FDA Issues Final Guidance Addressing Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities

On December 29, 2016, FDA issued final guidance reflecting its policy on Repackaging of Certain Human (Prescription) Drug Products by Pharmacies and Outsourcing Facilities, first issued in draft form in February of 2015, and blogged here.  FDA’s final guidance highlights certain sections because it includes information still subject to review (collection of information) by the Office of Management and Budget. FDA’s Federal Register Notice announcing the guidance seeks comments by February 17, 2017. FDA is still considering applicability of these policies to hospitals and healthcare systems, which it intends to address in yet another guidance document. FDA also issued a separate (revised draft) guidance document on repackaging of biological products, which will be the subject of a separate blog post.

Like the draft guidance, this guidance defines “repackaging:” The act of “taking a finished drug product from the container in which it was distributed by the original manufacturer and placing it into a different container without further manipulation of the drug.”  Repackaging also includes placing contents of multiple finished drug containers (e.g., vials) into one container, “as long as the container does not include other ingredients.”  FDA notes that “if the drug is manipulated in any other way, including if the drug is reconstituted, diluted, mixed, or combined with another ingredient,” then it is not considered repackaging.  The Agency states, for example, that if tablets are removed from a blister pack and placed in a different container, then that would be considered repackaging. However, if the blister packs are placed into a different container for later use (leaving the blister packs intact) then that would not be repackaging.

FDA’s guidance (like the earlier draft) describes generally the approval process for drugs, including FDA’s required review and approval of drug container closure systems. Repackaging may alter the characteristics of drug products in ways that FDA did not consider during the drug approval process, affecting stability, safety and efficacy. FDA notes that repackaged drugs are not subject FDCA’s exemptions in Sections 503A and 503B; thus FDA’s guidance describes when FDA will exercise enforcement discretion concerning stats-licensed pharmacies, federal facilities and outsourcing facilities that repackage drugs. Some highlights of the guidance include:

• The repackaged drug must be an approved product under FDCA Section 505 or an unapproved drug that appears on FDA’s drug shortage list (distributed during any period the drug is listed or 30 days after the shortage ends (which is a new guidance provision)).
• The drug must be repackaged by a state-licensed pharmacy, federal facility or outsourcing facility, and under the direct supervision of a pharmacist.
• If repackaged by a pharmacy or federal facility (but not an outsourcing facility), the drug must be pursuant to a prescription or order for an individually identified patient.  The final guidance does NOT include limits on repackaging in advance of receiving a prescription (which seemed like limits on “anticipatory repackaging”).
• Except for single-dose vials, the drug must be repackaged in a way that does not conflict with approved labeling. However, the guidance notes (unlike the draft) that the repackaging must be in accordance with the handling or storage instructions for the approved product so as to not conflict with approved labeling.
• The most significant changes between the draft and final guidance address beyond use dating (BUD) for repackaged products:
  • Sterile drug products repackaged by state-licensed pharmacies or federal facilities
    • If the repackaged product is an FDA-approved drug product with a specified in-use time, then the repackaged drug must be assigned a BUD that is established in accordance with the in-use time on the product or the expiration date on the product, whatever period is shorter.
    • If the repackaged product is an FDA-approved drug whose labeling does not specify an in-use time, or an unapproved product on FDA’s shortage list, considering the drug’s stated in-use time, the BUD is established in accordance with the revisions to USP<797> (published November 2015) or the expiration date on the drug being repackaged, whichever is shorter.
  • If the product is a sterile drug product repackaged by an outsourcing facility, the facility must establish a BUD in accordance with FDA’s guidance issued in July 2014.
  • If the drug is a non-sterile product repackaged by a state licensed pharmacy, federal facility, or outsourcing facility:
    • For an FDA-approved product with a specified in-use time, then the repackaged drug must be assigned a BUD that is established in accordance with the in-use time on the product, or the expiration date on the product, whatever period is shorter.
    • For an FDA-approved product without an in-use time or an unapproved product the BUD changes according to its formulation (non-aqueous, water containing oral formulations, or topical formulations (Guidance at 8).
• Also new (but as stated in other compounding guidance documents), if the product is repackaged in a pharmacy or federal facility, it must comply with USP<795> (non-sterile) or USP<797> (sterile) guidelines. If an outsourcing facility, it must comply with FDA’s cGMP requirements (other than the BUD guidelines, which must conform to the policy above),
• The drug to be repackaged may not appear on FDA’s list of drugs removed because they are unsafe or ineffective under 21 C.F.R §216.24.
• The drug may not be sold or transferred by an entity other than the entity that repackaged the drug (but does not include administration of a repackaged drug in a healthcare setting).
• The final guidance removes the requirement on page 9 of the draft guidance that the repackaged drug product must be accompanied by a copy of the prescribing information that accompanied the original drug product that was repackaged.
• Repackaged drugs may only be distributed in states in which the facility meets all applicable state requirements.
• Drugs repackaged by outsourcing facilities must include required information on their labels and meet other requirements of 503B, including adverse event reporting (pages 8-10).

Unlike the draft guidance, the final guidance addresses FDA’s establishment registration and listing requirements (i.e., for outsourcing facilities that engage in repackaging), and describes the exemption for pharmacies under Section 510(g) and 21 C.F.R. § 207.10. FDA does not intend to take action against those entities that do not qualify for the registration and listing exemptions (likely meaning pharmacies that also engage in compounding) for failure to register and list drugs that are repackaged in accordance with FDA’s repackaging guidance.