USP Compliance in Pharmacy: Federal Oversight P2.

Summary

In part one of this two-part article, we talked about how the FDA relies upon FDCA Sections 501(a), 503A, and 503B, and how USP standards are referenced to help set enforceable standards. When compounding, to achieve and maintain full compliance it is critical to be familiar with the details of these sections when assessing how they apply to your practice. In part two we will delve a little more into the history and details of these FDCA sections and types of FDA enforcement before concluding with key takeaways and some helpful FDA resources.

A Little History is Important

When enacted in 1938, the FDCA empowered the FDA to regulate commercially prepared drugs (by licensed manufacturers) through a pre-market approval process. Not surprisingly, the FDA relies heavily on this pre-market approval process, along with pre and pose-market inspections, to ensure these licensed manufacturers comply with the cGMPs required by FDCA Section 501(a)(2) and detailed in the federal rules (21 CRR Parts 210 and 211). 

But what about compounded drugs? When enacted in 1938, the FDCA did expressly address compounded drugs. Since it was assumed that these drugs would be prepared in small batches and quantities, until 2013 oversight of these drugs was therefore primarily left to the states. This does not mean, however, that the FDA was not concerned about these preparations – especially when compounded in larger quantities and provided across state borders. To understand the FDA’s perspective, a little history is helpful.

Adulterated Drugs: Section 501 was included in the original FDCA in 1938 to define adulteration of drugs and devices and has been amended over time. Section 501(a) specifically addresses the cGMPs and focuses on the conditions under which a drug may become adulterated. Section 501(b) addresses adulteration concerning official compendium standards, including the USP. While the FDA can use Section 501 as a general basis for inspecting facilities to ensure they meet overall quality and safety standards, it did not begin to focus on compounded drugs until Sections 503A and 503B were both finally added to the FDCA in 2013. 

The FDAMA: To express its interest and concern with compounded drugs, in 1992 the FDA issued a Compliance Policy Guide (CPG) with factors it would consider in assessing whether a compounder was really acting as a manufacturer – although it did not initially significantly enforce this guide. In 1997 much of the CPG was then incorporated into law through the Food and Drug Administration Modernization Act (FDAMA) – which amended the FDCA to add Section 503A “pharmacy compounding”. This section specifically addressed typical compounding by a licensed pharmacist or physician to serve individual patients with specific prescriptions. Drugs compounded in accordance with all 503A provisions permitted to be exempt from the FDA’s Section 505 new drug approval requirements, certain Section 503(f)(1) labeling requirements, and the rigorous CGMPs in 503B. 

The DQSA: Due to events that are beyond the scope of this discussion, Section 503A was challenged after the FDAMA and its validity remained uncertain until Congress passed the Drug Quality and Security Act (DQSA) in November 2013. The DQSA was in response to deaths and injuries caused by the 2012 fungal meningitis outbreak from drugs compounded by the New England Compounding Center (NECC). The DQSA amended the FDCA by making changes to the advertising language in Section 503A, thus ensuring its validity. It also created Section 503B to regulate human drug compounding within an “outsourcing facility” that produces and distributes sterile compounds without patient-specific prescriptions, often on a larger scale. 

Once the DQSA was passed, the FDA then issued numerous guidance documents clarifying, among other things, that in order for 503A pharmacy compounded drugs to remain exempt from the new drug approval process, labeling, and cGMP requirements, they must be compounded in compliance with “…the United States Pharmacopoeia (USP) chapters on pharmacy compounding…” (see www.fda.gov/media/94393/download). This reflected the FDA’s commitment to comprehensively regulating drug compounding under FDCA Sections 501(a), 503A, and 503B and the importance of USP standards in this process.

Types of FDA Enforcement

Since the passage of the DQSA, the FDA has utilized a variety of enforcement tools to regulate compounders, ranging from warning letters to remote assessments, inspections, and even criminal investigations. Details about this can be found at: https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations.

For instance, a pharmacist in South Carolina recently pleaded guilty of unlawfully compounding radioactive drugs. Inspections, observations, and warning letters are much more common than criminal investigations. For example, most pharmacists have heard of FDA Form 483 observations, and this is often a topic of conversation for compounders. These forms are issued at the conclusion of an inspection when the inspector has observed any conditions that may constitute an FDCA violation. The FDA maintains a Form 483 FAQ page at https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-references/fda-form-483-frequently-asked-questions.

Key Takeaways and FDA Resources

We have discussed in detail about how USP standards are referenced in the FDCA and how the FDA leverages both Section 501 and Sections 503A/503B as the basis for its regulation and oversight of compounded human drugs. As a compounder, full USP compliance is only the starting point. When compounding for individual patients with specific prescriptions, even if under the immediate-use provisions of <797>, it is critical to understand how these sections apply to your practice and facility to remain fully compliant and prepared. Below are links to some helpful FDA resources:

As you and your team build your compliance program to care for patients, be sure to review the USP chapters and FDA guidelines to ensure you are within scope and correctly preparing sterile (and non-sterile) compounds. We would love to talk about this more you, click here to learn more!