On April 6, 2023, the Food and Drug Administration (FDA) notified the public that it will formally exclude 10 bulk drug substances from the 503B Bulks List and include one bulk drug substance for oral use only.

For exclusion: (1) hydroxyzine HCl, (2) mannitol, (3) methacholine chloride, (4) metoclopramide HCl, (5) nalbuphine HCl, (6) potassium acetate, (7) procainamide HCl, (8) sodium bicarbonate, (9) sodium nitroprusside, and (10) verapamil HCl.

For inclusion (but limited to oral use): quinacrine hydrochloride (quinacrine).

All of these bulk drug substances previously underwent notice and comment, making this the FDA's final decision.

Unlike Section 503A, FDA-approved products are not, by themselves, appropriate for use by outsourcing facilities to compound. Rather, FDA must still evaluate the substance and determine whether the substance will be placed on the 503B Bulks List. If the bulk drug substance is a component of an FDA-approved product, FDA evaluates the substance based on the below questions:

  1. Is there a basis to conclude, for each FDA-approved product that includes the nominated bulk drug substance, that (a) an attribute of the FDA-approved drug product makes it medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation, and (b) the drug product proposed to be compounded is intended to address that attribute?
  2. Is there a basis to conclude that the drug product proposed to be compounded must be produced from a bulk drug substance rather than from an FDA-approved drug product?

All ten of the bulk drug substances FDA has decided to exclude from the 503B Bulks List were components of FDA-approved drug products and, therefore, were evaluated under these criteria. In its assessment, FDA determined that either the FDA-approved drug product was suitable to address the medical necessity used to support the nomination of the bulk drug substance or the bulk drug substance did not address the attribute that the FDA-approved drug product lacked. In other words, FDA did not believe that the "clinical need" for any of the nominated bulk drug substances was established.

The one bulk drug substance that FDA has determined will be placed on the 503B Bulk List (for oral use only), quinacrine hydrochloride, is not a component of an FDA-approved drug. Therefore, FDA evaluated the bulk drug substance using the below four factors, which FDA applied as a balancing test:

  • The physical and chemical characterization of the substance.
  • Any safety issues raised by the use of the substance in compounding.
  • The available evidence of effectiveness or lack of effectiveness of a drug product compounded with the substance, if any such evidence exists.
  • Current and historical use of the substance in compounded drug products, including information about the medication condition(s) that the substance has been used to treat and any references in peer-reviewed medical literature.

FDA determined that the physical and chemical characterization, safety, effectiveness, and historical and current use of quinacrine HCl weighed in favor of including quinacrine HCl on the 503B Bulks List.

Following its announcement, FDA updated category 1 of the interim 503B Bulks List and removed the aforementioned ten substances from the interim list, meaning that these bulk drug substances may no longer be used by outsourcing facilities for use in compounding. We encourage outsourcing facilities to remain attentive to changes to the 503B Bulks List and to update their compounding practices, accordingly.

This article is presented for informational purposes only and is not intended to constitute legal advice.