Recent FDA actions offer long-awaited clarity on what constitutes a ‘minor change’ to solid oral OTC dosage forms, providing manufacturers with a clearer pathway for certain modifications while maintaining a measured, incremental approach to innovation. The FDA docket is open until October 3 for comments.
On June 5, 2025, the Food and Drug Administration (FDA) released new guidance under the CARES Act for companies that wish to make dosage form changes for orally administered drugs that are subject to over-the-counter (OTC) monographs—now known as Final Administrative Orders. FDA’s Proposed Administrative Order OTC000038 and companion Draft Guidance for Industry provide much-needed clarity for those who wish to modify solid oral dosage forms without obtaining formal pre-market approval from FDA via a New Drug Application (NDA) or OTC Monograph Order Request (OMOR).
Manufacturers have faced significant challenges under the prior monograph framework, with the lack of predictability for new dosage forms often impeding innovation and market efficiency. Thus, as the OTC market continues to evolve under the post-2020 CARES Act regime, this new FDA guidance provides essential direction for stakeholders seeking to introduce novel dosage forms to the OTC drug market without compromising product safety or effectiveness. However, FDA has avoided genuine innovation by focusing on currently available and well-known dosage forms, rather than exploring the types of scientific data that would be needed to support truly new dosage form creations.
Background: The Evolution of OTC Monograph Regulation
For decades, the monograph system provided a framework for marketing certain OTC drugs without pre-market approval based on established standards for active ingredients, labeling, and dosages. However, Congress changed the framework in 2020 by replacing the prior rulemaking procedure with a new Administrative Order (AO) process under Section 505G of the Federal Food, Drug, and Cosmetic Act (FFDCA).
While these reforms were intended to modernize the system, ambiguities remained for manufacturers who wanted to market existing OTC ingredients via new or “non-monograph” dosage forms. Under Section 505G(c), sponsors may independently implement “minor changes” to OTC drug dosage forms without requesting an AO revision, via an OMOR submission to FDA.
To market the “changed” product, however, the sponsor must demonstrate that the change will not affect the safety or effectiveness of the drug and will not materially affect the active ingredient’s absorption in the body. In turn, FDA must issue an AO defining these terms and applying them to specific dosage forms. The recent FDA Draft Guidance represents the agency’s attempt to address these ambiguities for solid oral dosage forms like tablets and capsules, and provide a clearer pathway for minor changes, balancing regulatory oversight with the need for innovation and market responsiveness.
The Current Administrative Order Process and Its Challenges
Since the statute did not define what constitutes a minor change, the new framework resulted in regulatory uncertainty for manufacturers attempting to make OTC drug modifications in good faith. Moreover, the statute declared that dosage form changes backed by “insufficient” safety, effectiveness, and absorption information would be “misbranded” and therefore be at risk of enforcement action, causing industry paralysis.
Without clear guidance, manufacturers have faced challenges in designing studies, identifying comparator products, and compiling supporting data to meet FDA expectations.
Key Recommendations in the New Draft Guidance
FDA’s new guidance directly addresses some of these longstanding uncertainties by interpreting what constitutes a “minor change” in solid oral dosage forms under Section 505G(c). FDA specifies that converting a solid oral dosage form to a chewable tablet, orally disintegrating tablet (ODT), or film will qualify as a minor change, if the change does not affect the safety or effectiveness of the drug or materially alter the rate or extent of absorption or systemic exposure to the active ingredient when compared to a suitable reference product.
To support these determinations, FDA recommends comparative in vitro testing, such as dissolution studies, and outlines certain factors like active ingredient solubility and permeability that manufacturers should evaluate. FDA also described specific directions for use for the labeling of each changed dosage form and new unit-dose packaging requirements.
Additionally, the guidance underscores the importance of maintaining rigorous recordkeeping practices to establish compliance with regulatory requirements throughout the product’s lifecycle. When the guidance is finalized, these details may serve as a practical manual to help companies align their product development records with FDA’s expectations.
Next Steps: Compliance and Implementation
Although the FDA’s regulatory guardrails only permit three types of new oral dosage forms, sponsors now have more certainty about FDA’s scientific expectations related to permissible “minor changes” for new dosage forms. Manufacturers should carefully evaluate their product against the scientific criteria outlined by FDA and prepare documentation demonstrating that they have chosen a suitable reference product as a comparator, and that their dosage form change will not affect the OTC drug product’s safety, effectiveness, or absorption.
Stakeholders who wish to engage in the ongoing regulatory process may do so by submitting comments to the Draft Guidance through the FDA’s public docket by October 3, 2025. This feedback opportunity is critical for further refining the agency’s policies and addressing any ambiguities or practical challenges posed by the new 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.
Key Takeaways
This new guidance offers important details for manufacturers, enabling more confident navigation of minor dosage form changes within the OTC drug Administrative Order framework. By detailing scientific, data set and procedural expectations, it supports product innovation and potential improvements in patient convenience and medication adherence, initially through the introduction of chewable tablets, ODTs, or films for oral administration, thereby facilitating innovation while maintaining the safety and integrity of OTC monograph drugs.
With proactive engagement and adherence to the updated requirements, industry can navigate this new era of OTC drug regulation with confidence. Morgan Lewis lawyers with in-depth knowledge in OTC monograph compliance and related administrative processes stand ready to assist manufacturers and other stakeholders in interpreting these policy changes and developing compliant strategies for the market entry of new dosage forms.