♦Regarding the storage of APIs, the GMP Ministerial Order requires management under appropriate conditions that do not give impact to quality.

♦For APIs with an “expiration date” specified in the approval document, they can only be used during this valid period and never can be used after their expiration date. On the other hand, for APIs with a specified “retest period”, they can be used during the retest period, and even after the retest period has passed, they can be used if they pass a retest immediately prior to use (Refer to GMP Case Studies 1) GMP 21-4).

♦At the manufacturing site, tablets were manufactured using an API with an expiration date specified in the approval document. However, the procedure is specified in a way that allows for the use of API after the expiration date by conducting a retest.

♦Specifically, with the intention of reducing raw material waste and ensuring a stable product supply, the related SOP stipulated: “In principle, APIs that have exceeded their expiration date cannot be used. However, based on data supporting stability, they may be used for limited batches.”

♦Although the concepts regarding management and usability differ between APIs with specified expiration dates and those with specified retest periods, this manufacturing site established operational procedures at its own discretion that could allow for the use of APIs even after the expiration date.

♦The manufacturing site did not correctly understand the definitions of expiration date and retest period. Under such conditions, there is a risk that products with insufficient quality assurance could be distributed, and discrepancies with approved matters could potentially violate Article 3-2 of the GMP Ministerial Order.

♦Considering the consistency with the approved matters, the sentences starting with “In principle…” and “However…” in the procedure were deleted. This clarified that APIs that have passed their expiration date cannot be used.

♦Can you explain the respective definitions of the expiration date and retest period, as well as the handling of APIs after the retest period has passed?

♦For raw materials other than APIs, are you strictly complying with the approved matters and using them within the defined range based on data?

♦Are you fully aware that operations lacking objective grounds or ambiguous expressions in procedures pose a risk of causing inconsistencies with approved matters?

✓ Both the expiration date and the retest period are “approved matters” set based on scientific evidence to ensure the quality of the API, and they cannot be changed at the discretion of the manufacturing site. Since misunderstandings like this case are still frequently observed both at domestic manufacturing sites and overseas ones in recent years, we request that the definitions of expiration dates and retest periods, as well as their differences, be reconfirmed and thoroughly disseminated within manufacturing sites.

✓ Including manufacturing sites other than formulation plants, please re-check whether the descriptions in your procedures are consistent with regulatory terms and concepts and ensure that “provisos” or “exception rules” are not inadvertently permitting inappropriate operations as a result.

Source: PMDA, “ORANGE Letter” (Issue: June 2026)    https://www.pmda.go.jp/files/000281160.pdf