FDA targets sterile compounding pharmacies, finds numerous safety problems
Agency continues maneuvering for greater oversight in wake of fungal meningitis deaths
In surprise inspections of large-scale compounding pharmacies, FDA has uncovered 39 safety deficiencies at four facilities, according to reports posted on the agency’s website. FDA’s visits, which began February 19, are part of a targeted campaign that will expand to about 30 facilities in 11 states in the next 2 months, the Washington Post reported on March 1.
FDA is focusing on companies “that pose the greatest risk”—those that compound sterile injectable products such as steroids and have a history of problems linked to patient illnesses or death, Howard Sklamberg, Director of Compliance for FDA's Center for Drug Evaluation and Research, told the Post.
Compounding pharmacies have been in the spotlight since a fungal meningitis outbreak was identified in October 2012. As of March 4, the outbreak had caused the deaths of 48 people and sickened 672 others, according to CDC. The outbreak was traced to contaminated injectable steroids manufactured in unsanitary conditions at New England Compounding Center in Framingham, MA. “The company got greedy and overextended, and we got sloppy," Joe Connolly, a lab technician at the center, told 60 Minutes in an investigation that aired on March 10. “Quantities of drugs increased by a factor of 1,000. … We became a manufacturer overnight," Connolly said.
Wide variety of problems found
Inspectors found 13 deficiencies at PharMEDium Services in Cleveland, MS; 12 at AnazaoHealth in Tampa, FL; 7 at Central Admixture Pharmacy Services (CAPS) in Chicago; and 7 at Lee Pharmacy in Fort Smith, AR. The report listed numerous problems related to drug sterilization and testing; environmental and building conditions; equipment, containers, and closures; employee apparel; and production and process control procedures.
Inadequate procedures and testing to ensure sterilization, potency, stability, and appropriate beyond-use dates of sterile injectable drug products occurred at all four facilities. PharMEDium, for example, did not perform endotoxin testing on all finished sterile injectable drug products and assigned a 90-day expiration date for a drug without using “meaningful and specific test methods” to ensure stability, according to the report.
At AnazaoHealth, CAPS, and Lee Pharmacy, procedures designed to prevent contamination did not include validation of the sterilization process. CAPS did not test an adequate number of batches of each drug to determine appropriate beyond-use dates. Lee Pharmacy’s sterilization processes for suspensions and solutions were not designed to follow a scientific rationale and thus had no adequate controls to prevent failures.
Inspectors noted deficient environmental monitoring of aseptic processing areas, inappropriate air filtration systems, inadequate procedures for cleaning and disinfecting rooms and equipment, and improper storage and handling of equipment at all four facilities. At PharMEDium, inspectors also cited poor building maintenance, including a “rust-colored build-up of material behind the HEPA filter screen,” as well as quarter-inch holes in the walls and an “off-white colored residue” in the clean room. A PharMEDium employee was seen “dragging a full trash bag across the clean room floor,” and AnazaoHealth employees used a disinfectant spray on packages of components, containers, closures, and utensils before transferring them to clean rooms but “then wiped them off with a dirty rag,” the report states. At CAPS, a bag of citric acid in the warehouse had a hole, exposing the product to ambient air. Lee Pharmacy did not monitor “viable and nonviable particles during aseptic filling of sterile drug products,” FDA said.
Three of the facilities were cited for employee use of nonsterile or inappropriate clothing and incorrect gloving procedures. In the clean room of the CAPS facility, employees did not use hoods or goggles, and they wore nonsterile hairnets, beard covers, face masks, and clothing that exposed areas of the skin. At AnazaoHealth, employees “performing aseptic operations in ISO 5 hoods reused sterile cloth gowns throughout a production day,” and large open packages of gloves “were dated when opened but had no controls to prevent their use in aseptic operations once sterility is compromised,” the inspectors noted. Lee Pharmacy had no written procedures for changing or sanitizing sterile gloves during set-up and filling operations.
Inspectors also found unclean, nonsterile, and leaking drug product containers, bags, and closures, including many items not tested to ensure suitability for their intended use. At PharMEDium, for example, container closure systems “did not provide adequate protection against external factors” such as light, which could cause drug deterioration or contamination, the report states. At AnazaoHealth, nondepyrogenated glass vials and rubber stoppers were used in endotoxin testing of all sterile injectable drugs. The CAPS facility had not taken appropriate action to investigate and correct recurring leaks in sterile injectable total parenteral nutrition bags.
The complete inspection reports can be accessed on the FDA website.
Facilities serve a need
Compounding pharmacies serve a crucial need. Many hospitals outsource sterile compounding to avoid the costs of building, staffing, and maintaining their own clean rooms, which must comply with United States Pharmacopeia (USP) <797> standards. In New York, after the state pharmacy board issued a temporary ban on PharMEDium’s products for which there is no patient-specific prescription, some hospitals were left scrambling to prepare large volumes of compounded medications, according to the Post story. New York officials requested that FDA conduct inspections as soon as possible to enable PharMEDium to operate lawfully as a drug manufacturer.
PharMEDium spokesman Bob Szafranski said FDA inspects the company facilities routinely, and he welcomes FDA oversight. But an FDA spokeswoman told the Post that FDA does not “conduct routine inspections because [investigators] generally investigate these facilities only when they are alerted to complaints, such as contaminated products or patient illness or death.”
In an interview conducted before the inspections, Mike Koch, BSPharm, MBA, Vice President for Marketing and Support Services at CAPS, told pharmacist.com that the company is not opposed to better-defined regulation of compounding facilities. “We voluntarily register with FDA, so we understand they’re going to inspect us,” Koch said. “We also register with the board of pharmacy in every state in which our pharmacies exist, and we get cross-licensed with the board of pharmacy of every state that we ship into.”
The Post reported that FDA is “seeking authority from Congress to require registration, which would allow agency to demand that firms release detailed information about operations and give it greater authority to require [that] safety problems be fixed.”