Review of Changes in Topical Drug Product Classification

This article summarizes the classification systems for topical liquid and semisolid dosage forms used for dermatological application and notes some differences between FDA and USP classification.
Oct 01, 2008

In Remington's The Practice of Pharmacy, 5th edition, chapter LXVIII is dedicated to cerates, ointments, plasters, and papers, which are listed as solid extemporaneous preparations used externally (1). The 22 pages of this chapter carefully list the compositions and preparation procedures for 6 official cerates, 23 official unguentum, 7 official emplastra, 1 official Charta sinapis (mustard paper), and various unofficial topical preparations. Thus in 1907, classification of topical products was unambiguous and exactly defined within pharmacy practice.

During the next century, with the steady decrease in extemporaneous compounding, the introduction of highly effective topical steroids, and the adoption of over-the-counter monographs, the United States Pharmacopeia (USP) definitions of topical dosage forms became incomplete and ambiguous for classifying topical drug products. For example, USP does not define lotions but rather refers the reader to the sections describing solutions or suspensions (2). The definition of a water-removable ointment base begins "Such bases are oil-in-water emulsions...and are more correctly called 'creams'." Diprolene lotion 0.05% is an example of just how inaccurately a topical product can be classified. According to The Physician's Desk Reference, this reference-listed drug is "in a lotion base of purified water, isopropyl alcohol (30%); hydroxypropyl cellulose; propylene glycol; sodium phosphate monobasic monohydrate; phosphoric acid used to adjust the pH to 4.5" (3). Although it could be argued whether this slightly turbid alcoholic liquid should be classified as a solution or a suspension, neither scientific definition nor traditional use justifies this formulation being marketed as a lotion.

USP drug naming and taxonomies
For these reasons, topical drug product classification has recently received attention from the US Food and Drug Administration and USP (4, 5). Although an official guidance has not been issued, the questions asked of sponsors during the development of topical products clearly indicates that a classification system combining definitions from the publication Center for Drug Evaluation and Research (CDER) Data Standards Manual (click here) (6) and information from the Topical Drug Classification publication (4) have been combined to provide FDA reviewers working definitions of creams, lotions, gels, and other topical dosage forms. The accurate classification of a topical product has become increasingly important in recent years, primarily because of two factors. First, 21 CFR 314.101(d)97 effectively states that if a product is the same strength and a topical dosage form, then an abbreviated new drug application (ANDA), and not a 505(b)2 new drug application (NDA), should be filed. Second, insurance providers often only reimburse the lowest cost dosage form of a particular strength. Thus, if the efficacy and/or safety of an established active pharmaceutical ingredient are significanly improved by a novel topical formulation, the product may be either denied development as a 505(b)2 or denied insurance reimbursement based upon classification of the topical drug product.

Topical dosage forms applied to the skin surface

As quoted in CDER Data Standards Manual,

A dosage form is the way of identifying the drug in its physical form. In determining a dosage form, FDA examines such factors as the physical appearance of the drug product, the physical form of the drug product before dispensing to the patient, the way the product is administered, the frequency of dosing, and how pharmacists and other health professionals might recognize and handle the product (6).

This definition can be contrasted to the shorter, simpler definition by Buhse et al.: "A dosage form is a pharmaceutical formulation that contains an active pharmaceutical ingredient and one or more excipients" (4).