On January 18, 2018 the U.S. Food and Drug Administration (FDA) issued its 2018 Compounding Policy Priorities Plan, which outlines how the agency will implement certain key aspects of the Drug Quality and Security Act (DQSA) and other provisions of the law relevant to compounders.
DQSA put in place more robust oversight of compounders and enabled closer federal and state collaboration. It also established a clear legal framework that provides for compounding and created a new category of compounders, called outsourcing facilities (503B Facilities), which may engage in larger-scale, nationwide distribution unlike traditional compounders (503A Facilities).
The 2018 Compounding Policy Priorities Plan specifically details how the FDA will:
ADDRESS MANUFACTURING STANDARDS FOR OUTSOURCING FACILITIES
Drugs produced by outsourcing facilities must be compounded in compliance with current good manufacturing practice (CGMP) requirements and in an FDA-registered facility that is subject to regular, risk-based inspections and requires information to be reported to the FDA, which includes the products compounded at outsourcing facilities and the source of the active ingredients used.
Given the somewhat limited number of facilities that have elected to register as 503B outsourcing facilities, the FDA intends to make it more efficient and lower-cost for more compounding pharmacies to voluntarily meet the higher production standards under 503B as a way to promote more patient access to higher quality compounded medicines. The FDA plans to issue proposed regulations on CGMP requirements that these outsourcing facilities must meet. In the interim, the agency is revising the draft guidance to describe a new flexible, risk-based approach to CGMP requirements for outsourcing facilities.
It is intended that the policies described in the revised draft guidance will consider how CGMP requirements should be applied in light of the size and scope of an outsourcing facility’s operations. Additionally, the FDA’s revised draft guidance also will describe the circumstances under which the FDA generally does not intend to enforce against outsourcing facilities certain CGMP requirements applicable to conventional drug manufacturers.
REGULATE COMPOUNDING FROM BULK DRUG SUBSTANCES
Under current laws, 503A Facilities may compound drugs in accordance with the Food Drug Cosmetics Act using bulk drug substances that (i) are subject to an existing United States Pharmacopeia (USP) or National Formulary monograph standards; (ii) are components of FDA-approved drugs; or (iii) appear on a list developed by the FDA through regulation, after consultation with USP and the Pharmacy Compounding Advisory Committee (the 503A bulks list).
Whereas, 503B outsourcing facilities may use a bulk drug substance to compound a drug that complies with the Food Drug Cosmetics Act if the FDA has determined there is clinical need to compound with the substance and affirmatively places it on the 503B bulks list, or if the drug compounded appears on the FDA’s drug shortage list.
Although the FDA issued interim policy guidances to address compounding from bulk drug substances by 503A and 503B facilities while developing the bulks lists, the FDA notes these policies were temporary. The FDA cautions, that the exercise of enforcement discretion during this time period for a certain nominated substance consistent with the 503A or 503B interim policies does not reflect a determination that the substance belongs on the 503A or 503B bulks lists or that there is a clinical need under section 503B to compound with the bulk drug substance.
Regarding development of the 503A bulks list, the FDA solicited nominations for bulk drug substances to include on the 503A bulks list and presented 48 substances that were nominated to the Pharmacy Compounding Advisory Committee for its input. In December 2016, the agency issued proposed regulations to address 10 of these substances and establish the criteria it will use to evaluate substances for inclusion on the list. The FDA intends to issue a final regulation.
Regarding development of the 503B bulks list, the FDA solicited nominations for bulk drug substances for inclusion on the 503B bulks list. The next step is for the FDA to issue, in March 2018, a draft guidance document that proposes criteria for making clinical need determinations for purposes of establishing the 503B bulks list. The FDA intends to address these concerns in its draft guidance document, and it will carefully consider any additional concerns that may be raised during the public comment period for the draft guidance.
RESTRICT COMPOUNDING OF DRUGS THAT ARE ESSENTIALLY COPIES OF FDA-APPROVED DRUGS
A critical component of the Food Drug Cosmetics Act is its restrictions on compounding drugs that are essentially copies of FDA-approved or commercially available products and the FDA has published two final guidance documents regarding the copies provisions for 503A and 503B Facilities, respectively.
With respect to “essential copies” the FDA’s goal will be to make sure that patients do not receive compounded drugs unnecessarily when an FDA-approved drug is appropriate to meet their medical needs. The FDA plans to focus efforts on education and outreach to practitioners, including prescribers of compounded drugs who can determine whether there is a change between the compounded drug and the commercially available drug, or comparable approved drug, that produces a significant or clinical difference for an individual patient. In addition, the FDA intends to prioritize review of situations that could adversely impact the public health and premarket approval process, such as compounding using a bulk drug substance to produce a product that can otherwise be made by diluting an FDA-approved drug according to its labeled instructions.
SOLIDIFY THE FDA’S PARTNERSHIP WITH STATE REGULATORY AUTHORITIES
Last September, the FDA hosted an annual intergovernmental meeting with the state boards of pharmacy, and plans to issue a significantly revised draft MOU between the FDA and the states regarding compounding under section 503A. The draft MOU addresses the percentage of compounded drugs that could be shipped interstate by 503A compounders and state investigation of complaints.
Under the current draft MOU, if a pharmacy distributes an “inordinate amount” of compounded drug product interstate, the state would agree to take action. FDA had defined “inordinate amount” for states that have entered into the MOU as “an amount of compounded drug product distributed interstate in a given month that is equal or greater to 30 percent of all drug products dispensed or distributed by the pharmacist, pharmacy, or physician.”
Among some of the provisions of the revised draft MOU, the FDA intends to clarify that a compounder has distributed an inordinate amount of drug interstate if the number of prescriptions of compounded drugs distributed interstate during any calendar month is greater than 50 percent, which would than trigger certain reporting requirements.
PROVIDE GUIDANCE ON OTHER ACTIVITIES THAT COMPOUNDERS UNDERTAKE
The FDA’s recent Policy Plan announced the FDA finalized its guidance, Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application. The final guidance describes a mechanism for outsourcing facilities to assign beyond use dates (BUDs) to repackaged biological products that exceed the “default” BUDs of 24 hours, based on data.
In addition, the FDA soon intends to further clarify policies applicable to compounding by outsourcing facilities with a guidance on the “definition of a facility” in section 503B. This guidance will address the question of whether an outsourcing facility can be co-located with a 503A pharmacy, and whether an outsourcing facility also can manufacture FDA-approved drugs within the same facility
Finally, the FDA states it will issue revised draft guidance describing examples of conditions that the FDA considers to be insanitary and in violation of the Food Drug Cosmetics Act.
ENFORCEMENT
Since enactment of the DQSA, the FDA has conducted nearly 500 inspections, issued more than 180 warning letters advising compounders of significant violations of federal law, issued more than 70 letters referring inspectional findings to state regulatory agencies, overseen more than 150 recalls involving compounded drugs and worked with the Department of Justice on multiple civil and criminal enforcement actions. It is clear from this Policy Plan that the FDA intends to continue its in-depth evaluation of 503A and 503B compounders with serious effect.
Frier Levitt routinely assists both 503A and 503B compounders and can advise interested parties in navigating these complex and ever-changing regulatory schemes and evaluate impacts to existing business models. Contact us today to speak to an attorney.
