FDA issued two new Guidance for Industry Documents late in 2016: (1) Compounding and Repackaging of Radiopharmaceuticals by State-Licensed Nuclear Pharmacies and Federal Facilities (here) and (2) Compounding and Repackaging of Radiopharmaceuticals by Outsourcing Facilities (here). These represent the 25th and 26th draft and/or final Guidances issued by FDA relating to pharmacy compounding. More will be forthcoming, guaranteed.
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 good news for 503B Outsourcers is that FDA intends to apply section 503B of the FD&C Act to radiopharmaceuticals compounded by Outsourcing facilities. Guidance #2 above also describes the conditions under which FDA does not intend to take action for violations of sections 505 and 502(f)(1) when an Outsourcer repackages radiopharmaceuticals. The Guidance does not address: animal products; following FDA approved labeling instructions for mixing, repackaging and other such acts; PET drugs; non-radiopharmaceuticals; radioactive biologicals, and the compounding or repackaging by non-Outsourcers. Note that the Guidance does not alter the current regulations and Guidance for investigational new drugs.
In contrast to 503A of the FD&C Act, section 503B does not expressly exclude radiopharmaceuticals, so conditions for 503B apply to radiopharmaceuticals compounded by an entity that is registered as an Outsourcer.
For compounding of radiopharmaceuticals, bulk drug substances used must appear on a list developed by FDA for which there is a clinical need, or the drug compounded from the bulk drug substance appears on the drug shortage list at the time of compounding. For essential copies of commercially available radiopharmaceuticals, FDA does not intend to take action against an outsourcing facility provided that the outsourcing facility:
- compounds the radiopharmaceutical from FDA-approved radiopharmaceuticals, and not using bulk drug substances;
- makes minor deviations from the approved product labeling, and
- compounds all of its drugs in accordance with section 503B.
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 eleven conditions under which they do not intend to take action in the context of radiopharmaceutical repackaging (specifically, violations of sections 505 and 502(f)(1) as follows:
- The radiopharmaceutical being repackaged is a drug product approved under section 505.
- The radiopharmaceutical is repackaged by, or under the direct supervision of, a licensed, authorized nuclear pharmacist22 in an outsourcing facility that holds a RAM license issued by the NRC or by an Agreement State.
- The radiopharmaceutical is repackaged in accordance with applicable CGMP requirements.
- The radiopharmaceutical being repackaged does not appear on a list of drug products that have been withdrawn or removed from the market for reasons of safety or efficacy.
- Repackaged radiopharmaceutical is not sold or transferred by an entity other than the entity that repackaged such radiopharmaceutical.
- The repackaged radiopharmaceutical is distributed only in States in which the production of the radiopharmaceutical meets all applicable State requirements.
- The radiopharmaceutical is repackaged in accordance with all applicable NRC requirements.
- The label on the immediate container (primary packaging, e.g., the syringe) of the repackaged radiopharmaceutical includes the following: a. The statement “This radiopharmaceutical was repackaged by [name of outsourcing facility].”; b. The address and phone number of the outsourcing facility; c. The established name of the original, approved radiopharmaceutical that was repackaged; d. The lot or batch number of the repackaged radiopharmaceutical; e. The dosage form and radioactive dose of the repackaged radiopharmaceutical; f. A statement of either the quantity or volume; g. The date of repackaging; h. The BUD of the repackaged radiopharmaceutical; i. Storage and handling instructions; j. The National Drug Code (NDC) number of the repackaged radiopharmaceutical; k. The statement “Not for resale,” and, if the repackaged radiopharmaceutical is distributed by an outsourcing facility other than pursuant to a prescription for an individual identified patient, the statement “Office Use Only”; l. A list of the active and inactive ingredients.
- The label on the container from which the individual units are removed for administration (secondary packaging (e.g., the bag, box, or other package in which the repackaged products are distributed)) includes: a. The active and inactive ingredients, if the immediate drug product label is too small to include this information and b. Directions for use, including, as appropriate, radioactive dosage and administration, and the following information to facilitate adverse event reporting: fda.gov/medwatch and 1-800-FDA-1088.
- The radiopharmaceutical is included on a report submitted to FDA each June and December identifying the drug products repackaged by the outsourcing facility during the previous 6-month period.
- The outsourcing facility reports serious adverse events to FDA that may be associated with its repackaged radiopharmaceuticals.
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 that maintain establishments in conformance with applicable local laws regulating the practice of pharmacy and medicine, and that, are regularly engaged in dispensing prescription drugs or devices, upon valid prescriptions and that 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 outsourcing 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.
More Good/Not So Good News and Guidances to come as we discuss the FDA position on 503A compounding pharmacies tomorrow.