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LILLY PLEDGES TO REVIEW ALL ITS NDAs FOR UNAPPROVED DEVIATIONS IN RESPONSE TO FDA INSPECTION REPORT; INDIANAPOLIS PLANT MANAGEMENT REORGANIZED

Executive Summary

Lilly is beginning a long-term project to review all of its NDAs "to determine whether manufacturing supplements should be filed" as an outgrowth of a five-month inspection by FDA. In a Sept. 8 response to 90 pages of adverse observations by a three-man FDA inspection team, Lilly declared: "Ultimately, all Lilly NDAs will be reviewed to determine whether manufacturing supplements should be filed." Reprocessing drug products without approved NDA supplements was one of the key citations in the FDA 483 adverse findings report. Lilly responded quickly to the Aug. 25 inspection report by immediately halting production at the Indianapolis facility and stopping shipment to its distribution centers of all lots manufactured at the oral dosage form plant. The firm also immediately began a review of products cited for NDA deviations. That review led to a Sept. 12 recall of 18 lots of 10 drug products. The recall is being conducted to the wholesale level. Lilly's response to the 483 adverse findings report notes that "samples from each of ]the recalled[ lots have recently been reassayed and have been determined to meet specifications for potency and dissolution." The lots, Lilly continued, "are, therefore, being recalled only in light of the observations made by FDA with respect to technical compliance with NDA manufacturing commitments." A number of additional lots were cited in the 483 for NDA deviations. Lilly determined that "no recall is appropriate" for those products for one of three reasons: the lots were out of date; the repeat of production steps did not constitute reprocessing "that requires explicit approval in the NDA"; or supplements permitting reprocessing were approved subsequent to their production. Products cited by FDA for which Lilly believes the replicative processing did not constitute reprocessing include one lot of Axid, Darvon Compound, Darvon-N, and Nalfon; two lots of Ilosone caps; and three lots of Ilosone chewable tabs. The response notes that "while one or more of the approved production steps were repeated for the lots . . ., under accepted industry practice this is not reprocessing outside of what is permitted pursuant to the NDAs." Many of the citations in the 483 report center on inadequate documentation and record keeping procedures. "There was an overall failure to have written SOP's ]Standard Operating Procedures[ for many operations; documented reviews, evaluations and investigations by responsible management were generally not available; and record keeping problems were detected in nearly all areas inspected," the 483 states. "In nearly every system examined, the available data were found to be incomplete or inaccurately summarized." Some of the record keeping problems are not unlike objectionable documentation practices uncovered in the generic drug probe. For example, at Rep. Dingell's (D-Mich.) May 11 hearing, it was disclosed that the inspection of Par found that the firm was filling in deviations from operating procedures after the fact in an "off the record" book. Lilly's 483 notes a similar retrospective handling of records associated with product and process failures: "The Manufacturing Difficulty Reports were not maintained in batch ticket files and were not prepared contemporaneously at the time of occurrence by personnel performing the operations." Related documentation problems included situations where records were signed off although procedures had not been verified. In one instance, for example, "an employee was observed to initial steps on an in-process batch record for 'weight verified by' without observing the weigh in," the 483 notes. Although the Lilly inspection is not related to the ongoing investigation of generic drug companies, the two have been linked by coincidence and by comments by FDA under the stress of the media hunt for news on the generic situation. The adverse findings derived from a for-cause inspection of the Lilly facility, precipitated by a series of recalls (most recently Axid, in May 1988, and Darvon, in June 1988) involving failure to meet dissolution specifications during routine stability testing. Since the inspection began, the firm has conducted two other recalls because of stability problems: enteric coated thyroid tablets, on June 22, and all manufactured lots of 11 vitamin and mineral products, on June 30. Discussing Lilly's stability testing program, the 483 states that FDA's evaluation "revealed test failures without documented investigations or corrective actions. Written SOPs were lacking or inappropriate, and there was an overall failure to assure the stability of each product (container type, formula, etc.)." Data collection and retrieval systems, the report continues "were found to be ineffective, and many of the practices were informal (i.e., lacking written SOPs)." Lilly called its response to the 483 an "Action Plan" and proposed a series of measures for assuring the safety of products currently in distribution, testing lots that are being held at the plant, and resuming production. The efforts are being spearheaded by an 11-member task force that was appointed Aug. 25. The "Product Quality Task Force" is headed by Robert Williams, PhD, VP-quality control, quality assurance and environmental affairs. Williams, formerly a VP for Lilly Research Labs, was elevated to the newly created position on Aug. 18 as part of series of management changes in the quality control area. One of the key post-inspection changes was the separation of the quality control function from production. That is an organizational structure that FDA has favored for well over 10 years. Williams reports directly to Exec VP-Earl Herr, PhD. Reporting to Williams are two newly-created executive directors: Executive Director for Quality Control Alan Dinner, PhD, formerly director of product development and regulatory affairs, and Executive Director of Quality Assurance J. Ann Fulk, formerly director of personnel. Fulk's responsibilities will include enhancing the company's CGMP training and compliance auditing programs. The Lilly plant had resumed production of only one product at the time of the Sept. 8 response to FDA. Under the "Action Plan," the firm is evaluating each of the roughly 180 products produced at the plant to compare "manufacturing, testing and documentation procedures with the manufacturing and control section of the applicable NDAs" before resuming production. The response explains that if discrepancies are found, the firm will either await approval for an NDA supplement or resume manufacturing under the approved NDA methods. As part of the product-by-product review, Lilly has identified five "small volume" products to date that it plans to discontinue. Products currently being held at the manufacturing plant will be reviewed to compare production processes with the NDAs. "No lot from this group will be released to Lilly distribution centers unless and until it can be shown that the manufacturing operations were performed in compliance with any existing applicable NDA approval and in accordance with a validated process, and samples have been tested to ensure that the lot meets applicable specifications," Lilly's response states. The Product Quality Task force is also supervising a review of all in-date products currently in distribution. "Assays will be conducted using both house samples and samples obtained from Lilly distribution centers and wholesalers," the firm said. "Any batch that remains within established specifications but shows significant anomalies will be placed in the corporate stability monitoring program (pending sample availability), pursuant to which samples are assayed at regular intervals throughout the life of the product." Lots determined not to meet specifications will be recalled, "subject to considerations of medical necessity," Lilly said. At the time of the Sept. 8 response, batch analysis had been performed for all lots cited by FDA for NDA deviations and product and process control system problems. The firm has prioritized the review of remaining lots to begin with the most recently manufactured lots, higher volume lots, and those with the longest remaining time to expiration. Lilly's "Action Plan" estimates that the batch analysis review will be completed "in approximately four months." In addition to the review programs, the task force is also in charge of overseeing the development of revised quality control procedures. A group "of specialists in quality control has been engaged in writing procedures for the preparation of standard operating procedures and departmental operating procedures. In addition, 'umbrella' procedures are being written to govern the major areas of stability, change control, and deviation control," the response notes. Lilly describes the quality control revisions as a comprehensive reworking of all existing procedures: "Following the development of these procedures, . . . related procedures will be reviewed and revised as necessary with respect to specific drug manufacturing operations. Support systems for these procedures will then be developed, including the development of information systems, standard forms, and other items. Computer systems will be carefully reviewed and modifications made as appropriate. Comprehensive training in the new procedures and systems will take place . . . as the new procedures and systems become available." The new procedures form the basis of the firm's response to all of the issues cited in FDA's 483. For example, with regard to NDA deviations, the "Action Plan" states: "The umbrella procedures for 'Change Control,' 'Deviation Control,' and 'Quality Control Disposition Process' will provide formal systems through which Quality Control will determine whether or not a proposed action constitutes reprocessing and, if so, will assure that reprocessing is conducted in accordance with all applicable NDA commitments. Quality Control will have the responsibility for assuring that NDA approval is obtained or is in effect before any reprocessed lots will be approved for release." The "'Stability' procedure will ensure that appropriate samples are placed on stability for each marketed product with respect to plant site, container type, product formula, and other relevant factors," the plan states. "The procedures for 'Change Control' and 'Deviation Control' will assure that changes and deviations are reviewed with respect to stability requirements and approved only after those requirements are satisfied." LILLY SEPT. 12 RECALL: PRODUCT LIST Aventyl (nortriptyline HCI) 10 mg pulvules, one lot Darvon with ASA (propoxyphene HCI and aspirin) pulvules, one lot Darvon-N with ASA (propoxyphene napsylate and aspirin) tabs, two lots Dolophine HCI (methadone HCI) 5 mg tabs, two lots Nalfon (fenoprofen calcium) 600 mg tabs, one lot methadone HCI 40 mg diskets, one lot sulfadiazine 0.5 mg tabs, four lots sulfapyridine 0.5 mg tabs, three lots Tapazole (methimazole) 5 mg tabs, one lot Tapazole 10 mg tabs, two lots
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