In January 2018, the U.S. Food & Drug Administration (FDA) published two guidance documents on Compounded Drug Products That Are Essentially Copies Of Approved Drug Products under Section 503A and Section 503B of the Federal Food, Drug, and Cosmetic Act (the Act). As emphasized in a recent U.S. Department of Justice policy memorandum, FDA noted that its guidance documents do not establish legally enforceable responsibilities and, instead should be viewed only as agency recommendations, unless specific regulatory or statutory requirements are cited.

Section 503A Guidance

By way of background, Section 503A excludes certain compounded products from regulation as a “drug product” by FDA, if they are compounded for an identified individual patient with a valid prescription, and the compounding is done by a licensed pharmacist in a state-licensed pharmacy or Federal facility, or by a licensed physician. As provided under Section 503A, the compounding may be performed in limited quantities before receiving a valid prescription for an individual patient, but only if based on a history of receiving valid prescriptions for that patient in the context of an established relationship between the compounder, the individual patient, and the prescriber. Section 503A(b) includes a requirement that the compounding entity must not regularly compound (or compound in inordinate amounts) any drug products that are essentially copies of a commercially available drug product. In addition, 503A(b)(3) states that interstate transfer of more than five percent of the total prescription orders dispensed or distributed by a pharmacy or physician is not allowed unless there is a Memorandum of Understanding in place between the state and FDA.

The new 503A guidance explains that FDA does not consider a drug product to be “commercially available” if:

  • The drug has been discontinued and is no longer marketed; or
  • The drug product appears on the FDA drug shortage list, i.e., is in “currently in shortage” status and not “resolved” status.

The document also provides guidance on what FDA considers to be “essentially a copy of a commercially available drug product” including, among other things guidance relating to:

  • Making relatively small changes to a compounded drug where a prescribing practitioner has not determined that the change produces a significant difference in the patient.
  • Same active pharmaceutical ingredients (API)
  • Same, Similar or Easily Substitutable Strength
  • Same Route of Administration
  • Same Characteristics as Two or More Commercially Available Drug Products Combined

The 503A guidance states that compounders who intend to rely on the determination by the prescribing practitioner that the change will produce a significant difference should ensure that the determination is actually documented on the prescription.  The guidance does not insist on a particular format and FDA provides the following examples:

  • No Dye X, patient allergy
  • Liquid form, patient can’t swallow tablet
  • 6 mg, patient needs higher dose

The guidance also provides that where the prescription does not contain this information, the compounder may contact the prescriber or health care facility and, if confirmed, may notate that on the prescription or order.

For compounding where a drug is on the shortage list, the 503A guidance also recommends that the prescriber or compounder include a notation on the prescription that the drug was on the shortage list and the date the list was checked. The guidance also addresses what comprises compounding commercially available drugs “regularly” or in “inordinate amounts” and states that at this time FDA does not intend to take action where the compounder fills four or fewer prescriptions for the relevant drug in a calendar month, even where the compounded product is essentially a copy of a commercially available drug product produced regularly or in inordinate amounts.  The guidance also contains a section on recordkeeping recommendations, including that the records be kept at least three years.

Section 503B Guidance

Section 503B of the Act provides that a facility may register as an “outsourcing facility” and thereby qualify for certain exceptions from FDA drug approval and labeling requirements at Sections 502(f)(1), 505 and 582 of the Act. However, unlike with 503A compounding, Section 503B also provides that outsourcing facilities must still comply with the other requirements for pharmaceutical manufacturers, including current good manufacturing processes (cGMPs).

In the Section 503B guidance, FDA notes that because these drugs are subject to a lower regulatory standard, they should only be distributed to health care facilities or dispensed to patients where the medical needs cannot be met by an FDA-approved drug.

As with the 503A guidance, FDA discusses the restrictions on outsourcing facilities’ compounding of drugs that are essentially copies of approved products and states that it intends to make this finding when the drugs have the same:

  • active ingredient(s)
  • route of administration
  • dosage form
  • dosage strength and
  • inactive ingredients (excipients)

However, FDA notes that this finding would not be made where drugs that are essentially copies appear on the FDA’s drug shortage list at the time of compounding, distribution, and dispensing.  FDA clarifies that it did not intend to take action as long as the drug appeared on the FDA drug shortage list within 60 days of the outsourcing facility distributing or dispensing the drug.  The FDA reasons that the outsourcing facility may not be able to predict when a drug shortage will be resolved, and may have orders in house for these drugs.  However, the FDA cautions that it may take regulatory action if an outsourcing facility continues to fill new orders after the drug is removed from the shortage list.

With regard to documenting prescriber differentiation of clinical differences, unlike the 503A guidance where FDA recommended the compounder ensure the documentation is on the prescription, it notes that orders from an outsourcing facility are usually made for office stock and therefore FDA recommends that the outsourcing facility obtain a statement from the practitioner specifying the change in the compounding drug and indicating that the drug will be administered or dispense only to a patient for whom the change produces a clinical difference, as determined by the prescribing practitioner.

As with the documentation recommendations under 503A guidance, the 503B guidance notes that a particular format is not needed as long as the information is present.  FDA provides the following examples for outsourcing facility documentation:

  • “Liquid form, compounded drug will be prescribed to patients who can’t swallow tablet” (if the comparable drug is a tablet)
  • “Dilution for infusion solution to be administered to patients who need this formulation during surgery” (if the comparable drug is not available at that concentration, pre-mixed with the particular diluent in an infusion bag)
  • “1 mg, pediatric patients need lower dose” (if the comparable drug is only available in 25 mg dose)

On the other hand, where outsourcing facilities are compounding based on prescriptions for individual patients, FDA recommends that statements be made on the actual patient-specific prescription, as discussed above for the 503A guidance.

The 503B guidance also provides FDA recommendations for determining whether a drug was “essentially a copy” of a covered over-the-counter (OTC) drug.  It also notes that unlike approved drugs, the appearance of a covered OTC drug on the shortage list would not be viewed as an exception to the finding that it was “essentially a copy.”  The 503B guidance provides recordkeeping recommendations, including that the outsourcing facilities maintain records at least three years.