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Executive Summary

ASTRA's USE OF HOLDING TANKS IS "SIGNIFICANT MANUFACTURING CHANGE," FDA concludes in a March 13 letter. An inspection performed from Feb. 11 to April 3, 1991 revealed that Astra Pharmaceutical "had implemented the use of holding tanks in the manufacture of many of your drug products" at the company's Westborough, Mass facility, the letter states. "Through this letter we are informing you that the use of holding tanks in manufacturing is a significant manufacturing change." The warning was issued by FDA's Boston district office. Astra NDAs and ANDAs affected by the manufacturing change include Sensorcaine (bupivacaine HCl injection), furosemide, naloxone and pancuronium bromide, the letter states. "This is not intended to be an all inclusive list," FDA adds. "Inspectional evidence indicates that perhaps all approved drug products have been affected by this unapproved change." Astra has met with FDA on the holding tank issue a couple of times, both at the Boston office and with representatives of the Office of Generic Drugs at FDA headquarters in Rockville, Md. According to the letter, Astra said it had voluntarily discontinued the use of holding tanks in its manufacturing processes and would submit supplements for the change. However, FDA has not yet received a corrective plan. The warning letter states that the plan "should include, at a minimum, a list of all the drug products that had been manufactured with this change and the NDA/ANDA number; the date holding tanks were discontinued; and the date you have filed or are planning to file the supplements for each drug product," the letter advises. Astra says it is continuing to discuss the holding tank issue with FDA. In a second warning letter to Astra, also dated March 13, FDA asks the firm what actions it will take to remedy a problem with subpotency in lots of Astra's Xylocaine 1.8 ml dental cartridges. Astra says it has stopped shipments of Xylocaine and is recalling all batches of the lidocaine/epinephrine anesthetic. During an agency inspection of the Westborough facility between Jan. 21 and Feb. 11, 1992, FDA inspectors reported that 32 of 50 lots of Xylocaine dental cartridges "were found to be subpotent for epinephrine," the letter says. In addition to the subpotent epinephrine, Astra did not adequately validate its aseptic fill process for the products. The 32 lots therefore are adulterated because the product strength is less than the USP standard and because they were not manufactured in accordance with good manufacturing practices (GMPs), FDA said. Additionally, the lots are misbranded because the products do not contain the stated amount of epinephrine and do not meet the declared expiration dates. While Astra sent FDA three "field alert reports" between Feb. 4 and March 4 indicating that the 32 lots would be recalled from the market, FDA had not received a single letter as of March 13. "How can we be sure that these recalls will be handled in a timely manner?" the warning letter asks. "Where are these letters?" An Astra spokesperson said the company has since sent a recall letter to the agency.

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