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The FDA’s oversight of compounded drug manufacturing is evolving five years after a tragedy that tarnished the industry.
New instructions and plans will provide new flexibility for some facilities, add restrictions for others, and create conditions for more modern compounding involving biologics.
The FDA’s 2018 compounding policy priorities plan lays out how the agency will address quality standards for outsourcing facilities that make large amounts of compounded drugs. The plan also explains how the Food and Drug Administration will regulate compounding from bulk drug substances (active ingredients) and includes new ways of complying with the agency’s restrictions on making copies of FDA-approved drugs. The FDA also plans to clarify when it will rely on state regulatory authorities to oversee compounding pharmacies.
The agency’s goal is to make it more efficient and less costly for more compounding pharmacies to voluntarily meet the higher production standards for outsourcing facilities as a way to promote patient access to higher quality compounded drugs, FDA Commissioner Scott Gottlieb said Jan. 19 when announcing the plan. Outsourcing facilities voluntarily register with the FDA in order to be able to make large amounts of compounded drugs and are subject to higher standards than traditional compounding pharmacies.
Two final guidance documents that came with the plan explain the FDA’s restrictions on making compounded drugs that are copies of FDA-approved drugs. A third guidance explains the conditions under which the agency will refrain from taking action against pharmacies and outsourcing facilities that mix, dilute, or repackage certain biological products outside the scope of an approved biologics license application.
The Drug Quality and Security Act (DQSA) of 2013 gave the FDA more power to oversee drug compounders. It was enacted in response to a 2012 fungal meningitis outbreak associated with contaminated injectable drugs produced by a compounding pharmacy. The outbreak sickened 753 patients and caused 64 deaths.
“Robust enforcement and implementation of the federal compounding law is critical to protect patients who need these medications; five years after the fungal meningitis outbreak that triggered the law, illnesses and deaths associated with compounded drugs continue to occur,” Elizabeth Jungman, Pew’s director for public health programs, said in a Jan. 19 statement provided to Bloomberg Law.
In a June 2017 report, Pew identified more than 50 compounding errors or potential errors associated with 1,227 adverse events, including 99 deaths, from 2001 to 2017.
Jungman said the FDA’s plan “shows an intent to focus on key issues—like quality standards, preserving the approval process, and interstate distribution—that will have a meaningful impact on the health and safety of patients who need compounded drugs.”
Traditional compounding pharmacies custom-make medications in response to individual patient prescriptions. The DQSA established a new category of compounders, called outsourcing facilities, which can make large amounts of compounded drugs under additional FDA oversight if they voluntarily register with the agency. As of Jan. 5, 63 outsourcing facilities were registered.
In 2018, the FDA said, it will issue proposed regulations on current good manufacturing practice (cGMP) requirements for outsourcing facilities. In the interim, the FDA said, it will issue a revised version of a 2014 draft guidance to describe a new flexible, risk-based approach to cGMP requirements for outsourcing facilities.
Smaller outsourcing facilities may have less stringent cGMP requirements under the revised draft guidance as the FDA said it will consider the size and scope of a facility’s operations when determining how cGMP requirements should be applied.
But a consumer group has concerns that the FDA’s plan will create different manufacturing standards for different outsourcing facilities.
Michael Carome, director of Public Citizen’s Health Research Group, told Bloomberg Law Jan. 19 that the FDA’s plan “suggests that different outsourcing facilities will be held to different standards in terms of what good manufacturing practices they need to follow” and “that means for some of them the standards are going to be less rigorous.”
Before the DQSA was enacted, Public Citizen opposed the creation of the outsourcing facility category because “it created a second lower tier of drug manufacturers,” Carome said. “Outsourcing facilities are essentially engaged in manufacturing, not pharmacy” and “ultimately, these drugs made by outsourcing facilities are riskier than FDA-approved drugs made by traditional drug manufacturers.”
“We think the standards should be consistent across the industry,” Carome said.
The DQSA directed the FDA to develop lists of bulk drug substances, or active ingredients, that can be used in compounding for traditional pharmacies and outsourcing facilities. As an interim step, the FDA issued interim policy guidance documents on compounding from bulk drug substances as it develops the bulk lists.
The agency said it plans to issue a final rule explaining the bulk substances that may be used in compounding.
In March, the FDA also said, it plans to issue a draft guidance on the criteria for making clinical need determinations for establishing the bulk list for outsourcing facilities. The agency said bulk drug substances will be placed on the list for outsourcing facilities only when there is a clinical need for compounded drugs using these substances.
Traditional compounders are restricted from compounding products that are essentially copies of a commercially available drug, and outsourcing facilities are restricted from compounding an FDA-approved drug product. The final guidance documents explain these restrictions.
The FDA doesn’t intend to take action against pharmacies or outsourcing facilities that make drug products that have been discontinued and are no longer marketed; or if the drug product appears on the FDA’s drug shortage list, the agency said in both guidance documents.
These guidance documents “carefully balance preserving access to compounded drugs for patients who need them, while preventing compounders from undermining the drug approval process or unnecessarily exposing patients to risks associated with unapproved drugs,” Gottlieb said.
Public Citizen’s Carome said the guidance documents “are certainly a positive step in the right direction” because they explain the limits on compounding FDA-approved products.
The third guidance on mixing, diluting, or repackaging biological products outside the scope of an approved application is “intended to minimize public health risks, while preserving access to these products for patients who have a medical need for them,” Gottlieb said.
The International Academy of Compounding Pharmacies (IACP) said in a Jan. 19 statement it won’t take a formal position on the FDA’s plan and guidance documents until they’re done analyzing and obtaining input from IACP members.
The IACP said it “remains hopeful that any future guidance or proposed rules will reflect the input the agency has received from IACP and other pharmacy and provider groups on how their policies affect patient access to critical compounded medications.”
Previously, the IACP has expressed concerns that the FDA is overstepping its authority and jeopardizing patient access to compounded medications. It said the FDA misinterpreted Congress’s intent when it enacted the DQSA by not allowing office-use compounding. This is when a pharmacist compounds a drug without receiving a prescription and transfers it to a requesting physician to keep on hand for when it is needed by a patient. The group is also concerned that the FDA has issued no rules for compounding; only guidance documents, which aren’t legally enforceable.
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