FDA Draft Guidance on Expiration Dating of Unit-Dose repackaged Solid Oral Dosage Forms

Recommendation

7/8 May 2024

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The U.S. Food and Drug Administration (FDA) proposed to tighten the previously proposed expiration dates for oral solid drugs from one year to just six months after they are repackaged into unit doses, except under certain circumstances. This is in line with USP (United States Pharmacopeia) standards on expiration dating.

The FDA states that this action was taken in response to "an increasing demand in various health care settings for solid oral dosage form drug products repackaged into unit-dose containers, which hold a quantity of drug for administration as a single dose. The increase in unit-dose repackaging has led to questions regarding stability studies and appropriate expiration dates for these repackaged products".

The draft guideline Expiration Dating of Unit-Dose Repackaged Solid Oral Dosage Form Drug Products was announced on August 8, 2017, and replaces the draft guidance for industry Expiration Dating of Unit-Dose Repackaged Drugs: Compliance Policy Guide (2005). In addition, once final, it will supersede Compliance Policy Guide 480.200 Expiration Dating of Unit-Dose Repackaged Drugs (1995). Comments regarding the draft document should be submitted within 60 days of publication.

In the previous draft guidance on expiration dating issued in May 2005, the FDA had proposed to set the expiration date for nonsterile, unit-dose repackaged drugs to one year, which was also aligned with USP standards at the time for beyond use dating for unit-dose repackaging by dispensers.

According to the FDA, the present draft guidance "addresses repackaging of prescription and over-the-counter solid oral dosage form drugs into unit-dose containers by commercial pharmaceutical repackaging firms that are required to register with FDA under section 510 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and to comply with current good manufacturing practice (cGMP) regulations in 21 CFR parts 210 and 211".

The 7-paged guidance does not cover

• Other dosage forms (e.g., sterile, liquid, topical),
• Products repackaged by State-licensed pharmacies, Federal facilities, and outsourcing facilities as defined under section 503B of the FD&C Act.

Background:
FDA’s cGMP regulations for finished products require that "each drug product bear an expiration date determined by appropriate stability testing and that the date must be related to any storage conditions stated on the labeling, as determined by stability studies". Samples used for stability testing must be in the same container-closure system as the marketed drug to ensure the drug product’s safety and efficacy over its intended shelf life.

Additionally, United States Pharmacopeia (USP) General Chapter <7> Labeling states that “the label of an official drug product … shall bear an expiration date.” For unit-dose repackaged products, USP General Chapter <1178> Good Repackaging Practices recommends that the expiration date “not exceed

• 6 months from the date of repackaging; or
• the manufacturer’s expiration date; or
• 25% of the time between the date of repackaging and the expiration date shown on the manufacturer’s bulk article container of the drug being repackaged, whichever is earlier.”

FDA will not enforce certain stability study requirements for repackaged drug products in the following cases:

• if an expiration date that does not exceed 6 months from the date of repackaging is assigned, or
• if 25 percent of the time between the date of repackaging and the expiration date on the container of the original manufacturer’s product is used as expiration date, whichever time period is shorter, and if the following conditions are met:
• The unit dose container complies with Class A or Class B standards as described in USP General Chapter <671> Containers – Performance Testing, “Packaging System Classification for Single-Unit Containers and Unit-Dose Containers for Solid Oral Dosage Forms”;
• The unit-dose repacking container provides light protection equal to or greater than that of the drug product’s original container closure system if the drug product is sensitive to light;
• The drug product’s original container has not been opened before and the entire contents are repackaged in one operation;
• Repackaging and storage occur in an environment that is consistent with the conditions described in the original drug product’s labeling (e.g. temperature and humidity, otherwise, if not specified in the original labeling, refer to definitions for “controlled room temperature” and “dry place” in USP <659> Packaging and Storage Requirements); and
• The drug product’s labeling does not caution against repackaging.

The FDA also proposes to permit the expiration date to exceed the ones described above, provided the above-listed conditions are met and if repackagers have supportive data from appropriate studies (including a risk-based assessment), using an adequate number of samples. These samples need to demonstrate that the container closure system used for repackaging is at least as protective for the drug product as the original packaging. However, "the expiration date of the repackaged product does not exceed the original manufacturer’s expiration date".