Domperidone

The US Food and Drug Administration issued six pharmaceutical CGMP warning letters from 7 December 2004 through 7 January 2005. Five of the letters continued the agency's crackdown on compounding pharmacies (three veterinary, two human) and one extended the review of the Liverpool influenza vaccine plant belonging to Chiron Corp. (Emeryville, CA, www.chiron.com).

FDA's Center for Biologics Evaluation and Research (CBER, Rockville, MD, www.fda.gov/cber) issued the Chiron warning on 9 December. This letter was the official notice of the much-publicized shortcomings found during the 10-15 October inspection of Chiron's troubled Evans Vaccines flu vaccine plant (Speke, Liverpool, UK). 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 adequately:

* Detect and investigate production errors. The warning specifically cited 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.

* Investigate sterility problems when they did occur.

* 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.

* Monitor environmental conditions in the aseptic processing area.

* Establish defined areas for aseptic processing operations to prevent contamination or confusion.

* 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 10 December news release, 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."

On 12 January, Chiron CEO Howard Pien told the JP Morgan Healthcare Conference that he expected the MHRA, accompanied by FDA observers, to conduct a new of inspections at the Speke plant.

Although the inspections and remediation effort "may advance toward the restoration of the facility's license, as successive phases of manufacturing pass inspection by the MHRA," (in the words of a statement Chiron issued the day of the conference), according to the Wall Street Journal, "Pien said there is 'no basis yet to predict whether or when' the company will be able to resume production of flu vaccines for the US market."

Chiron has not responded to questions asking whether inspections actually have been scheduled.

Compounding crackdown continues

The other FDA warnings cited five large-scale compounding operations, two making human drugs and three making animal medicines.

* On 7 December, FDA's Florida District office issued a seven-page, 12-point warning to Lex, Inc. (Medley, FL). Among other complaints, FDA charged that the company's human prescription and over-the-counter drug operations lacked a quality control unit, failed to train its workers, didn't quality-test ingredients or finished products before shipping or using them, and neglected to test products for stability or microbial contamination.

* On 9 December, FDA's New Orleans District office warned Lincare, Inc. and Reliant Pharmacy Services, Inc. (associated companies at the same address in Clearwater, FL, www.lincare.com) 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 (e.g., 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.

During the period, two midwestern district offices cited three veterinary compounding operations, charging that the scale of their operations made them subject to the same regulations as a registered manufacturing facility, observing that they often produced compounds identical or nearly identical to commercially available products, and citing them for failure to guarantee that drugs known to be harmful would not find their way into food-animal populations:

* On 8 December, FDA's Dallas District office 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. 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).

* 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, often in formulations identical or nearly identical to commercially available treatments, for distribution through third-party resellers. The Agency again questioned possible use of chloramphenicol and diethylstilbestrol in food animals.

* And on 7 January, the Kansas City District Office (Lenexa, KS) cited Omaha's Essential Pharmacy Compounding (Omaha, NE, www.kohlls.com) also for mass-producing veterinary drugs from bulk active pharmaceutical ingredients. The warning cited large-scale compounding of altrenogest, amikacin sulfate, dipyrone, flunixin meglumine, ketoprofen, ivermectin, ompeprazole, phenylbutazone, and tripelennamine hydrochoride, "among many others."

All six warnings demanded a written replies within 15 working days. As of 26 January, FDA had not posted any replies. The warnings can be viewed online at www.fda.gov/foi/warning.htm.

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