The GDUFA II reauthorization process involved a lot of agreements from the FDA.  One of those agreements was for the Agency to publish a guidance on changes to drug substances that addressed the type of changes, their categories for submission (PAS, CBE, CBE-30, or annual report) and the necessary documentation that must be submitted to support the proposed changes.  It also outlines the responsibility of the DMF holder relative to updating their DMFs, as well as notification to each of their customers.

The document states “[A] central principle underlying this draft guidance is that a change in the drug substance manufacturing process can be adequately assessed by comparing three consecutive pilot or commercial scale batches of pre- and post-modification material to determine if the quality of the post-modification material is equivalent to or better than the quality of the pre-change material.” Comparisons of impurities, physicochemical properties, and stability or pre- and post-change drug substances are critical to declaring the products the same.  In addition, the draft outlines, in tabular format, when certain of these comparisons might not be necessary based on the history of the product, the dosage form, and the potential impact or lack thereof that certain of the criteria are likely to have on the finished dosage form.

Want to know if you will likely need to manufacture a batch of finished dosage form to confirm the drug substance change did not impact drug product quality?  Check out Section IV B.1 of the document.  What about bioequivalence studies and in vitro dissolution testing.  Well, it is like Prego Spaghetti Sauce – it’s in there!

There are 42 marvelous pages of advice, recommendations and glorious charts and tables that will provide you many hours of joyful reading pleasure that will delight both regulatory, quality, scientific, and manufacturing professionals.  The draft guidance will likely give rise to heated discussion about what does really need to go in the submission and how much lab work, testing and/or manufacturing will need to accompany each type of submission.  No guidance document can alleviate that, now can it?

So here is the link to the document (here), have fun and let me know when the first internal company disagreement breaks out!