FDA Proposes New Rule on Bulk Substances Used to Compound Drugs

Regulatory NewsRegulatory News | 15 December 2016 |  By 

The US Food and Drug Administration (FDA) on Thursday issued a proposed rule that looks to add six bulk drug substances to a list of such substances that can be used in compounding and to remove four other bulk drug substances that FDA evaluated and should not be included in the list.

If the proposed rule is finalized, the six bulk drug substances proposed for inclusion will be the first to be included on what’s known as the 503A bulks list. FDA’s Pharmacy Compounding Advisory Committee (PCAC) discussed the proposed additions and exclusions to the list in 2015, and the committee has since met three times in 2016 to discuss the inclusion and exclusion of other drug substances on the list.

“Because of the amount of time that had passed between the publication of the 1999 proposed rule and the enactment of the [Drug Quality Security Act] DQSA, FDA felt it was necessary to begin again to develop the 503A Bulks List,” the agency said in Thursday’s Federal Register.

In addition to the new additions and exclusions, FDA also proposes via this new rule to use the following criteria when evaluating nominated substances for inclusion on the list:

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

FDA proposes to consider each criterion and balance them on a substance-by-substance basis, to decide whether a substance is appropriate for inclusion on the list.

The Federal Register notice announcing the proposed rule provides additional details about the kind of information proposed to be considered for each criterion and how FDA proposes to weigh the information.

Inclusion in 503A List

Based on FDA’s evaluation, as well as consultation with the Pharmacy Compounding Advisory Committee, the agency is proposing to include six bulk drug substances on the list:

  • Brilliant Blue G, also known as Coomassie Brilliant Blue G-250, as a dye used in staining for visualization during ophthalmic procedures
  • cantharidin (for topical use only), for the treatment of warts and molluscum contagiosum
  • diphenylcyclopropenone (for topical use only) for the treatment of alopecia areata and nongenital warts
  • N-acetyl-D-glucosamine (for topical use only) for the treatment of hyperpigmentation and other skin conditions
  • squaric acid dibutyl ester (for topical use only) for the treatment of alopecia areata and recalcitrant nongenital warts
  • thymol iodide (for topical use only) for ulcerations and skin infections, as well as an intrapleural treatment for pleural effusions

Exclusion From 503A List

FDA is proposing that the following four substances not be included on the 503A list:

  • oxitriptan (evaluated as a treatment for depression and insomnia)
  • piracetam (evaluated as a treatment for enhancing cognitive skills)
  • silver protein mild (for use as an anti-infective agent for ophthalmic use)
  • tranilast (for the treatment of allergic disorders, arthritis, dry eye syndrome, keloids, and hypertrophic scars. It is approved in South Korea and Japan for the treatment of asthma, keloids, and hypertrophic scarring, and as an ophthalmic solution for allergic conjunctivitis)

Regulatory Action Against State Pharmacies

FDA also notes in the proposed rule that it generally does not intend to take regulatory action against a State-licensed pharmacy, Federal facility, or licensed physician for compounding a drug product using a bulk drug substance that is not the subject of an applicable USP or NF monograph or a component of an FDA-approved drug product, if the other conditions in section 503A and the Food Drug & Cosmetics Act (FD&C Act) are met, until the substance is addressed in a final rule.

However, the agency also notes that any claims that FDA has approved a compounded drug made with a bulk drug substance that appears on the 503A list will cause the drug to be misbranded.

Individuals and organizations may petition FDA to add or delete bulk drug substances at any time after the final rule is published. Comments on the proposal need to be made in 90 days.

List of Bulk Drug Substances that can be used to Compound Drug Products


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