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FDA SVP PLANT INSPECTIONS: PROBLEMS FOUND ARE NOT "HIGH-TECH,"

Executive Summary

FDA SVP PLANT INSPECTIONS: PROBLEMS FOUND ARE NOT "HIGH-TECH," but involve lack of attention to day-to-day operations and employee practices, FDA investigator Ronald Tetzlaff, PhD, told a March 11 meeting of the Pareneral Drug Association (PDA) in Washington, D.C. In a survey of GMP problems at small volume parenteral (SVP) manufacturers during 1981-1985, Tetzlaff found that "the vast majority of those objections dealt with day-to-day, people-type problems." According to the survy, the most frequently cited area among SVP manufacturers was filling room operations. Tetzlaff noted that approximately one-quarter of the 4,500-plus sterility-related observations during the study period involved "the actual assembly operations that are normally associated with filling rooms." Most "remarkable" about this finding, Tetzlaff emphasized, was that almost all of the observations related to "employee practoces -- [i.e.] observed conditions that the FDA investigator could visually see during the inspection involving filling rooms." Environmental monitoring was another frequently cited problem among SVP manufacturers. Tetzlaff noted that 90% of the environmental monitoring observations included in his inspection survey "dealt with people and day-to-day operations." Only three of the 359 observations dealt with calibration of environmental monitoring instruments, while about 10% of the citations dealt with validation, he reported. The FDA investigator told the PDA meeting that he had recently completed three inspections of "major" parenteral manufacturers, all of which failed to get FDA clearance for production start-up in spite of sophisticated equipment. Environmental monitoring was the key problem area in all three cases, he said. The three inspections were all requested by the firms. Two of the inspections, Tetzlaff explained, involved new facilities, which had not been inspected previously, with "brand new state-of-the-art equipment." However, the FDAer emphasized, the problems found during the inspection were serious enough "not to approve the facilities, not to approve the NDAs; to result in their plants not coming on line." The third inspection involved a firm asking for a reinspection in the belief that all problems noted previously had been corrected, he said. Tetzlaff explained that when the problems were made known, there was "not a single individual" in those firms "who disagreed with my findings; who didn't agree that the problems were serious and that they were objectionable." The problems occurred, Tetzlaff maintained, in spite of the fact that the key people in those companies were "clearly conscientious people" who wanted "to do a good job," but simply didn't know "that the conditions were as bad as I detected on the inspection." In general, Tetzlaff emphasized, the real problems that FDA is finding "are very simple -- they are just the basic stuff that is going on in your plant." The FDA parenteral investigations specialist advised the PDA manufacturers to "get back to the basics. Think about the real day-to-day activities that impact on your facility." He suggested that more emphasis be placed on employee training. "People are the single biggest problem" in making sure that parenteral plants are actually operating in a state of control, Tetzlaff said. "And yet people are not given [near] the degree of systematic attention by team management that they should be." While the problems occuring among SVP manufacturers may not be high-tech in nature, FDA's methods for uncovering those problems are becoming increasingly sophisticated. At the PDA meeting, Tetzlaff noted that he is one of a handful of FDA investigators who are now bringing computers into play during plant inspections as an aid in sorting out the firm's data and uncovering potential problems. The use of a computer, Tetzlaff explained, allows the investigator "to systematically see whether or not" the firm's employees "are doing what they should be doing." Due to the quantity of data involved, environmental monitoring is one area that particularly lends itself to computer analysis during field audits, Tetzlaff explained. He noted that the computer, in combination with an analytical system he has developed, allows him to rapidly review a firm's environmental data and to monitor trends and determine "whether or not the system is under control." The use of more sophisticated monitoring techniques by FDA investigators, may, in turn, result in higher agency expectations for the firms being investigated. Tetzlaff maintained that if he can "come into a plant" and in a few hours detect significant problems that a manufacturer is unaware of, than the firm itself "ought to have systems in place to have detected that long before I got there." Tetzlaff said that he would "seriously question" whether or not a sterile manufacturer without formal environmental monitoring systems "are really under an actual state of validation." Tetzlaff informed the PDA group that other investigators are currently using computers as an investigatory tool and that "down the road very shortly you are going to be seeing investigators coming to your plant with computers." He noted that he has submitted a proposal to FDA to make his computer system for environmental monitoring more generally available. FDA investigators, in the near future, may also be looking to review a firm's data electronically. A disk containing the firm's original data will then be reviewed by the investigator back in his office, Tetzlaff explained. In general, he said, the agency encourages the increasing trend toward paperless systems. "Paper doesn't make a record good and FDA certainly supports paperless systems." In fact, he noted, "I am working myself toward a paperless inspection."
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