The US Food and Drug Administration issued four Form 483 warning letters in December 2004, including three to compounding pharmacies (two veterinary, one human) and one to Chiron Corp. (Emeryville, CA, www.chiron.com). The Chiron letter is based on the agency's October investigation of the company's Evans Vaccines influenza-virus process in Speke, Liverpool.

FDA's Center for Biologics Evaluation and Research (CBER, Rockville, MD, www.fda.gov/cber) issued the Chiron warning on December 9. This was the official notice of the much-publicized shortcomings found during the 10-15 October inspection of Chiron's troubled Speke flu vaccine plant. FDA made the inspection in the wake of the UK Medicines and Healthcare Products Regulatory Agency's (MHRA's) 5 October suspension of the plant's license.

The six-page, eight-point letter specified failures to:

• Detect and investigate production errors. The warning specifically cited apparently high levels of microbial contamination (even after fumigation) a "bulk sterility failure" in one lot pool, and inadequate investigation of several lots that had exceeded the company's alert levels for overall numbers of colony forming units (cfu).
• Follow procedures or adequately investigate sterility problems when they did occur.
• Appropriately provide for consistent identity, strength, quality and purity; follow procedures to prevent microbial contamination; and establish procedures that would have prevented the contamination (by Serratia and other microbes) that prompted MHRA to condemn the operation.
• Adequately monitor environmental conditions in the aseptic processing area.
• Establish defined areas for aseptic processing operations to prevent contamination or confusion.
• Establish and follow procedures to ensure cleaning and maintenance of process equipment.

The warning also criticized Chiron's process-simulation program, saying that the existing process-simulation media fills covered only the final vial filling, "which is not representative of the entire aseptic process."

Chiron acknowledged the warning in a brief news release on 10 December, saying, "Chiron has since responded to many of these observations in the remediation plan the company submitted to the FDA in November, which is currently underway... Chiron has met with the FDA to discuss these observations, and further meetings are scheduled." As for any additional information requested by FDA, the company said, "Chiron intends to cooperate fully with the FDA in response to the warning letter."

The agency also took action against three compounding operations during December:

On 9 December, the FDA's New Orleans District office warned Lincare, Inc. and Reliant Pharmacy Services, Inc. (associated companies at the same address in Clearwater, FL,) that its large-scale human-drug compounding operation "is akin to that of a drug manufacturer."

FDA based its conclusion on the observation that several of the company's products (acetylcysteine, budesonide) were produced in "enormous amounts of what are essentially copies of commercially available drugs." The agency said that this practice "goes well beyond the scope of traditional pharmacy compounding and instead more closely resembles a drug manufacturing operation." In consequence, the agency argues, these products constitute manufactured drugs, and cannot be distributed interstate without proper process approvals.

The Agency's Dallas District Office warned two large-scale veterinary compounding operations.

On 8 December, the agency warned Veterinary Enterprises of Tomorrow, Inc. (VET, Mountain View, OK) that its compounding of veterinary drugs (including nitrofurazone, chloramphenicol palmitate, enrofoxacin, omeprazole, dipyrone, and others) from bulk active pharmaceutical ingredients constituted manufacturing without proper approvals. The agency expressed concern that VET was itself producing bulk drugs, for distribution and resale through veterinarians, rather than compounding individually to fill specific prescriptions. In addition, the Agency said, VET's formulations duplicated commercially available products. The warning also voiced concern that VET's products might produce "unsafe drug residues in edible tissues" if administered to food animals, and that the company did not warn against such applications of known hazardous drugs such as "nitrofurarone" (sic), chloramphenicol and diethylstilbestrol (DES).

And on 17 December, the same office sent a similar warning to Red River Pharmacy Services, Inc. (Texarkana, TX). The letter cited compounding and distribution of veterinary apomorphine, domperidone, chloramphenicol, and nitrofurazone from bulk active pharmaceutical ingredients, for distribution through third-party resellers. Here, too, the agency observed that the products being compounded were identical or nearly identical to commercially available products from inspected and approved manufacturers. The Agency again questioned possible use of chloramphenicol and diethylstilbestrol in food animals.

All of the warnings demanded a written reply within 15 working days of receipt. As of 12 January, FDA had not yet released any replies.

–Douglas McCormick