et al1 raise interesting and important points regarding our study.2 Our study analyzed epinephrine autoinjectors (EAIs) in a laboratory setting, and thus our findings are not able to comment on the clinical ability of the expired EAIs to blunt an anaphylactic response. Lan et al bring this further to light in encouraging patients to continue to carry in-date EAIs, and we concur, based on current labeling and expiration dating done by the Food and Drug Administration (FDA) in collaboration with drug manufacturers. Full-Text PDF