FDA issued the draft Guidance “Compounding and Repackaging of Radiopharmaceuticals by State-Licensed Nuclear Pharmacies and Federal Facilities” (here) in late December 2016.
FDA reminds us that, under current law, radiopharmaceuticals that are compounded by entities that are not registered with FDA as outsourcing facilities (503B), and radiopharmaceuticals that are repackaged are subject to all applicable provisions for the production of drugs under the FD&C Act. Congress explicitly excluded radiopharmaceuticals from section 503A of the FD&C Act and compounded radiopharmaceuticals are not eligible for the exemptions under section 503A from section 505 (new drug approval requirements), section 502(f)(1) (labeling with adequate directions for use), and section 501(a)(2)(B) (current good manufacturing practice [CGMP] requirements). In addition, Congress did not exempt repackaged radiopharmaceuticals from any provisions of the FD&C Act.
The Guidance above was issued by FDA to describe the conditions under which FDA will not take action for violations of sections 505, 502(f)(1) and 501(a)(2)(B) when a State-licensed or Federal facility compounds or repackages radiopharmaceuticals. The Guidance does not address: mixing, reconstituting, combining, diluting, or repackaging of a radiopharmaceutical; production of positron emission tomography (PET) drugs; drug products that are not radiopharmaceuticals; radioactive biological products that are subject to licensure under section 351 of the Public Health Service (PHS) Act; and radiopharmaceuticals for use in animals. FDA’s current regulations and guidance addressing investigational new drugs are not altered.
In this Guidance, FDA regards compounding as the combining, admixing, mixing, diluting, pooling, reconstituting, or otherwise altering of a drug or bulk drug substance to create a drug. FDA recognizes that in some cases, State-licensed nuclear pharmacies compound a radiopharmaceutical from an FDA-approved drug product with one or more minor deviations (as described below) that are necessary to accommodate circumstances not contemplated in the FDA-approved labeling, such as the rate of radioactive decay or geographical distance from the patient.
FDA regards a minor deviation as a change from the approved labeling in radioactivity, volume, and/or the step-by-step procedures made when compounding the radiopharmaceutical from an FDA-approved drug product in a patient-ready dose. FDA also recognizes that, due to individual patient needs, compounding may occur where the radiopharmaceutical preparation may differ in inactive ingredients, dosage form, or mass dose, and where an FDA-approved radiopharmaceutical has been discontinued or appears on the FDA Drug Shortage List.
The policy in this Guidance explains the conditions under which FDA does not intend to take action regarding violations of the Act when radiopharmaceuticals are compounded or repackaged by State-licensed or Federal facilities (that are not Outsourcers).
FDA lists thirteen conditions other than minor deviations where FDA does not intend to take action include for compounding radiopharmaceuticals (note this is not for repackaging):
- The radiopharmaceutical is compounded by or under the direct supervision of a licensed, authorized nuclear pharmacist in a State-licensed nuclear pharmacy or a Federal facility that holds a RAM issued by the NRC or by an Agreement State.
- The radiopharmaceutical is distributed only after the receipt of a valid prescription order.
- If the radiopharmaceutical is compounded in advance of receipt of a valid prescription, it is compounded in a quantity that does not exceed the expected demand for the radiopharmaceutical within the beyond use date (BUD) of the product, based on a history of receipt of prescriptions for the radiopharmaceutical for that time period. The radiopharmaceutical is not distributed before the receipt of a valid prescription.
- If the radiopharmaceutical is compounded using bulk drug substance(s), the bulk drug substance(s) comply with the standards of an USP monograph, if a monograph exists. If a monograph does not exist, the bulk drug substance(s) are components of a drug product approved under section 505 of the FD&C Act. For purposes of this condition, a bulk drug substance includes a radioisotope, a ligand, or other substance, such as a precursor that becomes an active ingredient.
- If the radiopharmaceutical is compounded using bulk drug substance(s), the original manufacturer of the bulk drug substance(s) and any subsequent manufacturers, including repackers, are establishments that are registered under section 510 of the FD&C Act and each bulk drug substance is accompanied by a valid certificate of analysis.
- If the radiopharmaceutical is compounded using ingredient(s) other than bulk drug substances, the ingredients comply with the standards an applicable USP or NF monograph, if a monograph exists.
- The radiopharmaceutical is compounded in compliance with the following USP Chapters <795> or <797>, as applicable (except for the BUD).
- The compounded radiopharmaceutical does not appear on a list of drug products that have been withdrawn or removed from the market because they have been found to be unsafe or not effective.
- The compounded radiopharmaceutical is not essentially a copy of a marketed FDA-approved radiopharmaceutical.
- The radiopharmaceutical is not identified on a list of drugs or categories of drugs that present demonstrable difficulties for compounding.
- The compounded radiopharmaceutical is not sold or transferred by an entity other than the entity that compounded such radiopharmaceutical.
- The compounded radiopharmaceutical is distributed only in States in which the compounding of the radiopharmaceutical meets all applicable State requirements.
- The radiopharmaceutical is compounded in accordance with all applicable requirements of the NRC (e.g., labeling requirements) in a facility that meets all applicable requirements of the NRC, and the nuclear pharmacist who compounds or supervises the compounding of the radiopharmaceutical meets all applicable NRC requirements.
FDA regards repackaging as the act of removing an FDA-approved radiopharmaceutical from the container in which it was distributed by the original manufacturer and placing it into a different container without further manipulation of the product. Repackaging also includes the act of placing the contents of multiple containers (e.g., vials) of the same finished drug product into one container, as long as the container does not include other ingredients. If a radiopharmaceutical is manipulated in any other way, including if it is reconstituted, diluted, mixed, or combined with another ingredient, that act is not considered repackaging.
FDA goes on to describe radiopharmaceutical compounding that constitutes minor deviations and repackaging and lists eight conditions:
- The radiopharmaceutical is compounded or repackaged from a drug product approved under section 505 of the FD&C Act.
- No substances are added to the radiopharmaceutical unless they are specified in the FDA-approved labeling for the radiopharmaceutical being compounded.
- If the radiopharmaceutical is compounded (and not repackaged), the compounding constitutes a minor deviation(s).
- The radiopharmaceutical is compounded or repackaged by or under the direct supervision of a licensed authorized nuclear pharmacist in a State-licensed nuclear pharmacy or a Federal facility that also holds a RAM license issued by the NRC or an Agreement State.
- The radiopharmaceutical is compounded or repackaged in compliance with USP Chapters <795> or <797> (except the BUD).
- The radiopharmaceutical is compounded or repackaged in accordance with all applicable requirements of the NRC (e.g., labeling requirements) in a facility that meets all applicable requirements of the NRC, and the nuclear pharmacist who compounds or repackages, or who supervises the compounding or repackaging of the radiopharmaceutical, meets all applicable NRC requirements.
- The compounded or repackaged radiopharmaceutical is distributed only in States in which the compounding or repackaging of the radiopharmaceutical meets all applicable State requirements.
- The compounded or repackaged radiopharmaceutical is not sold or transferred by an entity other than the entity that compounded or repackaged such radiopharmaceutical.
Once again, don’t forget the Establishment Registration and Drug Listing requirements where, under section 510(b)(1), between each October 1 and December 31, every person who owns or operates any establishment in any State engaged in the manufacture, preparation, propagation, compounding, or processing of a drug is required to register with FDA, and under section 510(j) must list its drugs with the Agency. Outsourcing facilities that are State-licensed pharmacies that compound or repackage radiopharmaceuticals may qualify for an exemption. Specifically, under section 510(g)(1), the registration and listing requirements do not apply to: pharmacies which maintain establishments in conformance with applicable local laws regulating the practice of pharmacy and medicine and which are regularly engaged in dispensing prescription drugs or devices, upon valid prescriptions and which do not manufacture, prepare, propagate, compound, or process drugs or devices for sale other than in the regular course of their business of dispensing or selling drugs or devices at retail.
With respect to State-licensed or Federal facilities that do not qualify for the exemptions from registration under section 510, FDA does not intend to take action under section 502(o) for failure to register and list radiopharmaceuticals that are compounded or repackaged in accordance with the guidance.
A lot to digest but, given the posture of the FDA with regards to enforcement action, a must for understanding the Agency position.