The US Food and Drug Administration recently posted a Warning Letter to Bristol-Myers Squibb (BMS, New York) on its website. The letter describes violations of current good manufacturing practice that the agency observed at the company’s Manati, Puerto Rico, manufacturing facility. BMS responded to FDA’s observations in a letter dated Apr. 14, 2010, but the agency remarked that the response lacked sufficient corrective actions.

In the letter, FDA claimed that the Manati facility had not established or followed appropriate written procedures to prevent microbiological contamination of sterile drug products. The agency claimed that operators repeatedly failed to comply with BMS’s procedures for aseptic operations, including procedures for intervening in a Class 100 zone, in which no more than 100 particles larger than or equal to 5 µm are allowed per cubic foot of air.

In its response to FDA, BMS said that the facility would use a log book to document supervisory observation of the aseptic filling process, but the agency commented that a log book would not ensure adequate supervision. In the Warning Letter, FDA asked BMS for a plan that evaluates the effectiveness of the company’s training program and ensures that personnel comply with aseptic processes before they are certified to work in an aseptic area.

FDA also asserted that BMS had not thoroughly investigated the failure of a batch to meet its specifications, whether or not the batch had already been distributed. BMS did not thoroughly investigate the recurrence of environmental excursions in its facility and failed to verify the effectiveness of corresponding corrective actions, according to the Warning Letter.

In its response, BMS claimed that the environmental excursions occurred in nonproduct-contact areas and did not adversely affect the product. FDA disagreed, noting that many of the sample locations were in the Class 100 room used to load and unload lyophilizers, an area prone to personnel contamination.

In addition, FDA stated that the company had not ensured that its supplier of cleanroom gowns had taken steps to prevent defective gowns from being used in BMS’s cleanrooms. The agency urged BMS to ensure that its cleanroom gown supplier has adequate inspection procedures to remove damaged gowns from its cleanroom gown supply.

Finally, FDA said that the company had not established scientifically sound and appropriate standards, sampling plans, and test procedures for ensuring drugs’ identity, strength, quality, and purity. The agency called BMS’s response inadequate, saying that the company failed to provide a sound scientific rationale for establishing acceptance criteria or classifying defects upon visual inspection of lyophilized products.

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