Today, the FDA published a draft guidance titled Recommendations for Complying With Over-the-Counter Monograph Procedure for Minor Changes C001: Minor Changes to Solid Oral Dosage Forms for Certain Over-the-Counter Monograph Drugs (here). This document discusses the conditions under which minor changes in dosage form (i.e., tablet or capsule to chewable tablets, orally disintegrating tablets (ODT), or films) may be appropriately made under Proposed Administrative Order (OTC000038, also called C001) without requesting an official change to an existing Administrative Order. However, the pathway to making the changes, unfortunately, results in a lot of work and documentation to be completed and maintained at the products’ manufacturing site.
In the guidance, changes would be limited to monograph drug changes where the active ingredient(s) are highly soluble and highly permeable. Dissolution studies as well as permeability studies must be performed. Interestingly, there are limitations to packaging that may be utilized for ODT and film products that will require the use of unit-of-use or unit-dose packaging. For chewable products, the FDA still has some concern about the friability and potential for moisture to impact product quality in multidose packaging (such as bottles) but still “recommends” the use of unit-of-use or unit-dose packaging. However, it appears that whether multidose packaging will be acceptable may depend on how the quality attributes of the specific chewable tablet can be justified over the expiration dating of the proposed product.
The guidance describes the type of data that must be generated to support the proposed change in dosage form to include both in vivo and in vitro testing as well as the permeability studies that must be conducted to demonstrate high solubility and high permeability.
This draft guidance applies only to oral dosage forms and, if finalized, will provide a down regulation of the requirements without requiring “the issuance of an order under section 505G(b) of the FD&C Act for the new dosage form if they [the manufacturer] maintain information necessary to demonstrate that the change: (1) will not affect the safety or effectiveness of the drug; and (2) will not materially affect the extent of absorption or other exposure to the active ingredient(s) in comparison to a suitable reference product. The change must also be in conformity with the requirements of an applicable administrative order issued under section 505G(c)(3) of the FD&C Act,” including cGMPs.
The minor change in a dosage form for an OTC monograph product has always been a thorny issue for regulated industry as well as the FDA as there has never been a clear articulation as to what changes would be appropriate under an existing OTC monograph that included a general statement “that the product is appropriate for oral administration.” In the past, changes in dosage form made without specific concurrence from the FDA (by applying for a monograph change) have resulted in enforcement action by the Agency if it determined that the change in dosage form could impact the safety or efficacy of the changed product. If and when this guidance is finalized, there will then be a clear path for making such changes as long as the conditions in the guidance are followed.
Please note that “[t]he recommendations provided in this guidance do not apply to drugs that are the subject of an application submitted under section 505(b) or section 505(j) of the FD&C Act or biological products that are the subject of an application submitted under section 351 of the Public Health Service Act.”
