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Two Draft FDA Guidance Documents Stir Controversy
The Food and Drug Administration (FDA) has a message for hospital pharmacies and bulk compounding facilities that evokes an old Anheuser-Busch commercial: “This BUD’s for you.” But the BUD the FDA is trying to sell—the “beyond use date” of repackaged pharmaceuticals or biologics—isn’t going down easy with hospital pharmacists, or anyone else involved.
BUDs and drug repackaging are on tap in two FDA draft guidance documents with unwieldy titles. One is Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application.1 The other is Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities.2 Both cite provisions of USP 797 and USP 71, the compounding guidelines produced by the U.S. Pharmacopeia,3 as justification for the BUD requirements.
The FDA’s promotion of these draft guidances is in large part an effort to fill in a gap in the Drug Quality and Security Act (DQSA), which Congress passed in November 2013. The DQSA had two sections. One was a response to the deaths caused by contaminated compounded drugs produced by the New England Compounding Center (NECC), and to questions about compounded medications in general. It set up a new drug-compounding regulatory program focused on large-scale compounders, referred to as outsourcing facilities. They are allowed to voluntarily enter the new 503B program, which the FDA oversees. The law also made some changes to the existing 503A program, which allows states to inspect retail and hospital pharmacies.
But the law created some confusion, particularly for hospital pharmacies in health systems that compound and repackage sterile drugs and that compound biologics for shipment to outlying affiliated pharmacies. These two guidance documents, taken together, attempt to fill that regulatory gap. It should be noted that guidance documents are only advisory—they do not have the power of legal statute. However, the FDA uses them as a guide to enforcing the laws under its authority.
The point of both documents is to give three categories of pharmacies clear direction on when their repackaging practices will be legal, and therefore not subject to FDA enforcement. Those three categories are: state-licensed pharmacies, federal facilities, and outsourcing 503B facilities. Hospital pharmacies would fall under the state-licensed category. The states inspect 503A pharmacies, but the FDA can issue fines.
The FDA regards repackaging as 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 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 drug is manipulated in any other way—reconstituted, diluted, mixed, or combined with another ingredient—that act is not considered repackaging.
Improper repackaging of drug products can cause serious adverse events (AEs). Of particular concern is repackaging of sterile drug products, which are susceptible to contamination and degradation. For example, failure to properly manipulate sterile drug products under appropriate aseptic conditions could introduce contaminants that could injure or kill patients. Repackaging practices that conflict with approved product labeling could result in drug-product degradation and AEs associated with impurities in the product or lack of efficacy because the active ingredient has deteriorated.
Repackaged drug products are generally not exempt from any of the provisions of the Food, Drug, and Cosmetic (FD&C) Act4 related to the production of drugs. For example, repackaged drug products are generally subject to the premarket approval, misbranding, and adulteration provisions of the FD&C Act, including section 505, concerning new drug applications; section 502(f)(1), concerning labeling with adequate directions for use; and section 501(a)(2)(B), concerning current good manufacturing practice (CGMP).
The repackaging guidance would absolve hospital pharmacies from enforcement action based on potential FD&C Act violations as long as certain conditions are met. One condition concerns the receipt of an individual prescription for an individual patient or a written order in a patient’s chart that does not exceed the amount of drug product provided to that patient in a previous period of 14 consecutive days. The drug product must be repackaged by or under the direct supervision of a licensed pharmacist.
Like It or Not, This BUD’s for You
Then there is a long list of BUD requirements that differentiate in some respects between sterile and nonsterile drugs and in some instances between state-licensed and 503B pharmacies. One general rule applies to the “in-use” date on the drug that is about to be created via repackaging. If the original package of one of the ingredients specifies an in-use time, the repackaged drug product is assigned a BUD that is: 1) established in accordance with the in-use time on the drug product being repackaged; or 2) the expiration date on the drug product being repackaged, whichever is shorter. If the original drug doesn’t have an in-use time, or if it is an unapproved drug product on the FDA drug-shortage list, the repackaged drug product is assigned a BUD that is: 1) established in accordance with the time frame for sterile and nonsterile drugs, which are different; or 2) the expiration date on the drug product being repackaged, whichever is shorter.
The guidance for sterile drugs is controversial, especially because it creates different ground rules for hospital and 503B pharmacies. If the drug is repackaged in a state-licensed pharmacy or federal facility, the repackaged drug product should be assigned a BUD that is:
But if the drug is repackaged in an outsourcing facility that conducts a sterility test in accordance with CGMP requirements (e.g., using the sterility test described in USP 71) and receives passing results before release, then the repackaged drug product must be assigned a BUD that is:
The FDA justifies the longer BUD dates for outsourcing facilities based on the fact that the 503B pharmacies will be subject to new CGMPs being developed specifically for 503B facilities, and because 503B facilities are subject to FDA inspections on a risk-based schedule. “Conditions maintained to comply with CGMP requirements provide greater assurance of the quality of manufacturing operations and the products that are produced at the facility,” the draft guidance document says. The FDA has issued yet another draft guidance entitled Current Good Manufacturing Practice—Interim Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act.5 This interim CGMP guidance, when finalized, will describe the FDA’s expectations regarding outsourcing facilities and the CGMP requirements until more specific CGMP regulations for outsourcing facilities are established. It is anyone’s guess when that will be.
Outsourcing facilities get longer BUDs for sterile drugs not only because they must comply with CGMPs, but because they must also meet other requirements. There is a separate list of things an outsourcing facility must do, such as what has to appear on the label of the repackaged drug. It is quite a long list. The original prescribing information has to go with the new container. The drug must be on a list sent to the FDA that includes the active ingredient, the source of the active ingredient, and other information. Finally, the outsourcing facility must tell the FDA about serious AEs that may be associated with its repackaged drug products.
Health systems are unhappy with BUDs that are tighter for them than they are for the 503B facilities. “We are concerned that the guidance allows only extremely small quantities to be repackaged and imposes unreasonably short BUDs,” says Ann E. Byre, PharmD, Director of Pharmacy Services for Allina Health System, a 13-hospital, 90-clinic operation providing services primarily in Minnesota and Wisconsin. “We fear these extreme limitations will move hospitals to increase nonsterile bedside preparation of products that are currently being repackaged in pharmacy sterile clean-room environments, which could increase risk to patients.”
Some have assailed the drug guidance for creating different repackaging regimens for sterile “repackaged” drugs and sterile “compounded” drugs. “From a patient safety standpoint, we do not understand why repackaged drugs should be prepared under more restrictive conditions than compounded drugs, the latter of which are manipulated beyond a simple sterile transfer,” says Thomas W. Rasnic, Vice President of Quality Assurance, Regulatory Affairs, and Research and Development for PharMEDium Services, LLC. PharMEDium, the nation’s leading provider of hospital-outsourced, ready-to-use sterile admixture services, has registered four facilities with the FDA under the 503B program.
The point, Rasnic says, is that while PharMEDium is not performing repackaging, the FDA has “blurred the lines a little bit” between repackaging and outsourcing with some of its definitions. “Our concern is primarily about consistency,” he explains. “We would like to see clear lines of demarcation.”
The Biologics Guidance
The second draft guidance pertains to the mixing, diluting, and repackaging of certain types of biological products that have been licensed under section 351 of the Public Health Service Act. These would be therapeutic proteins, monoclonal antibodies, allergenic extracts, blood and blood derivatives, cell-therapy products, gene-therapy products, preventive vaccines, and therapeutic vaccines. Probably the most common reason for repackaging biologics involves pediatric or ophthalmic use.
Many biological products are particularly sensitive to storage and handling conditions. They can break down or aggregate if exposed to heat and/or light, if dropped, or if shaken during storage and handling. Accordingly, diluting or mixing a biological product with other components, or repackaging a biological product by removing it from its approved container/closure system and transferring it to another container/closure system, is, in the absence of manufacturing controls, highly likely to affect the safety and/or effectiveness of the biological product.
So this is a group of pharmaceuticals distinct from those covered in the repackaging guidance (i.e., drugs approved under the FD&C Act). The guidance applies to the same three groups of pharmacies as the repackaging guidance. A key point for hospital pharmacies is that the guidance will not apply to diluting or mixing a biological product at the point of care for immediate administration to a single patient after receipt of a patient-specific prescription or order for that patient (e.g., diluting or mixing into a syringe to administer directly to the patient). Nor does it apply to blood and blood components for transfusion, vaccines, cell-therapy products, and gene-therapy products.
Again, as with the repackaging guidance, BUDs are a big issue here. Those maximum time frames are different for hospital pharmacies and outsourcing facilities. For the former, it cannot be longer than four hours, or equal to the time within which the opened product is to be used as specified in the approved labeling, whichever is shorter. It can be no longer than 24 hours if microbial challenge studies performed on the formulation of the biological product in the type of container in which it will be packaged demonstrate that microbial growth will not progress to an unacceptable level within the period of the BUD.
Outsourcing facilities are divided into two categories by the draft, based on whether they “mix and dilute” or whether they “repackage.” In the first instance, the maximum BUD is identical to that for hospitals: four hours or the time within which the opened product is to be used as specified on the approved labeling, whichever is shorter. However, the BUD is up to 24 hours if microbial challenge studies demonstrate minimal microbial growth.
The guidance runs through a list of requirements for microbial testing. Each facility would conduct a microbial challenge study at least once for each mixed, diluted, or repackaged biological product. The microbial challenge study should be repeated if the formulation or the container-closure system is changed. The challenge microbes should include the panel provided in USP 51, Antimicrobial Effectiveness Testing. The panel should also incorporate typical skin microflora and nosocomial agents as well as strains of the tribe Klebsielleae.
Where outsourcing facilities are doing “repackaging,” they are also subject to the four-hour and 24-hour limitations. But they are given a third option: up to five days provided that the outsourcing facility conducts adequate compatibility studies on the container-closure system.
Again, the FDA rationalizes the longer lead times for outsourcing facilities based on their unique CGMPs and inspections. This longer BUD is not provided for mixed or diluted biological products because these activities are more likely to alter the characteristics of the biological product in ways that could harm patients, even if performed under CGMP conditions. To provide a sufficient basis for the FDA to conclude that a longer BUD on a mixed or diluted product was justified, an outsourcing facility would need to submit a biologics license application that included data on the impacts of diluting or mixing the specific product.
Again, as with the repackaging guidance, the biologics guidance has rubbed hospitals the wrong way. According to Linda E. Fishman, Senior Vice President of the American Hospital Association:
These extremely short BUDs would result in increased waste of biological products, potentially creating shortages and limiting access to biologics for patients, including access to important biological products such as repackaged bevacizumab (Avastin), mixed doses of infliximab (Remicade), mixed doses of rituximab (Rituxan), and many other lifesaving products. Currently, hospitals and health care systems utilize longer BUDs that are based on the U.S. Pharmacopeia Convention Chapter 797 as well as available evidence, including peer-reviewed literature. These sources show that these biological products remain stable, sterile, and effective with BUDs longer than those proposed by the FDA when following standardized aseptic process to ensure sterility, stability, and safety.
Hospitals have criticized the four-hour limit as being scientifically baseless, although the draft says four hours “is consistent with many licensed biological products.” Jayne Hart Chambers, Senior Vice President for Quality at the Federation of American Hospitals, argues, “This is not a scientific rationale for such a severe restriction.” She states that hospitals should be given the flexibility to determine the BUD based on the following criteria: 1) manufacturer product label; 2) the hospital’s own microbial challenge studies; 3) well-designed published sterility/stability studies; 4) the conditions under which the product was repackaged; and 5) the conditions in which the product will be stored.
The guidance also relieves hospital’s central pharmacies from registering under section 510 of the FD&C Act in the event of a drug shortage. Chambers thinks centralized pharmacies ought to be exempt regardless of whether there is a drug shortage or not.
But compounders are just as unhappy with the biologics draft guidance as the hospitals. David Miller, RPh, Executive Vice President and CEO of the International Academy of Compounding Pharmacists (IACP), says, “The IACP strongly opposes this arbitrary assignment of BUDs.” He argues the FDA has chosen to ignore reasonable possible BUDs that may be longer than four hours even when they are supported by approved package labeling. He adds that a microbial challenge test as outlined in the draft guidance may support a BUD of greater than 24 hours. He cites USP 71, referenced within 797, which he argues specifically provides for means by which additional testing for potency and sterility may support longer BUDs for sterile medications.
The FDA got heaps of criticism after the NECC compounding disaster, some of it fair, some of it not. But it is obviously attempting to insulate itself from future brickbats because of lax enforcement with these two draft guidances, which must be finalized to take effect. There is no telling when that will be. But it would not be surprising to see the FDA err on the side of shorter BUDs, although the agency could adjust the BUDs a smidgen to acknowledge hospital and 503B pharmacy complaints.
Of course, FDA guidance documents are only as good as the quality and quantity of FDA inspections make them.
- Food and Drug Administration. Mixing, diluting, or repackaging biological products outside the scope of an approved biologics license application. Guidance for industry. Draft guidance. February 2015;Available at: https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm434176.pdf. Accessed July 16, 2015
- Food and Drug Administration. Repackaging of certain human drug products by pharmacies and outsourcing facilities. Guidance for industry. Draft guidance. February 2015;Available at: https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm434174.pdf. Accessed July 16, 2015
- USP Compounding Compendium Rockville, Maryland: U.S. Pharmacopeial Convention. 2015;
- Food and Drug Administration. Federal Food, Drug, and Cosmetic Act (FD&C Act). Available at: https://www.fda.gov/regulatory-information/legislation/federalfooddrugandcosmeticactfdcact. Accessed July 16, 2015
- Food and Drug Administration. Guidance for industry. Current good manufacturing practice—interim guidance for human drug compounding outsourcing facilities under section 503B of the FD&C Act. July 2014;Available at: https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm403496.pdf. Accessed July 16, 2015