Finally Getting Bulky: Six Years After Enactment of the DQSA, FDA Publishes First Final Rule for the Section 503A Bulks Substance List (and It Includes Six Drug Substances!)

March 1, 2019By Karla L. Palmer

On Tuesday, February 19, 2019, FDA released its first Final Rule (of many likely to follow…) identifying six substances that FDA has determined are appropriate for use in compounding by Section 503A pharmacies.  The Final Rule relates back to FDA’s 2016 Proposed Rule nominating certain bulk substances and setting forth proposed criteria for bulk substance evaluation by FDA and its Pharmacy Compounding Advisory Committee.  The Final Rule also identifies four substances that FDA has determined may not be used in compounding, and provides information on factors that FDA will consider when it reviews bulk substance nominations submitted under Section 503A.  Lastly, the Federal Register notice announcing the rule addresses in its preamble the dozens of comments submitted to the docket announcing the proposed rule.

First, concerning substances: FDA added the following to Bulks List 1:

  • In addressing one comment, FDA Brilliant Blue G—otherwise known as Coomassie Brilliant Blue G-250
  • Cantharidin (for topical use only)
  • Diphenylcyclopropenone (for topical use only)
  • N-acetyl-D-glucosamine (for topical use only)
  • Squaric acid dibutyl ester (for topical use only)
  • Thymol iodide (for topical use only).

The following will not be added to FDA’s Bulks List 1:

  • Oxitriptan
  • Piracetam
  • Silver Protein Mild
  • Tranilast

Concerning comments filed after publication of the proposed rule, a few highlights:

FDA acknowledges (at page 4701) that unless otherwise indicated, “inclusion of a substance on the 503A Bulks List is not limited to a specific use.”  But, for purposes of evaluation of a substance for inclusion, FDA does find it necessary to examine a substance in the context of a specific or proposed use, noting it would not be possible for FDA to consider all uses for all nominated substances.

FDA also addresses (in response to several comments) whether USP dietary supplement monographs should be considered an “applicable USP or NF monograph” under Section 503A, and thus permitted for use in compounding human drug products.  As set forth in Section 503A(b)(1)(A)(i), a bulk substance may be used in compounding if it meets one of the following criteria; (1) complies with the standards of an applicable USP or NF monograph if one exists, and the USP chapter on drug compounding; (2) if such a monograph does not exist, it is a component of an FDA-approved drug; or (3) if such a monograph does not exist and it is not a component of an approved drug, then it is on a list of bulk drug substances that may be used in compounding, to be developed by FDA through regulation (which is the point of the Final Rule).  FDA’s 2016 Proposed Rule on use of bulk substances under Section 503A, advises that the “applicable USP or NF monograph” must be a USP or NF “drug “ monograph, and not a USP dietary substance monograph.  Further elaborating on this issue, FDA states that its interpretation is both “legally supportable and in the best interest of the public health.”  This is because, among other stated reasons, dietary supplements and drug substances have different regulatory schemes, and pharmacy compounding involves the compounding of drug products and not dietary supplements.  FDA further states its interpretation is in the best interest of the public health because USP dietary supplement monographs can differ significantly from drug monographs due to the “differences between dietary supplements and drug products.“  Noting that dietary supplements are for ingestion, those standards are not necessarily appropriate for compounding drug products that may be used for different routes of administration such as injection, topical, or intramuscular use.  FDA further states that USP limits for impurities are different for these two types of products; specifically, the bioburden allowable for dietary supplements is considerably higher than allowed for drug substances.  Reliance on dietary supplement standards, although “USP” could also put patients at risk, FDA states.  FDA notes, however,  that the availability of a substance as a dietary supplement is not a criterion that FDA considered when evaluating a substance for inclusion on 503A’s Bulks List. Concerning a comment on the applicability of the Homeopathic Pharmacopeia of the United States or other types of monographs as also “applicable” monographs for use in compounding under Section 503A, FDA states that it declines to consider such a compendium an “applicable monograph” under Section 503A.

We are sure more Bulks Lists — proposed and final rules — for both Sections 503A and B will follow in the coming months and years.  This one is effective as of March 21, 2019.