FDA Giveth and Taketh Away as It Publishes Its Second Proposed Rule Concerning the Section 503A Bulk Substances List

On September 5, 2019, FDA published its proposal to amend its Section 503A bulk substances regulation, 21 C.F.R. § 216.23, to add five bulk drug substances that FDA considered to the Section 503A Bulks List, and not to add 26 substances.  Prior to this latest proposed rule, FDA has only finalized via the final rulemaking process its Section 503A Bulks List for ten substances (as blogged about here).  Six of those substances made the cut (and can be used in compounding) and four did not.  Importantly, FDA’s Current Interim List 1 (as of April 2019) of substances that may be used by Section 503A compounders may change significantly as a result of FDA’s latest proposal.  Those that are interested in the substances either remaining on FDA’s list or their removal should submit a comment to Docket No. 2018-N-4845, by December 4, 2019.

For ease of reference, FDA proposes the following:

Addition to the Section 503A Bulks List:

• Glutaraldehyde (topical use at concentrations of 10% or lower)
• Glycolic acid (topical use at concentrations up to 70%)
• L-citrulline (oral use)
• Pyruvic acid (topical use)
• Trichloroacetic acid (TCA) (topical use)

Of important note for compounding pharmacies: FDA specifically states that when a salt or ester of an active moiety is listed on FDA’s Bulks List, only that particular salt or ester may be used for compounding.  The base compound and other salts or esters of the same active moiety must be evaluated separately for inclusion on FDA’s List.  Furthermore, where a substance is included subject to certain restrictions (i.e., topical use only), only those drug products that conform to that restriction may qualify for Section 503A’s exemptions.  So, in short, compounders should pay attention to any limitations that FDA places on substances that it adds to the Bulks List, and should limit compounding to the specifically identified substances.

Non-inclusion/removal from the Section 503A Bulks list:

• 7-keto dehydroepiandrosterone (DHEA)
• Acetyl-L-carnitine (ALC)
• Alanyl-L-glutamine
• Aloe vera 200:1 freeze dried
• Artemisinin
• Astragalus extract 10:1
• Boswellia serrata extract (BWSE)
• Cesium chloride
• Chondroitin sulfate
• Chrysin
• Curcumin
• D-ribose
• Deoxy-D-glucose
• Diindolylmethane
• Domperidone
• Epigallocatechin gallate (EGCG)
• Germanium sesquioxide
• Glycyrrhizin
• Kojic acid
• Nettle
• Nicotinamide adenine dinucleotide (NAD)
• Nicotinamide adenine dinucleotide disodium reduced (NADH)
• Rubidium chloride
• Sodium dichloroacetat
• Vanadyl sulfate
• Vasoactive intestinal peptide (VIP)

FDA states that it consulted with both the Pharmacy Compounding Advisory Committee (PCAC) and USP in its evaluation of the substances, and included criteria considered for the substances’ addition or exclusion as required by Section 503A.  FDA will publish its Final Rule amending 21 C.F.R. § 216.23 based on FDA’s consideration of the public comments received.  It will also continue to add or decline to add other substances to its final list on a rolling basis.  FDA notes that, concerning other substances that have already been either added or removed from the list, interested individuals and organizations may petition FDA to amend the Section 503A Bulks List to consider information that is “different from that which FDA presented to the PCAC” (citing the citizens petition rule at 21 C.F.R. § 10.20).  FDA also states that, for substances that have not “yet been addressed in a rulemaking,” interested individuals and entities should submit comments to FDA’s bulks docket (FDA-2015-N-3534).  Lastly, it is important to remember that Section 503A pharmacies can also compound drug products from substances that are the subject of a USP/NF drug monograph, or substances that are components of FDA-approved drug products.