In proposed rule, FDA offers up a (surprisingly sparse) list of drugs that present demonstrable compounding difficulties


Mar. 20, 2024

FDA yesterday released a long-awaited proposed rule on a list of drug products that present demonstrable difficulties for compounding. This proposed rule has been in the works for over 20 years, during which time the regulation of drug compounding has gone through many changes. Now, the proposed list is out, and its limited length may be a surprise to stakeholders.

Background: Drug compounding in the U.S.

  • What is drug compounding? Per 21 USC 353b, compounding is when a facility combines, mixes, dilutes, pools, reconstitutes, or otherwise alters a drug or bulk drug substance to create a product. Compounded products are intended to provide an important option for patients who may have unique needs and cannot take an approved product for a variety of reasons. For example, patients may be allergic to certain inactive ingredients used in off-the-shelf drug formulations or they may not be able to swallow a pill. Compounded drugs are meant to accommodate those individual, specific needs and limitations.
  • FDA addressed the expanding practice of drug compounding in 1992 by issuing a compliance policy guide that clarified that pharmacies which compounded products at certain scales, for certain purposes, or without FDA approval were clearly operating “outside the bounds of traditional pharmacy practice.” As explained in a 2013 Government Accountability Office report, the intent of the CPG was to “identify those circumstances under which the agency believed establishments with retail pharmacy licenses were engaged in ‘manufacturing, distributing, and promoting unapproved new drugs’ in a manner outside the traditional pharmacy practice of compounding.”
  • However, in recognizing that compounded products can benefit patients in certain circumstances, Congress passed the FDA Modernization Act of 1997 (FDAMA), which provided an alternative to FDA’s previous policy, stating that products could be compounded but only if specific requirements were met. The result was the addition of Section 503A to the FD&C Act. Products compounded by 503A pharmacies are specifically exempt from needing to adhere to Current Good Manufacturing Practice (cGMP) requirements, labeling regulations and new drug approval requirements.
  • Requirements for 503A pharmacies have since been updated, most notably under the Drug Quality and Security Act ( DQSA) of 2013, which established new requirements for 503A pharmacies as well as a new category of compounding pharmacies, known as outsourcing facilities (503B pharmacies).
  • An “outsourcing facility” per Section 503B is a registered location that engages in the compounding of sterile drugs but is not required to be a licensed pharmacy. As is the case for products compounded at 503A facilities, the products compounded at these locations are not FDA-approved, and the locations are exempt from certain regulations such as labeling requirements and drug supply chain security act requirements. However, they are subject to all provisions of the FD&C Act that apply to conventionally manufactured drugs (i.e., cGMP requirements) along with a plethora of other differences which distinguish them from 503A facilities.
  • All compounders, including both 503A and 503B facilities, are prohibited from compounding drugs that present “demonstrable difficulties for compounding.” Under section 503A(b)(3)(A) of the FD&C Act, a drug used in compounding must not be “identified by the Secretary by regulation as a drug product that presents demonstrable difficulties for compounding that reasonably demonstrate an adverse effect on the safety or effectiveness of that drug product.” Similarly, in section 503B(a)(6)(A), a drug used in compounding must not be identified on “a list published by the Secretary of drugs or categories of drugs that present demonstrable difficulties for compounding that are reasonably likely to lead to an adverse effect on the safety or effectiveness of the drug or category of drugs, taking into account the risks and benefits to patients.” However, enforcement of this rule cannot occur until such a list is actually published.

Regulatory context: Products that present demonstrable difficulties for compounding

  • The concept of products that present “demonstrable difficulties for compounding,” or the “difficult to compound (DTC)” list, dates back to 1997. As noted above, 503A was originally added to the FD&C act in 1997 as part of FDAMA. Although a list of such products was specifically referenced in this section of the law, it was not formally discussed by an advisory committee (the Pharmacy Compounding Advisory Committee, or PCAC) until July 2000. In this meeting, PCAC provided FDA with advice about the agency’s efforts to develop this list of drugs. Around the same time, the FDA published a concept paper discussing the criteria that may be used for creation of the list, as well as some product categories that could be included on the list.
  • Efforts to develop the DTC list were placed on hold from 2002 to 2013. As a result of legal challenges to other portions of section 503A, the FDA placed the development of the DTC list on hold in 2002. It was not until the passage of the DQSA in 2013 that the validity of section 503A was confirmed, and work could move forward. Since the DQSA also established section 503B which incorporated a reference to the DTC list, there was renewed interest in the development of the list.
  • In late 2013, the FDA posted a request for nominations of drug products to the DTC list. The FDA stated that it was seeking assistance in identifying “candidates for the difficult-to-compound list” and looking for interested parties to nominate “drug products or categories of drug products that are difficult to compound for inclusion on the list.” In total, 34 comments were received from individuals, life sciences companies, and non-profit organizations. The FDA estimated that they received approximately 71 unique nominations for the list within these comments.
  • In many cases, life science companies submitted requests for individual products, citing various concerns about adequate quality control. Nominated products included intrathecal formulations of baclofen and melphalan (due to sterility concerns), methylprednisolone acetate for epidural use (due to safety concerns), dimethyl fumarate (due to risk for sublimation), and deoxycholic acid (due to the use of non-sterile bovine/ovine sources). In one extreme example, GlaxoSmithKline submitted a request for all of its respiratory drug products to be included on the list. Another company, Auxilium Pharma, submitted three separate requests for its erectile dysfunction drugs (papaverine injection, alprostadil injection, and implantable testosterone pellets).
  • Various stakeholders and non-profit organizations submitted requests for consideration of entire classes of drug products. Some of these submissions, including one from Biotechnology Industry Organization (BIO), simply requested confirmation that biologics not be included in sections 503A and 503B, but, if necessary, should be added to the DTC list. Public Citizen requested that specific drug delivery formulations be included on the list, including metered dose inhalers (MDIs), transdermal delivery systems, and enteric coated (EC) preparations. PharMEDium Services and Public Citizen requested that the entire practice of “non-sterile to sterile” compounding be considered for the list. (A quick side note: Non-sterile to sterile compounding is the practice of using non-sterile ingredients to produce a sterile final product. It is considered a medium- to high-risk form of compounding, although it is technically permitted under USP<797> guidelines, which are followed by registered pharmacies for sterile compounding.)
  • In 2016, the FDA finalized a set of criteria that could be used to evaluate whether a drug product or category of drug products belongs on the DTC list. The FDA sought input on these criteria from the PCAC in 2015 and again in 2016. The final six criteria consider the complexity of 1) the formulation, 2) the drug delivery mechanism, 3) the dosage form, 4) characterizing or controlling bioavailability, 5) the compounding process, and 6) physiochemical or analytical testing.

With the final criteria in place, the FDA began the work of developing the actual list

  • Over the course of three PCAC meetings in 2016-2017, four product formulation categories were unanimously approved for addition to the DTC list. The first formulations presented to the committee were MDIs and dry powder inhalers (DPIs), a category that excludes nasal delivery or non-pressurized inhaled delivery devices. The next category was transdermal and topical delivery systems, which specifically excludes the traditional formulations of “liquids or semi-solids such as gels, creams, lotions, foams, ointments, or sprays.” Rather, this category was focused on complex delivery systems that are highly dependent on various ingredients and components for appropriate delivery. Oral solid modified release drug (MRD) products were also presented, defined as consisting “of an active ingredient-containing core enclosed within a polymeric coating membrane” that is intended for local or systemic action. Of note, this does not include “simple matrix systems” which are mixtures of “active ingredients with release-controlling polymers, which are filled into capsules or compressed into tablets.”
  • In late 2017, the FDA proposed two additional product formulation categories to the PCAC, with mostly positive, but mixed, responses. The first, liposome drug products, were defined as “a drug product in which the active pharmaceutical ingredient is contained within the liposomes.” The committee voted nine to one in favor of adding it to the list, with the single no vote citing concerns that topical liposome drugs should not be included on the list. Finally, the FDA presented products that use hot melt extrusion (HME), a process that converts a chemical into an amorphous, or non-crystalline, form, often to “enhance the solubility of poorly water-soluble drugs.” This formulation received seven yes votes, two no votes, and one abstention. Members that voted against adding this formulation to the list cited the fact that many compounding pharmacies perform processes that utilize extruders and require high temperatures (i.e., suppositories).
  • In July 2017, the FDA posted a notice for the establishment of a public docket so that “interested parties can nominate drug products or categories of drug products for inclusion on the Difficult to Compound List, resubmit previous nominations with additional supporting information, or submit comments.” This time, the FDA received 26 comments. Interestingly, none of the comments were resubmissions of previous nominations. This may be due, in part, to the fact that a number of the previously submitted requests were actually addressed by the prior PCAC discussions.
  • A comment from Outsourcing Facilities Association (OFA) requested clarification as to how many DTC lists will actually be published. The letter noted that the mention of the DTC list in both 503A and 503B seems to imply that two lists will be published. “The OFA respectfully requests that FDA clarify that two Difficult to Compound Lists will be established, and independent consideration will be given to drugs compounded by 503Bs for inclusion on the Difficult to Compound List.” In the 2013 request for nominations, the FDA did state that it “intends to develop and publish a single list of drug products and categories of drug products that cannot be compounded and still qualify for any of the exemptions set forth in sections 503A and 503B because they present demonstrable difficulties for compounding.”
  • Submissions from life sciences companies again focused primarily on individual drug products. The drugs presented for inclusion covered a broad range, such as sucralfate oral suspension (due to the need for specific excipients), cantharidin (due to extraction from blister beetles), mechlorethamine (due to high chemical reactivity), topical nifedipine (due to light reactivity), and ophthalmic mitomycin-c (due to instability). For the most part, the nature of these submissions mirrored those received in 2014.
  • Compounded bioidentical hormone therapies (cBHTs) were the most popular nomination during the comment period. Multiple individuals submitted requests for the addition of these products to the list, which were then followed by extensive supportive submissions from Catalent Applied Drug Delivery Institute and the Endocrine Society. These letters requested the addition of selected reproductive hormone drug products to the list, including estradiol, estriol, progesterone, progesterone with estradiol, and testosterone. Additionally, the National Academies of Sciences, Engineering, and Medicine (NASEM) submitted a report (commissioned by the FDA) recommending that the PCAC review 10 specific cBHTs for addition to the DTC list, and also consider all BHT preparations formulated as pellet dosage forms for addition to the list.

The proposed rule to establish a DTC list has finally arrived, and the list is smaller than expected

  • On August 29, a proposed rule was submitted to the White House for review. As submitted to the White House’s Office of Information and Regulatory Affairs (OIRA), the proposed rule was titled: “Drug Products or Categories of Drug Products That Present Demonstrable Difficulties for Compounding Under Sections 503A or 503B of the Federal Food, Drug, and Cosmetic Act.”
  • Six months later on March 11, OIRA cleared the proposed rule, and the FDA published it on March 20. It’s worth noting that this lengthy review time is somewhat unusual. OIRA typically completes its reviews within 90 days. However, this proposed rule was expected to be somewhat contentious due to the significant implications it could have for a number of corporations. During that review period, the White House hosted two meetings, one with the Outsourcing Facilities Association and one with the American Pharmacists Association.
  • An important note up front: The agency has not altered the six criteria that it identified for this purpose back in 2016. These continue to consider the complexity of: 1) the formulation, 2) the drug delivery mechanism, 3) the dosage form, 4) achieving bioavailability, 5) the compounding process, and 6) physiochemical or analytical testing. In the proposed rule, the FDA clarifies that these criteria are not mutually exclusive, and that a product only needs to meet one or more criteria to be considered demonstrably difficult to compound.
  • Another important note: There will eventually be two separate DTC lists. “FDA is proposing to amend its regulations to add two lists identifying drug products or categories of drug products that present demonstrable difficulties for compounding under the FD&C Act.” The products listed in this proposed rule are intended for both 503A and 503B facilities; however, the agency is specifically requesting comment from stakeholders on whether the items proposed should be included for both or only one facility type.
  • The proposed list contains only three product categories, all of which were reviewed and voted on by the PCAC between 2016 and 2017, and none of which were included in the most recent round of comments submitted under the open public docket. These are: 1) Oral solid modified-release drug products that employ coated systems (MRCS), 2) Liposome drug products (LDPS), and 3) Products produced using heat-melt extrusion (HME).

A closer look at the three product categories proposed for the DTC list

  • Oral MRCS are defined as: “Oral solid drug products that consist of, or are intended to consist of, a drug-containing core enclosed within a polymeric coating to release an API at specified rates, patterns, or onsets through the GI tract to produce systemic, enteric, or local action.” Currently, there are two types of coating systems that affect the rate of release – diffusion and osmotic. Diffusion systems utilize a polymeric coating enclosing a core tablet or multiple cores of active ingredient and excipient. Osmotic systems utilize a semipermeable polymeric membrane coating over a compressed core that contains the active ingredient, an osmotic agent, and “one or more mechanical or laser drilled orifices for drug release.”
  • MRCS are considered complex due to the formulation and drug delivery mechanisms, for which incorrect production could result in “sub- or supra-therapeutic release, GI mucosa irritation, and variability in performance within and across batches.” This could present a significant safety risk to patients. The delivery mechanism is complex because it is highly precise and relies on a number of factors; the formulation is complex because “subtle changes to any of the product’s components or manufacturing processes could significantly impact its bioavailability and performance characteristics.”
  • LDPS are defined as: “A drug product in which the API is generally contained in or intended to be contained in liposomes.” These products are composed of a bilayer or a series of bilayers that are separate by aqueous compartments. Many LDPS products contain cytotoxic compounds which, if released inappropriately, could present serious safety risks.
  • LDPS are considered complex due to the formulation, drug delivery mechanism, and bioavailability concerns. FDA explained that the formulation is considered complex because of “(1) the attributes of lipids, including chemistry and structure; (2) the attributes of inactive ingredients (e.g., cholesterol and polyethylene glycol (PEG) or PEG derivatives), including grade, ratio, and concentration range; and (3) the stability of the liposome, which can be affected by a number of formulation-related factors.” The delivery mechanism is considered complex because it requires precise design that delivers a specific amount of drug per unit time, and in many cases, to a specific location in the body. Characterization of LDPS bioavailability can be altered by subtle changes in composition, raw material purity, or the manufacturing process, and is thus also considered complex.
  • HME is defined as: “A continuous process operation that achieves or is intended to achieve the molecular mixing of APIs and inactive ingredients ( e.g., polymers) at temperatures above their glass transition temperatures and/or melting temperatures within an extruder. The objective of an HME process is to enhance the solubility of poorly water-soluble drugs by converting the formulation components into an amorphous phase (not crystalline) product with uniform content.” Many of these products are developed for the purpose of enhanced bioavailability, enhanced stability and delivery rate control.
  • Products prepared by HME are considered complex due primarily to the formulation and the compounding process. The extrudate in the formulation must be entirely uniform and thermally stable, and be distributed and arranged to a certain specification that changes with each product. This is considered a complex formulation because inadequate assurance of these factors could result in significant variability in product performance between batches and may ultimately alter bioavailability. The HME process requires the use of specialized equipment and sophisticated controls, which introduces a particularly complex compounding process that can be affected by poor technique “at any step.”


  • For some stakeholders – ranging from public watchdogs to life sciences companies – this list will likely be considered far too short and incomplete. The vast majority of stakeholders that submitted comments to the open public docket requested the addition of far more products and categories to this DTC list. These included some notably broad categories such as nonsterile-to-sterile preparations and compounded bioidentical hormones. Life sciences companies also submitted a variety of individual proprietary products (or, in the case of GlaxoSmithKline, an entire product portfolio) which, in many cases, could truly present difficulties in compounding.
  • That being said, compounding facilities are likely relieved to see that many potential product categories were spared from the list. In fact, per the FDA, there appear to be no products currently on the market that will be affected by its proposed rule. As a result, the agency anticipates that the only impact to compounders at this time will involve “administrative costs to read and understand the rule.”
  • Interestingly, the FDA opted not to include two product categories which the PCAC voted to add to the list: Metered dose inhalers/dry powder inhalers and complex transdermal and topical delivery systems. Although these were nominated by independent stakeholders, vetted by the FDA, and then supported by the PCAC, they have been purposely left off of this list. The FDA acknowledges this omission and notes that they may be addressed in future rulemaking, but provides no further explanation for their absence. It is possible that the inclusion of these products categories may have affected currently marketed products, which would have introduced additional barriers and pushback for the agency as it attempts to finalize the rule.
  • Although many stakeholders have submitted requests for the inclusion of individual drugs to the list, the FDA seems to be approaching the list from a higher-level angle. To date, only product category types have been presented to the PCAC for review, and the agency has included only product categories in this initial proposed rule. However, the title of the proposed rule would still allow for the inclusion of individual products in the future.

What’s next?

  • The FDA has opened a new public docket for this proposed rule, which is open for comment until June 18. Within the proposed rule, the FDA has specifically requested input on the following items: 1) the assumption that the proposed rule will not affect any currently marketed products; 2) whether lack of access to these three product types via compounding facilities would negatively impact patients; 3) whether each product type should be added for both 503A and 503B; and 4) whether certain entries should include specific limitations.

To contact the author of this item, please email Chelsey McIntyre ( [email protected]).
To contact the editor of this item, please email Alexander Gaffney ( [email protected])

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