FDA Concludes Determinations on 11 Bulk Drug Substances Listed on 503B Bulks List

US: On April 6th, 2023, the FDA announced its final decision to remove 10 drug substances from the 503B Bulks list, while adding one new oral-use-only substance. The excluded substances include Hydroxyzine HCl, Mannitol, Methacholine Chloride, Metoclopramide HCl, Nalbuphine HCl, Potassium Acetate, procainamide HCl, Sodium Bicarbonate, Sodium Nitroprusside, and Verapamil HCl. Meanwhile, quinacrine hydrochloride (quinacrine) will be added to the list for oral use only. The FDA's decision was made after a notice and comment period for each substance.

Section 503B of the Food, Drug, and Cosmetic Act (FDCA) grants outsourcing facilities exemptions to section 505, section 502(f)(1), and section 582 of the FDCA if they meet specific requirements. These exemptions relate to the approval of drugs under new drug applications (NDAs) or abbreviated new drug applications (ANDAs), the labelling of drugs with adequate directions for use, and drug supply chain security requirements.

To be eligible for exemptions under Section 503B, outsourcing facilities must follow specific requirements. One such requirement is that they cannot use a bulk drug substance for compounding, unless the substance appears on the 503B Bulks List established by the Secretary of Health and Human Services. Alternatively, the drug compounded from the bulk drug substance must appear on the drug shortage list under section 506E of the FDCA at the time of compounding, distribution, and dispensing.

Per Section 503B guidelines, the FDA reviews bulk drug substances and releases a notice in the Federal Register proposing which substances should be added or removed from the 503B Bulks List, along with the reasoning. Stakeholders have a minimum of 60 days to provide feedback on the notice. Based on the input received, the FDA finalizes its evaluation and publishes another notice in the Federal Register that designates the bulk drug substances to be included or excluded from the list, as per 21 U.S.C. 353b(a)(2)(A)(i)(I)-(III).

In December 2013, the FDA initiated its evaluation process by inviting the industry to propose bulk drug substances for consideration on the 503B Bulks List through a notice in the Federal Register. Additional direction regarding the necessary information for FDA to evaluate nominated bulk drug substances was provided in July 2014, when the nomination process was reopened. The FDA then assessed each bulk drug substance to determine whether it satisfied the "clinical need" criterion for use in compounding. For FDA, "clinical need" requires two things: first, there must be a clinical need for an outsourcing facility to compound the drug product; second, the drug product must be compounded utilizing the bulk drug substance.

The use of FDA-approved products alone is not suitable for outsourcing facilities to compound, unlike Section 503A. An evaluation by the FDA is still required to determine if the substance can be included in the 503B Bulks List.

According to the FDA, all ten bulk drug substances excluded from the 503B Bulks List were already present in FDA-approved drug products. Thus, the FDA evaluated these substances based on their compatibility with medical necessity and determined that either they were not necessary for the FDA-approved drug product or did not address the attribute that the drug product lacked. In simple terms, the FDA did not find sufficient evidence to establish a clinical need for any of the nominated bulk drug substances.

The FDA has made a declaration that quinacrine hydrochloride, a substance that is not included in any FDA-approved medication, will be added to the list of approved drugs.

The FDA has concluded that quinacrine HCl's safety, effectiveness, and historical use, along with its physical and chemical characteristics, support its inclusion on the 503B Bulks List. As a result, the FDA has removed ten substances from category 1 of the interim 503B Bulks List. This implies that outsourcing facilities should no longer use these bulk drug substances in compounding. It is recommended that outsourcing facilities stay up to date with modifications to the 503B Bulks List and adjust their compounding practices accordingly.