jueves, 19 de enero de 2017

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

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

Posted: 18 Jan 2017 08:51 PM PST
By Karla L. Palmer –

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Like the draft guidance, this guidance defines “repackaging:” The act of “taking a finished drug product from the container in which it was distributed by the original manufacturer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.
Posted: 18 Jan 2017 05:33 PM PST
By Riëtte van Laack –

As we previously reported, FDA issued final rules updating the nutrition labeling regulations, 21 C.F.R. §§ 101.9 and 101.36, and the serving size regulation, 21 C.F.R. § 101.12, on May 27, 2016. Despite the rather extensive preamble, the final rules left many questions unanswered. FDA promised to address a number of issues in guidance. The timing of that guidance is crucial because the compliance date for the final rules is July 26, 2018 (smaller businesses with annual food sales of less than 10 million dollars have until July 26, 2019).

Early in August, 2016, FDA created a webpage with industry resources which provided some answers.  Then, on January 4, 2017, FDA announced the availability of two arguably overdue draft guidance documents: a draft guidance clarifying aspects of the final rule regarding nutrition labeling, and a draft guidance providing examples of food products that belong to product categories included in the tables of Reference Amounts Customarily Consumed (RACCs) used to determine serving size.

The draft guidance concerning nutrition labeling answers questions about the nutrition labeling rules and the compliance date. Topics addressed include:

  • Compliance date: In August, 2016, FDA interpreted compliance date to mean that food products that are initially introduced into interstate commerce on or after that date would need to include the new version of the Nutrition Facts and Supplement Facts labels. Apparently, this statement resulted in more questions. So, FDA revised its thinking and, according to the draft guidance, will consider the date the food product is labeled for purposes of the compliance date. The location of a food in the distribution chain (e.g., is the product in the warehouse of the manufacturer or in the warehouse of the distributor) is not relevant. In the draft guidance, FDA also clarifies that the 10 million dollar annual sales limit need not be met for all three years prior to the date of the final rule (i.e., 2013, 2014, and 2015), but is met if the smallest sales volume from one of these previous three years is less than 10 million. The sales do, however, concern total food sales, i.e., domestic and international.
  • Added sugars: Not surprisingly, since the requirement for listing added sugars is a new (and probably the most controversial) requirement, about 50% of the draft guidance covers questions and answers about the calculation and declaration of “added sugars.” Questions include scenarios for when a juice concentrate constitutes an added sugar, how to declare added sugars in fermented foods, how to determine added sugars when Maillard browning occurs, whether fruit powders and pastes are added sugars, and compliance criteria. FDA provides some helpful examples. The Federal Register Notice announcing the availability of the draft guidance also includes a request for comments to three specific questions regarding added sugars and fruit or vegetable juice concentrates.
  • In the discussion, FDA acknowledges that sugars, whether added or naturally present, are biochemically equivalent. The added sugars, however, provide consumers a measure of “empty calories.”
  • Rounding of the declaration of quantitative amounts of vitamins and minerals: The new requirement to declare the quantitative amounts (in addition to the percentage Daily Value) of vitamins and minerals (excluding sodium) in the Nutrition Facts box also generated some questions and uncertainties. In response to these questions, FDA prepared a table specifying the recommended rounding of the vitamins and minerals. In addition, the draft guidance discusses the basis for these recommendations.
The draft guidance regarding RACCs provides examples of food products that belong to each product category included in the tables of Reference Amounts Customarily Consumed (RACCs) that may be useful for industry in identifying the correct food category (and therefore the serving size) for a product. Although few may be surprised to see that all watermelon falls in the category of watermelon, the fact that bagel thins are not bagels (with a RACC of 110 g) but are bread (with a RACC of 55 g) may be less obvious. The guidance provides examples, not an all-inclusive list of all products on the market (see here).

The draft guidances are accessible on the industry resources webpage.  That page also includes a link to the draft guidance for Scientific Evaluation of the Evidence on the Beneficial Physiological Effects of Isolated or Synthetic Non-digestible Carbohydrates Submitted as a Citizen Petition (Comments due February 13, 2017).

Comments to the draft guidances are due March 6, 2017.

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