The FDA has been working with the Pharmacy Compounding Advisory Committee (PCAC) since the year 2000 to develop a list of drug products that present demonstrable difficulties for compounding.  Concerns relative to bioavailability, variations in batch-to-batch consistency, and dosage-form release characteristics that could present significant safety (or other) issues are outlined in and provide a basis for the Proposed Rule (here).

The FDA identified six criteria for placing a specific drug or category of drugs on the Demonstrable Difficulties for Compounding (DDC) Lists:

    1. Complex formulation;
    2. Complex drug delivery mechanism;
    3. Complex dosage form;
    4. Bioavailability achievement complexity;
    5. Compounding process complexity; and
    6. Physicochemical or analytical testing complexity.


The Proposed Rule provides an excellent overview of the regulatory history and actions of the FDA and stakeholders over the last twenty-four years, leading up to the publication of the Proposed Rule, and outlines specifically what the categories of drug products are and why each category is included in the Proposed Rule.

The Rule proposes the following three categories in the first DDC list:

  • Oral Solid Modified-Release Drug Products That Employ Coated Systems (MRCs)
  • Liposome Drug Products (LDPs)
  • Drug Products Produced Using Hot Melt Extrusion (HMEs)

“A drug product that the Secretary has identified as presenting demonstrable difficulties for compounding pursuant to section 503A(b)(3)(A) or section 503B(a)(6) may not be compounded under either section 503A or section 503B.”  However, the Proposed Rule notes that there may be times when a specific drug or drug category is included in a DDC list for 503A compounding but permitted for 503B compounding and indicates that there will be separate lists for the two categories of compounders.  This is because there may be manufacturing, control, or compounding issues for certain product categories; these products are best performed under CGMPs and, therefore, 503B outsourcing compounders may be better equipped to perform the required manufacturing operations and have the necessary control procedures in place.  In the particular instance of the first DDC list, the three drug categories identified would not be appropriate for either 503A or 503B compounders.

It is interesting to note that the FR Notice mentions that there are three other categories of products that the FDA and PCAC also discussed for inclusion on the DDC list; these were: (1) drug products that employ transdermal or topical delivery systems; (2) metered-dose inhalers; and (3) dry powder inhalers.  They are not being addressed in this Proposed Rule; however, this is a very good indicator that the FDA may address these categories in future rulemaking.

The FR Notice announcing the Proposed Rule notes, “The Agency does not intend to consider cost and convenience as factors that would be relevant to the risk-benefit analysis for the DDC Lists.”  There is a question of how this stance will impact potential drug shortage issues for products in these categories, and perhaps that is added impetus for the Proposed Rule.

“The Agency proposes that any final rule based on this proposal becomes effective 30 days after the date of publication of the final rule in the Federal Register.”  There is no indication as to how fast the Agency will move on finalizing the Rule, however.  The categories of drugs included in the first proposed DDC list undoubtedly present significant manufacturing, control, and quality issues and may (as noted in the Proposed Rule) present safety issues that are significant.  It will be interesting to see how this plays out and what comments are received by the Agency in response to the Proposed Rule.