Toward Better-Quality Compounded Drugs — An Update from the FDA

Five years ago, methylprednisolone acetate and other drugs compounded by the New England Compounding Center (NECC; Framingham, Mass.) and administered to patients throughout the United States caused a fungal meningitis outbreak involving more than 750 infections and at least 64 deaths. The extent of this episode drew widespread attention, but smaller clusters of infections and other adverse events caused by contaminated or otherwise improperly made drugs compounded by various U.S. pharmacies occurred before this outbreak and continue to occur. In 2013, in the wake of the NECC case, Congress passed the Drug Quality and Security Act, which created a new category of compounder, called an “outsourcing facility,” that is held to higher production standards than other compounding facilities. Our experiences at the Food and Drug Administration (FDA) with pharmacy compounding since the passage of this law reinforce the ongoing need to improve the quality of compounded drugs, particularly those intended to be sterile.

The purpose of pharmacy compounding has traditionally been to allow a licensed pharmacist to customize a medication for an individual patient whose needs cannot be met by an FDA-approved drug. For example, a patient who is allergic to a certain dye in an FDA-approved drug may need a drug compounded without that ingredient. Similarly, a liquid-compounded drug may best meet the needs of a child or elderly patient who cannot swallow an FDA-approved tablet or capsule. Such prescription-based, individualized compounding by pharmacies continues to fill a niche that mass-produced pharmaceuticals cannot fill.

However, the conventional view of pharmacy compounding as a practice limited to a local pharmacy making a product for an individual patient is clearly at odds with the realities of modern drug-compounding practices, as the NECC episode illustrates. The tragic proportions of the NECC case were largely attributable to the company’s large-scale, multistate distribution of an injectable drug intended to be sterile that had been prepared under inappropriate conditions. The FDA’s experience in monitoring pharmacy compounding has demonstrated the need for further improvement in compounding practices.

Table 1. Table 1. Actions Related to FDA Oversight of Compounding Facilities after Passage of the Drug Quality and Security Act.

Since the 2012 meningitis outbreak, the agency has conducted more than 425 inspections of compounding pharmacies. We have observed problematic conditions during the vast majority of these inspections and have overseen more than 140 recalls of compounded drugs (see Table 1). Examples of observations include dead insects in compounding areas designated for sterile processing, visible mold on ceiling tiles in compounding rooms, and dog beds and dog hairs in close proximity to compounding areas.¹

The FDA has received reports of serious adverse events, including deaths, associated with improperly compounded drugs as recently as this year. In July, for example, the agency issued a statement concerning at least 43 patients who experienced diminished visual function, such as blurred vision and loss of color perception, after receiving intraocular injections of a compounded drug containing a combination of a steroid and an antiinfective agent.² In August, the FDA posted a compounding risk alert about two patients who had severe hypersensitivity reactions, one of them fatal, after receiving intravenous infusions of a compounded curcumin product containing an ungraded excipient, which would be suitable for industrial use or research purposes but typically is not considered suitable for human consumption or therapeutic use.³

Table 2. Table 2. Examples of Adverse Events Associated with Drugs Prepared by Compounding Facilities over the Past 5 Years.

In fact, the FDA has received a steady stream of reports of serious adverse events related to compounded drugs since 2012 (see Table 2). In 2016, three infants received a compounded morphine sulfate preparation at a strength nearly 25 times that indicated on its label. In 2013, bacterial bloodstream infections developed in 15 patients, and 2 patients died, after receiving contaminated infusions that the FDA subsequently found had been compounded under inappropriate conditions. Because the vast majority of compounding facilities do not report adverse events to the FDA, our records probably include only a small proportion of the adverse events that actually occur.

These problems emphasize the need to improve the quality of compounded drugs, and efforts to raise production standards are under way. The laws that govern production standards for compounding pharmacies vary from state to state. Many states have adopted, in whole or in part, standards established by the U.S. Pharmacopeia, which are currently undergoing substantial revision. In 2015, revisions to Chapter 797 (on sterile compounding) were proposed to help ensure that sterile compounded drugs are free from contaminants. Because these revised standards are still in draft form, however, states have not yet adopted them.

In 2016, in a complementary effort, the FDA published draft guidance that describes examples of “insanitary conditions” — involving the presence of filth or other conditions that could result in an injurious product — observed in compounding facilities and actions that companies should take if they identify such conditions at their facilities.⁴ The FDA issued the draft guidance to assist compounding facilities in identifying and correcting insanitary conditions and to assist state regulatory agencies in assessing whether the conditions they observe during inspections would be considered insanitary.

We are also in the process of developing standards for the new category of outsourcing facilities created by the Drug Quality and Security Act. Under federal law, outsourcing facilities are subject to current good manufacturing practice (CGMP) requirements — the main benchmark used by the FDA for ensuring production of high-quality pharmaceuticals. Outsourcing facilities are intended to meet the needs of hospitals, freestanding outpatient surgery centers, clinics, and other health care facilities for customized drugs and dosage forms that are not in high enough demand to be manufactured by pharmaceutical companies. Some clinicians want to keep a supply of these compounded drugs on hand so they can administer them to patients who present with an immediate need for them. At least in principle, these drugs are more safely prepared in centralized facilities subject to CGMP standards than in health care facilities. The FDA draft guidance proposes tailoring these standards to the scale and scope of outsourcing-facility operations.⁵

The outsourcing-facility sector is growing, although it is still young and must continue to adjust to tighter production standards. About 75 entities are currently registered with the FDA as outsourcing facilities, the majority of which had been compounding drugs for years before the passage of the Drug Quality and Security Act and are currently taking steps to conform to new production standards. Because outsourcing facilities are permitted to compound sterile drugs in large volumes and ship them anywhere in the United States without patient-specific prescriptions, the move toward CGMP adherence is critical. We intend to continue to work closely with key stakeholders to help outsourcing facilities throughout the country to meet CGMP standards.

Much of the patient harm caused by compounded drugs is preventable, and the implementation of higher production standards (such as CGMP standards for outsourcing facilities and revised U.S. Pharmacopeia standards, once finalized, for other compounding pharmacies) will be essential to reducing harm associated with pharmaceutical compounding. All stakeholders have a role to play, including regulatory agencies such as the FDA and state boards of pharmacy, outsourcing facilities and other compounding pharmacies, and health care practitioners and systems that will need to make informed choices about prescribing and purchasing compounded drugs. Five years after the tragic fungal meningitis outbreak is a good time to reinvigorate efforts to ensure that the compounded drugs given to patients who need them are made in facilities that are held to appropriate production standards.