FDA finalizes determinations on 11 bulk drug substances on 503B Bulks List

14 June 2023 Reed Smith Client Alerts

Home Perspectives FDA finalizes determinations on 11 bulk drug substances on 503B Bulks List

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.

Authors: Rachael G. Pontikes Emily L. Hussey Kelly J. Kearney Susan J. Dewey Amica J. Nesbitt Madhav Y. Bhatt

By way of brief background, Section 503B of the Food, Drug, and Cosmetic Act (FDCA) provides outsourcing facilities with exemptions to section 505 (21 U.S.C. 355) (concerning the approval of drugs under new drug applications (NDAs) or abbreviated new drug applications (ANDAs)), section 502(f)(1) (21 U.S.C. 352(f)(1)) (concerning the labeling of drugs with adequate directions for use), and section 582 of the FDCA (21 U.S.C. 360eee–1) (concerning drug supply chain security requirements) when certain requirements are met. In order to qualify for Section 503B’s exemptions, in addition to other requirements, outsourcing facilities cannot use a bulk drug substance to compound unless (1) the bulk drug substance appears on a list established by the Secretary of Health and Human Services (the Secretary) identifying bulk drug substances for which there is a clinical need (the 503B Bulks List), or (2) the drug compounded from the bulk drug substance appears on the drug shortage list in effect under section 506E of the FDCA (21 U.S.C. 356e) at the time of compounding, distribution, and dispensing.

In accordance with the instructions set forth in Section 503B, after FDA evaluates bulk drug substances, it publishes a notice in the Federal Register proposing bulk drug substances to be included or excluded from the 503B Bulks List, including the rationale for such a proposal. Interested parties are provided not less than 60 calendar days to comment on FDA’s notice. After considering the comments, FDA completes its evaluation and then publishes a notice in the Federal Register designating bulk drug substances for inclusion on or exclusion from the list. (21 U.S.C. 353b(a)(2)(A)(i)(I)-(III)).

FDA began its evaluation process by publishing a December 2013 notice in the Federal Register inviting the industry to nominate bulk drug substances for FDA to consider for inclusion on the 503B Bulks List. (78 FR 72838). The nomination process was reopened in July 2014, after FDA provided additional direction regarding the information it required to evaluate nominated bulk drug substances. (79 FR 37747). FDA then evaluated the bulk drug substance to determine whether a “clinical need” existed to support the bulk drug substance’s use in compounding. FDA has interpreted “clinical need” to mean (1) there is a clinical need for an outsourcing facility to compound the drug product, and (2) the drug product must be compounded using the bulk drug substance.

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:

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?
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.

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