FDA Publishes Interim Guidance on Compounding Using Bulk Drug Substances and Once Again Establishes a Time Period for Comments and Nominations

By Karla L. Palmer –  

FDA announced (here and here) earlier this week the availability of two draft guidances (here and here) for compounders using bulk substances under FDCA Sections 503A and 503B.  FDA also published final guidance for compounders under Section 503A (see our previous post addressing that guidance).  As previously addressed, FDA published the long-awaited proposed bulk substance lists after industry’s submission of two rounds of nominations and comments.  Recall that the Agency required an industry-wide “do-over” of the nomination process after too many substances were submitted (including en bulk submissions of entire pharmaceutical compendia), and with allegedly insufficient clinical information concerning many of the nominations (see our previous posts here and here).

The underlying enabling legislation, the Drug Quality and Security Act, Title I (DQSA) (Pub. L. No. 113-54) requires FDA to publish the list of bulk substances for which there is a “clinical need” that may be used in compounding under 503B.  A similar provision exists in Section 503A, but the statute does not contain an explicit “clinical need” requirement.  The publication of the bulk substances lists (which FDA now terms the “bulks”) is occurring during FDA’s Pharmacy Compounding Advisory Committee (PCAC) (Oct. 26 and 27).  This is the third PCAC meeting this year, at which the PCAC has addressed certain nominated substances (for both the so-called positive and negative lists).  FDA notes in the Section 503B interim guidance that, unlike Section 503A bulks nominations, FDA is not required to consult with the PCAC before publishing its nominations.

One of the conditions necessary for an outsourcing facility to qualify for certain exemptions from the FDCA is that it may not compound drug products using a bulk drug substance unless: (1) it appears on a list established by the Secretary identifying bulk drug substances for which there is a clinical need (see Section 503B(a)(2)(A)(i) or (2) the drug product compounded from such bulk drug substances appears on the drug shortage list in effect under FDCA Section 506E at the time of compounding, distribution, and dispensing (Section 503B(a)(2)(A)(ii)). 

For Section 503A compounders, one of the conditions that must be met to qualify for Section 503A’s exemptions from certain provisions of the FDCA is that it: (1) comply with the standards of an applicable United States Pharmacopeia (USP) or National Formulary (NF) monograph, if a monograph exists, and the USP chapter on pharmacy compounding; (2) if such a monograph does not exist, they are components of approved drugs; or (3) if such a monograph does not exist and the drug substance is not a component of an approved drug, it appears on a list developed by the Secretary. (See Section 503A(b)(1)(A)(i)).

The guidance documents set forth the conditions under which FDA does not intend to take action against an outsourcing facility or licensed pharmacy for compounding a drug product from a bulk drug substance that does not appear on a list of substances that may be used in compounding while FDA develops (or finalizes) the lists.

Set forth below are the details:

Section 503A

Approximately 740 substances were nominated. 

• Approximately 275 substances are already eligible for use in compounding (i.e., components of approved drugs, the subject of a USP/NF monograph), and do not need to appear on the list. 
• At least one (Maalox) is not a bulk substance.
• At least one (sodium hexachloroplatinate (IV) hexahydrate) is a biological product subject to approval pursuant to a BLA.  No biological products subject to BLA approval will be eligible for the 503A bulks list.
• At least two are radiopharmaceuticals (GHRP-2 and GHRP-6), to which Section 503A does not apply, and thus the substances are ineligible. 
• At least four appear on the FDA’s list of drugs withdrawn or removed as unsafe or ineffective (chloroform reagent, cobalt chloride hexahydrate, cobalt gluconate, and phenacetin).
• One substance (an extract of cannabidiol and tetrahydrocannabinol) has no currently accepted medical use and is listed in Schedule I of the CSA; it is not eligible for the bulks list.
• About 390 substances were nominated without sufficient supporting evidence for FDA to evaluate them.
• Remaining nominations contained sufficient supporting information; however, FDA determined some raise safety concerns.

FDA has published on its website (and attached to the guidance) four Section 503A bulks lists:

• 503A List 1 – Bulk Drug Substances Under Evaluation:  Bulk substances that may be eligible for inclusion and were nominated with sufficient information for FDA to evaluate them and do not appear on any other list.
• 503A List 2 – Bulk Drug Substances that Raise Safety Concerns: Nominated with sufficient supporting information; however, because FDA has identified safety concerns, FDA has placed these substances on a list that may not be used in compounding unless and until FDA publishes a final rule authorizing their use under Section 503A.
• Section 503A List 3 – Bulk Drug Substances Nominated Without Adequate Support: May be eligible for inclusion on the list but nominations did not include sufficient supporting information.  These may be renominated with sufficient supporting information.
• Section 503A List 4 – Bulk Drug Substances That May Not Be Used to Compound Drug Products under Section 503A (to be developed):  These bulks were considered for inclusion on the list, but after notice-and-comment rulemaking, FDA determined that they should not be used. 

The guidance describes the FDA’s rulemaking process for the nominated substances, including the balancing of the four factors FDA considers when reviewing substances.

FDA states it does not intend to take enforcement action if: (1) the bulk substance appears on List 1; (2) the substance was “originally manufactured” by an establishment that is registered under Section 510, and is accompanied by a certificate of analysis from the original manufacturer (importantly, note that FDA defines “original manufacturer” as the entity that originally produced the bulk drug substance and not a subsequent packer, repacker, labeler, or distributor); (3) the drug is compounded in compliance with all other sections of Section 503A. 

Section 503B

In response to the requests for nominations, approximately 2,590 unique substances were nominated. 

• Approximately 1,740 are biological products subject to approval pursuant to a BLA.  No biological products subject to BLA approval will be eligible for the 5o3B bulks list.
• At least one (Maalox) is not a bulk substance.  Finished drug products are not eligible for the list. 
• At least four are radiopharmaceuticals (strontium chloride, sodium iodide I-131, GHRP-2 and GHRP-6), to which Section 503B does not apply, and thus the substances are ineligible.  Radiopharmaceutical compounding will be addressed in a separate guidance.
• At least five appear on the FDA’s list of drugs withdrawn or removed as unsafe or ineffective (chloroform reagent, cobalt chloride hexahydrate, cobalt gluconate, and phenacetin, and methapyrilene fumarate).
• One substance (an extract of cannabidiol and tetrahydrocannabinol) has no currently accepted medical use and is listed in Schedule I of the CSA; it is not eligible for the bulks list.
• About 650 substances were nominated without sufficient supporting evidence for FDA to evaluate them.
• Remaining nominations contained sufficient supporting information, and may be eligible for inclusion. 

FDA has published on its website (and attached to the guidance) four Section 503B bulks lists:

• 503B List 1 –Bulk Drug Substances Under Evaluation:  Bulk substances that may be eligible for inclusion and were nominated with sufficient information for FDA to evaluate them and do not appear on any other list.
• 503B List 2 – Bulk Drug Substances that Raise Safety Concerns: Nominated with sufficient supporting information; however, because FDA has identified safety concerns, FDA has placed these substances on a list that may not be used in compounding unless and until FDA publishes a final rule authorizing their use under Section 503B.
• Section 503B List 3 – Bulk Drug Substances Nominated Without Adequate Support: May be eligible for inclusion on the list but nominations did not include sufficient supporting infuriation.  These may be renominated with sufficient supporting information.
• Section 503B List 4 – Bulk Drug Substances That May Not Be Used to Compound Drug Products under Section 503BA (to be developed):  These bulks were considered for including on the list, but after notice-and-comment rulemaking, FDA determined that they should not be used.

As with FDA’s Section 503A bulks guidance, FDA’s guidance set forth the process for developing the lists.  Like Section 503A, it will publish nominations on a rolling basis.  In order to “avoid unnecessary disruption to patient treatment” while FDA considers bulk substances nominated with sufficient support and for which FDA has not identified safety concerns.  

FDA does not intend to take enforcement action for compounding from bulk under Section 503B provided that: (1) The substance appears on List 1; (2) the substance was “originally manufactured” by an establishment that is registered under Section 510, and is accompanied by a certificate of analysis from the original manufacturer; (3) if the bulk substance is the subject of a USP/NF monograph, the substance complies with it; and (4) the drug product is compounded in compliance with all other provisions of Section 503B.

To ensure that the Agency considers any comments on the draft guidance documents before it finalizes them, interested persons must submit comments by December 28, 2015.  Each guidance document contains a one-page chart (Appendix) setting forth a neat summary of FDA’s bulks policies for Sections 503A and 503B, and FDA’s current lists of bulk substances.