FDA Warning Letters December 2004

The US Food and Drug Administration issued four Form 483 warningletters 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 thecompany's EvansVaccines influenza-virus process in Speke, Liverpool.

FDA's Center for Biologics Evaluation and Research (CBER, Rockville,MD, www.fda.gov/cber) issuedthe Chironwarning on December 9. This was the official notice of themuch-publicized shortcomings found during the 10-15 Octoberinspectionof Chiron's troubled Speke flu vaccine plant. FDA made the inspectionin the wake of the UK Medicines and Healthcare Products RegulatoryAgency'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 warningspecifically cited apparently high levels of microbial contamination (even after fumigation) a "bulk sterility failure" in one lot pool, andinadequate investigation of several lots that had exceeded thecompany's alertlevels for overall numbers of colony forming units (cfu).

• Follow procedures or adequately investigate sterility problemswhen they did occur.

• Appropriately provide for consistent identity, strength, qualityand purity; follow procedures to prevent microbialcontamination; and establish procedures that would have prevented thecontamination (by Serratiaand other microbes) that prompted MHRA tocondemn the operation.

• Adequately monitor environmental conditions in the asepticprocessing area.

• Establish defined areas for aseptic processing operations toprevent contamination or confusion.

• Establish and follow procedures to ensure cleaning andmaintenance of process equipment.

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

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

The agency also took action against three compounding operationsduring December:

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

FDA based its conclusion on the observation that several of thecompany's products (acetylcysteine, budesonide) were produced in"enormous amounts of what are essentially copies of commerciallyavailable drugs." The agency said that this practice "goes well beyondthe scope oftraditional pharmacy compounding and instead more closely resembles adrug manufacturing operation." In consequence, the agency argues, theseproducts constitute manufactured drugs, and cannot be distributedinterstate without proper process approvals.

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

On 8 December, the agency warnedVeterinary Enterprises of Tomorrow, Inc. (VET, Mountain View, OK)that its compounding of veterinary drugs (including nitrofurazone,chloramphenicol palmitate, enrofoxacin, omeprazole, dipyrone, andothers) from bulk active pharmaceutical ingredients constitutedmanufacturing without proper approvals. The agency expressed concernthat VET was itself producing bulk drugs, for distribution and resalethrough veterinarians, rather than compounding individually to fillspecific prescriptions. In addition, the Agency said, VET'sformulations duplicated commercially available products. The warningalso voiced concern that VET's products might produce "unsafe drugresidues in edible tissues" if administered to food animals, and thatthe company did not warn against such applications of known hazardousdrugs such as "nitrofurarone" (sic), chloramphenicol anddiethylstilbestrol (DES).

And on 17 December, the same office sent a similar warningto Red River Pharmacy Services, Inc. (Texarkana, TX). The lettercited compounding and distribution of veterinary apomorphine,domperidone, chloramphenicol, and nitrofurazone from bulk activepharmaceutical ingredients, for distribution through third-partyresellers. Here, too, the agency observed that the products beingcompounded were identical or nearly identical to commercially availableproducts from inspected and approved manufacturers. The Agency againquestioned possible use of chloramphenicol and diethylstilbestrol infood animals.

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

–Douglas McCormick