A Bad Date; How Did I Fail to Get a Second?

We initiated a project two years ago to extend the shelf life of our blood pressure medication. The tablets have 20mg of active ingredient, 98% cellulose and other common excipients packaged in a HDPE primary bottle with 0.5g desiccant. In an attempt to reduce production runs we would like to extend the dating to 48 months from the current 24 months. The product has shown remarkable stability, but we had little data beyond 30 months until this project, and now, after extending our 2021 annual studies we have demonstrated decent stability through 36 months.

Due to some unexpected results at 36-months we inserted a 42-month interval and that’s where our problems really became apparent. The product failed miserably when moisture spiked from a high of 2.6% (spec is ≤ 3.0%) at 36 months to 4.7% at 42 months. At the same time potency, impurities and micro remained within expectations with only slight trends that do not threaten the specification and would probably make it to 48 months.

I’m tasked with making recommendations to QA and regulatory management on this project. Here are three options for which I’d appreciate your feedback and comment:

1. Test the desiccant in the failed samples.
   1. If the desiccant is no longer effective (saturated), increase the desiccant amount to 1.0g and restart the studies.
   2. If the desiccant is still effective, change the primary packaging to something more protective than the HDPE we have been using.

   Either a or b means starting from scratch and at least 4 years before an extension.

2. Take the 36-month dating that the data offers but consider implementing some manufacturing controls to ensure release moisture remains low enough to avoid the danger of an OOS at expiry.
3. Since moisture does not appear to impact product stability, submit a filing to remove or raise the moisture specification. Then continue the current studies to 48 months.

I put my money on option 2. Being more conservative and taking a slight win now doesn’t prevent your company from implementing one or all of the other options in the future. While making the product more profitable now you then have an opportunity to modernize the packaging and specs in the relatively near future. What do the rest of you think?