USP-NF Stimuli Article on Quality by Design (QbD) Principles in Method Development

In the Pharmacopeial Forum, PF 49(1), a stimuli article entitled "A Novel Approach Using Quality by Design to Develop and Implement Flexible Methods in Non-Application Over-the-Counter Monographs" was published.

The article starts with an introduction highlighting the importance of nonprescription drugs (over-the-counter drugs, OTC), which are useful for the treatment of symptoms of minor, self-limiting conditions. It is pointed out that "products marketed under the FDA OTC Monographs do not go through FDA’s premarket approval process and frequently lack specific drug product compendial standards." Therefore, "the US Pharmacopeia (USP), US Food and Drug Administration (FDA), and Consumer Healthcare Products Association (CHPA) have committed to work collaboratively to develop and implement a path forward on establishing product-specific compendial standards".

Creating such a compendial standard for an OTC product can be a challenging task. In the article, "a proposed approach for generating flexible compendial organic impurity methods for drug products where multiple versions of products exist or that undergo frequent changes in formulation with respect to flavor, color, and excipients striving to meet consumer preferences in a fast-moving, competitive marketplace" is discussed.

In the following section, the concept of Design Space is explained. "Design Space" in the context of the stimuli article is defined as follows: "The multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide assurance of quality. The analytical method is identified by a range of operating conditions that are defined by the analytical design space."

To develop such a multidimensional space, a logical stepwise approach is followed:

• Primary Design Space: It denotes the conditions that resolve the API, degradation products, and process impurities as defined in the analytical target profile (ATP);
• Secondary Design Space: It resolves the ingredients within the primary design space with the addition of the most common excipients;
• Tertiary Design Space: It resolves all components of a drug product within a specific formula.

The main part of the article provides the method and development process for diphenhydramine oral solutions. This was agreed to be the first test case product. With this example, the procedure is explained in detail. The results are illustrated by several figures and tables.

The full article is available on PF Online via the USP Website Access Point. The deadline for submitting comments is 31 March 2023.