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LYPHOMED LAYS OFF 25% OF MELROSE PARK PLANT WORKERS

Executive Summary

LYPHOMED LAYS OFF 25% OF MELROSE PARK PLANT WORKERS in response to ongoing compliance problems with FDA, according to a press release issued by the firm March 18. The company announced that it was laying off 73 of the 291 workers employed at the plant. The firm also reported that it was transferring 50% of the production volume from Melrose Park to its plants in Grand Island, N.Y., and Orlando, Fla. The move is intended "to give our people in Melrose Park time to implement the enhancements to the quality control procedures we have initiated as a result of the FDA inspection," LyphoMed Chairman and CEO John Kapoor explained. "No quality control or quality assurance people were among those laid off," Kapoor noted. LyphoMed explained that the layoff and production changes were expected to be short-term. "We consider this to be a short-term situation, and we fully anticipate that we will resume increased production levels at the Melrose Park plant in the future," Kapoor stated. The LyphoMed action came in response to an FDA 483 adverse findings report issued the firm on March 11 following reinspection of the Melrose Park facilities. In a March 18 response to the FDA report, LyphoMed informed the agency that the firm is "committed to effectuating immediate improvements in each of the areas observed" on the report, and that "approximately 75% of these changes were implemented during the course of the inspection or have now been implemented." Among the remaining 25%, LyphoMed noted, "are changes which can not be considered fully implemented due to lack of an approved supplement to a particular ANDA/NDA." FDA has not been processing and approving ANDAs submitted by LyphoMed since November, when the company receieved a regulatory letter from FDA addressing the company's ongoing compliance problems. Since then, LyphoMed has issued two separate recalls: in December, LyphoMed recalled approximately 26,000 vials of several small volume parenteral anticancer drugs for lack of sterility assurance; and in January, the firm recalled the antifungal amphotericin B due to greater than expected side effect problems. During the reinspection, FDA extensively reviewed LyphoMed's batch records, procedures and processes for the recalled products, and several of the entries on the FD-483 report relate to problems that were found during this review. Some of these entries involve an alleged failure of LyphoMed's quality control unit to make sure that established procedures were followed and that all process deviations were recorded and throughly reviewed. Ironically, one problem area cited on the FD-483 involved "new or revised standard operating procedures (SOPs)" instituted by LyphoMed following an earlier FDA inspection completed in July of 1987. LyphoMed did not evaluate the impact the changes would have on existing NDA commitments, the follow-up investigation report states. According to the FD-483, "between 7/1/87 and 12/9/87, revisions were made to 37 microbiology QC SOPs, 100 chemistry QC SOPs, and 240 QA department SOPs. Some of these revisions affected existing NDA commitments relating to manufacturing procedures, in-process controls, monitoring procedures, analytical methods, etc." A significant number of observations on the reinspection report related to process and formulation changes from those approved in NDAs without formal agency clearance. Unapproved formulation and process changes have been a key focus of FDA investigators since 1985 following clarification of the requirements for supplemental filings in the NDA rewrite and a specific directive from compliance headquarters to look for the changes during inspection visits. Among the unapproved changes made by LyphoMed, the FD-483 states, were alterations in the operations and parameters for lyophilization as specified in the master record. "These are usually accompanied by a deviation form stating that the modifications were made to 'optimize' the lyophilization cycle," the FDA report notes. However, "there is no documentation that the modifications had been validated nor is there an explanation as to why the optimizing had not been accomplished during product development." In its response to the 483, LyphoMed noted that several changes have been made in its quality control and assurance (QA/QC) policies and procedures to help ensure that the approved procedures are followed. In addition to an increase in day-to-day on-line compliance functions by the QC-QA department including a daily audit, LyphoMed said that "a formal QC investigation mechanism has been developed to address any and all deviations in the components, processing, and testing of all products." Prior to any in-process adjustment, the firm said, "a written evaluation will be required to determine the cause of any 'out-of-limit' results" and corrective action taken "to prevent a recurrence of the same." Another significant change made by LyphoMed since its compliance problems surfaced has been the replacement of key quality control and management personnel. LyphoMed noted that the former QC/QA director of its Grand Island and Orlando facilities, Wayne Kvetkosky was upgraded to the position of corporate director of QC/QA in mid-November of 1987. The firm also noted that as of March 1, former Riker and Bristol-Myers regulatory official Roland Catherall joined the firm as senior director of regulatory affairs. As such, he will be responsible for corporate regulatory affairs activities as well as new corporate audit functions, the firm explained. LyphoMed has also solicited help in implementing its quality control changes from outside GMP consulting groups including New York-based Lachman Associates, and Washington-based Arthur Checchi. LyphoMed said that Leon Lachman, PhD, helped with the response to the FD-483. The independent auditors, LyphoMed said, "will carefully review our manufacturing plants and recommed steps beyond those suggested by the FDA."
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