WASHINGTON, DC 09 Mar 2016—FDA inspectors have visited more than 230 pharmacy compounding operations since late 2013—and the agency's findings indicate that unsafe practices are all too frequent.
"It's really appalling what we're seeing out there," said Jane Axelrad, associate director for policy and head of FDA's compounding oversight activities, during the Food and Drug Law Institute's (FDLI's) February 23 meeting on drug quality and security, held in Washington, D.C.
Axelrad said FDA officials have seen insanitary conditions and other problems at traditional compounding operations, which are primarily regulated by the states, and at compounding outsourcing facilities, which are overseen by FDA.
She said inspectors have reported finding dead insects in ceilings as well as dog beds, dog feces, and dog hairs near a room used for sterile compounding—situations that could result in the contamination of drug products. And workers have been seen preparing sterile drug products without first covering their skin, which can lead to bacterial and particulate contamination.
Other problems, Axelrad said, include "coffee filters—like you use for your coffee in the morning—that are used to filter particulates. Toaster ovens used for sterilization; kitchen dishwasher and detergent used to clean sterile compounding equipment and utensils. Renovations [taking place] right next to sterile compounding operations, without taking precautions to prevent contamination of sterile products."
She said nothing really surprises her after 25 years at FDA. But she was puzzled as to why, after contaminated products made by a compounding pharmacy in 2012 resulted in a nationwide outbreak of fungal meningitis, pharmaceutical compounders aren't "looking at their operations and cleaning up their acts."
More than a dozen people affiliated with the New England Compounding Center (NECC) in Framingham, Massachusetts, are awaiting trial on criminal charges related to the meningitis outbreak, which sickened hundreds and left 64 people dead.
Axrelrad said FDA has investigated "numerous other outbreaks" since late 2013, when Congress responded to the NECC-related outbreak by granting FDA new authorities to oversee compounding operations.
"It's not just an isolated event. And [we've seen] other serious adverse events, including those associated with compounded drugs that were either contaminated or otherwise compounded improperly," she said.
Axelrad said any organization that can't follow proper procedures "shouldn't be making sterile drugs."
"The stakes are just too high," she said.
State oversight. States are primarily responsible for overseeing the operations of compounding pharmacies that fall under section 503A of the Federal Food, Drug, and Cosmetic Act (FDCA). In general, these pharmacies perform what is sometimes referred to as traditional compounding pursuant to the receipt of a prescription for a specific patient.
But a recent survey indicates that oversight of compounding practices varies among the states, said Gabrielle Cosel, manager for drug safety at the Pew Charitable Trusts.
The nonprofit organization last year commissioned a survey of state pharmacy boards to gather information on compounding oversight, particularly the oversight of sterile compounding. In all, responses were received from 42 states and the District of Columbia. Survey results were released at the FDLI meeting.
Cosel said 42% of the pharmacy boards that responded to the survey track the number of pharmacies that perform compounding in the state, and 56% track those that perform sterile compounding. She said 44% track pharmacies that ship or dispense compounded drugs to out-of-state patients or healthcare providers.
In all, 49% of the states require that sterile compounding be performed in full compliance with United States Pharmacopeia (USP) chapter 797 requirements, and 30% of states require partial compliance with the standards. An additional 16% of respondents said a pending policy change will mandate compliance with applicable USP 797 requirements.
"Anywhere sterile compounding occurs, 797 should apply," Cosel said. She noted that Pew has declared compliance with USP standards, including chapters 795 and 800, a best practice that should be enforced by state regulators.
States also vary in how they classify sterile compounding activities, the survey showed. In all, 16% of respondents include repackaging of medications as a compounding activity under USP chapter 797, 23% define reconstitution, diluting, or pooling of medications as compounding activities, and 33% limit the definition of compounding to activities that require combining at least two ingredients.
According to the survey, 58% of states do not require pharmacies that perform sterile compounding to report voluntary product recalls to either the state or FDA, and 60% do not require the reporting of serious adverse events related to compounded sterile products.
The survey also asked about state inspections of compounding operations. Cosel said 21% of respondents estimated that each inspection takes less than four hours, and 47% estimated that surveys last four to eight hours.
And in 63% of states, she said, direct observation of sterile compounding is not a required part of inspections of facilities that make compounded sterile products.
Pew recommends that inspections of compounding pharmacies by state regulators last long enough to permit direct observation of the highest-risk compounding activity performed at the site or, if that's not possible, a simulation of the most challenging compounding activities.
Outsourcing facilities. Axelrad said about 57 entities have registered with FDA as outsourcing facilities (i.e., entities that perform compounding under section 503B of the FDCA).
Federal law requires outsourcing facilities to follow current good manufacturing practice (CGMP) provisions. But these facilities are exempt from the marketing approval and product labeling requirements that apply to drug manufacturers.
"An outsourcing facility is not required to be a licensed pharmacy, but compounding must be by or under the direct supervision of a licensed pharmacist. And also the facility may or may not obtain prescriptions for identified individual patients," Axelrad said.
Many states also perform some oversight of outsourcing facilities, primarily through registration or certification activities.
According to the Pew survey results, 12% of responding states have created a licensure or registration category for outsourcing facilities, and 28% are developing a category.
Cosel said 9% of states license or register outsourcing facilities as manufacturers, 9% license or register them as wholesalers, and 5% license or register them as pharmacies. In all, 12% of respondents do not license or register outsourcing facilities.
Axelrad said some entities that have registered as outsourcing facilities don't really qualify for the designation. FDA in August of 2015 finalized a guidance document for entities that are considering whether to register as outsourcing facilities.
FDA has high expectations for compounding activities at outsourcing facilities.
"If you register as an outsourcing facility, you are indicating your intent for all drugs compounded at the facility to be regulated under [FDCA] section 503B and not 503A. So all drugs compounded at the facility have to be compounded under current good manufacturing practice requirements whether or not the facility is getting patient-specific prescriptions for some of the drugs that are compounded at the facility," Axelrad said.
She said that outsourcing facilities must be engaged in the compounding of at least some sterile drug products. And all nonsterile products compounded at the facility must be prepared in accordance with CGMP requirements.
Axelrad said FDA conducts "for-cause inspections" of compounding facilities under FDCA sections 503A and 503B, and the agency will continue such inspections this year. The agency will also conduct follow-up inspections at outsourcing facilities that have had compliance problems and inspect facilities that should be registered as outsourcing facilities but have not done so.