The QMN Weekly Bulletin

The FDA is recommending that generic manufacturers pay close attention to polymorphic forms of drug substances used in pharmaceutical processing operations, according to a new guidance issued last month. Polymorphism refers to the existence of different forms of the same substance.

Generic drugmakers should investigate whether active pharmaceutical ingredients can exist in crystalline, amorphous, solvate and hydrate forms, the FDA says, as polymorphic forms of a drug substance can have different chemical and physical properties, such as chemical reactivity, apparent solubility and dissolution rate.

In turn, “these properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution and bioavailability. Thus, polymorphism can affect the quality, safety and efficacy of the drug product,” the guidance says.

The effect of polymorphism on pharmaceutical processing also depends on the formulation and the manufacturing process itself, according to the FDA. For example, for drugs manufactured via direct compression, the solid-state properties of the active ingredient will likely be critical to manufacturing the final product.

However, for a drug product manufactured via wet granulation, the solid-state properties of the active ingredient are often masked by the resultant granulation, and the solid-state properties of the active ingredient are less likely to affect the manufacture of the final product, the FDA says.

The guidance, “ANDAs: Pharmaceutical Solid Polymorphism: Chemistry, Manufacturing and Controls Information,” can be viewed at www.fda.gov/cder/guidance/7590fnl.pdf.