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By A.J. Day, PharmD, PCCA Vice President of Clinical Services, and Matt Martin, PharmD, PCCA Clinical Compounding Pharmacist
This article was updated: 04/26/2019
The 2013 Drug Quality and Security Act established criteria for what 503A pharmacies can use as active ingredients in human compounding. A substance must meet one of the following criteria to be used as an active ingredient by a 503A pharmacy:
According to the Drug Quality and Security Act, ingredients only need to comply with one of the criteria above, and those that do not meet any of them cannot be used as active ingredients for human compounding by 503A pharmacies.
Ingredients that are on the FDA “negative list” also cannot be used as active ingredients for human compounding unless a specific route or dose is allowed on the list, as is the case with oral doses of diethylstilbestrol under 25 mg. You can find a current copy of the negative list here.
The Positive List & Interim Guidance Policy Effective March 21, 2019, the FDA has a final rule regarding 10 substances nominated to the 503A Bulk Substances List. This rule creates the positive list and is limited to the 10 items that were the subject of a proposed final rule on December 15, 2016. The final ruling is identical to that original proposal.
This rule does not address any other items that have been nominated for the 503A Bulk Substances List, and it does not address any other items that the FDA’s Pharmacy Compounding Advisory Committee has reviewed. In addition to the final rule, which adds six ingredients to the positive list and excludes four others, compounders must also be aware of the interim guidance for other ingredients that have been nominated for the 503A Bulk Substances List.
While they work to develop the full positive list, the FDA has finalized a guidance document that discusses an interim policy for active ingredients that are not a component of an FDA-approved drug and that do not have what the FDA considers to be an applicable USP monograph. Note that the FDA does not consider USP monographs in the Dietary Supplement section of USP to be applicable monographs, so any of these substances that are desired for compounding should go through the FDA review process described in Category 1 below.
You can access the FDA’s interim guidance policy here. This policy creates three categories of active ingredients, which you can find listed here.
Category 1 The first category contains ingredients submitted for review with the appropriate documentation. Compounders can use these as active ingredients until the FDA makes a final determination as to whether they will be placed on the positive list.
These substances have been or will be reviewed by the Pharmacy Compounding Advisory Committee, which will make recommendations to the FDA as to whether these items should be on the positive list. The FDA will take these recommendations and then periodically propose a rule that will state its intention to include or not include some of the ingredients on the positive list. The proposed rule will have a comment period, and at some point after that comment period closes, the FDA will make the final rule as to whether those ingredients will be on the positive list.
Once each rule is finalized by the FDA, the ingredients added to the positive list will continue to be available as active ingredients in human compounds. The ones that are not added to the positive list by each final rule will no longer be available as active ingredients in human drug compounding in the United States. Until the FDA completes the process of creating the full positive list, any items that remain in Category 1 of the interim substance list are still eligible as active ingredients for human compounding.
As of March 21, 2019, the positive list contains six items for 503A pharmacies. These items were formerly in the Category 1 list, and are now on the official positive list instead:
Four other items that were formerly on the Category 1 list have been removed, and the FDA has decided not to add them to the positive list:
You can find the final rule that established the positive list here, and the positive list itself is here.
Category 2 The second category of substances created by the FDA’s interim policy contains active ingredients that are not allowed in human compounding due to FDA concerns about patient safety. Notably, this category includes domperidone.
Category 3 The third category contains chemicals that cannot be used as active ingredients in human compounding because they were submitted for FDA review without sufficient documentation. Notable ingredients include hyaluronic acid sodium salt and dinitrochlorobenzene. Note that it may be appropriate to use a chemical from Category 3 as an inactive ingredient in a compounded preparation, which is acceptable.
As of this publication, this interim substance list was last updated on March 21, 2019. It may be updated periodically as chemicals come off the list either because they have been approved or rejected for the positive list by the FDA, or potentially because a finished drug product is approved by the FDA, in which case the active ingredient would be allowed for compounding.
Summary 503A pharmacies can use bulk drug substances as active ingredients for human compounding as long as those substances fulfill one of the following criteria:
A.J. Day, PharmD, is the Vice President of Clinical Services at PCCA. His focus areas include veterinary compounding, aseptic compounding, pain management, regulatory compliance and compounding technique. A.J. has provided CE and non-CE presentations to thousands of physicians, veterinarians and pharmacists around the world. He has provided expert testimony to the FDA on behalf of the compounding profession on multiple occasions. A.J. is active with the International Academy of Compounding Pharmacists, currently serving on their Board of Directors; the National Community Pharmacists Association, currently serving on their Compounding Expert Committee; the Society of Veterinary Hospital Pharmacists; and several other pharmacy groups.
Matt Martin, PharmD, is a Clinical Compounding Pharmacist at PCCA. He joined the PCCA Clinical Services department in September 2014. Matt graduated from Morehead State University with a BS in Chemistry in 2002, and received his PharmD from the University of Kentucky College of Pharmacy in 2006. Prior to joining the PCCA team, Matt worked in compounding pharmacy for more than eight years, and has experience with both sterile and non-sterile preparations.
A version of this article originally appeared in the Apothagram, PCCA’s members-only magazine.