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Executive Summary

FDA's generic sampling effort has not revealed an industry-wide problem in the quality of generic drugs, FDA Compliance Office Director Daniel Michels told NDMA's annual manufacturing controls seminar in Baltimore, Md. Oct. 6. The "statistics could change" as further analysis is conducted on the generic samples, Michels said. "At this point we do not see that we have a major quality problem," he noted. "These products are meeting potency, dissolution, USP specifications, and other appropriate product specifications." Michels observed that FDA's "findings with respect to the generic industry have not been sweeping -- that all of the industry is bad. We have some very serious problems with a small number of firms and a fair number of products." However, he added, "time will tell as to how bad the situation is with respect to the industry." FDA reported in an Oct. 3 "Talk Paper" that "nearly all of the products tested" as part of its sampling "sweep" of the top 30 generic drugs "were found to be within acceptable specifications, but about 1.6% (a rate approximating normal industry conditions) were found to be deficient in potency or dissolution." According to the agency release, the drugs are being checked for a variety of quality parameters including potency, dissolution, and composition, at 16 FDA laboratories around the country. To date, 1,874 samples, not including duplicates, have been collected, and almost all of these (1,827) have been analyzed, FDA said. Several hundred samples remain to be collected. The "Talk Paper" points out that findings of subpotency during the generic product testing resulted in a Sept. 27 recall by Pharmaceutical Basics of 16 lots of its antifungal nystatin tablets. FDA expects to release a summary of its test findings on the 30 drugs by the end of October. FDA's inspections of the generic industry in the wake of the scandal have progressed in three phases. Last spring, FDA began "for-cause" inspections of 11 generic firms as fall-out from revelations coming out of the Congressional investigation into generics. Two more firms, Sidmak Labs and Pharmafair, were subsequently added to this initial "for-cause" group. The effort was broadened in early August, when FDA began sampling products from all manufacturers representing the 30 most prescribed multi-source drugs. FDA expanded the inspections further to include the 20 largest generic houses not involved in the "for cause" inspections. Regarding FDA's inspections of the 20 generic drug firms, Michels said that FDA is "inspecting those [companies] with the same intensity and approach which we took with the first eleven -- looking at GMPs; looking at adherence to the ANDA commitments; and also looking at the authenticity of records underlying . . . approvals of those applications." According to the Oct. 3 release, all of the 20 inspections "are ongoing" at this time "and no final conclusions have been reached." FDA said it expects this inspection program to be completed by Nov. 16. Initial findings by FDA on one of the 20, Quantum, involving misrepresentation of data in three of the firm's ANDA applications, have resulted in the suspension of production and distribution by Quantum of its 21 generic products ("The Pink Sheet" Sept. 25, p. 7). Summarizing the results to date of the initial 13 "for cause" inspections, Michels pointed to "other instances" of false data in applications. "We have found improper recordkeeping and false manufacturing data," Michels said. "We have found substantive GMP problems and we have found substantial deviations from commitments made in applications." Michels noted that the generics investigation so far has revealed that illegal substitutions were made by "a small number of firms" involving "a small number of products." However, Michels noted: "We have found a number of other false submissions in the same general area where there was mischaracterization of the samples submitted for biostudy. There have been false statements made associated with the manufacturing of these test materials." Generic firms have claimed "that 80,000 or 100,000 units were produced" for bioequivalence samples, while FDA "inspections have revealed that in some cases substantially smaller numbers of units" were actually produced. At the Sept. 11 Dingell hearing, FDA Compliance Office staffer Paul Vogel reported that a few of the firms in the initial 13 grouping, including Able Labs and Zenith, have come through with a relatively clean bill of health from FDA ("The Pink Sheet" Sept. 18, p. 7). In the case of Zenith, the talk paper explains that FDA found "several minor GMP problems at Zenith's Puerto Rico plant, but that location is inactive at this time and no further action is warranted." Despite findings of a variety of deviations in Quad's recordkeeping practices during a previous round of inspections in late 1987 and an implication through its former president, Dilip Shah, of involvement with illegal gratuities, the FDA release reports that the current inspection of the firm's facilities "found no significant GMP deficiencies." FDA notes that significant GMP violations were found during the inspections of Pharmaceutical Basics and Watson Labs, and that these findings have resulted in regulatory letters being issued the two firms. A reg letter was issued Watson on Sept. 8 citing GMP deficiencies in the the firm's recordkeeping and laboratory operations. Pharmaceutical Basics received a reg letter Sept. 7 addressing GMP deficiencies involved with oral and topical liquid production at its Morton Grove, Ill. plant. At the NDMA meeting, Michels commented on the extensive resource commitment involved in the current generic industry review. He noted that there are now 13 FDAers that have been reassigned on a full-time basis and "several others" assigned part-time to what "we are calling informally the 'generic drug compliance staff.'" The compliance group focusing on the generics problem is headed by Manufacturing and Product Quality Division Director Edmund Fry. Michels reported that FDA "will be assigning more people in the next several days to that staff." Michels also noted that, "in the next few days," he will be putting together another FDA team "to begin looking at the parameters of what we need to be doing in . . . the longterm future with respect to other problems that we have uncovered in generics." Michels maintained that "clearly there will be a spillover" of these parameters to pioneer firms and to the OTC industry. Describing the overall impact of the generic industry investigation, Michels stated: "I don't think there is any doubt that more intensive inspections of facilities both manufacturing side as well as pre-approval audits will be the outcome of what has transpired here." Michels suggested that FDA will be looking to its clinical trial auditing program as a role model for the pre-approval manufacturing audits. "The principles that the agency has employed in performing those inspections are certainly models that need to be considered with respect to bioequivalence studies, with respect to looking at the stability and other data which is generated prior to approval of all types of products," the compliance director stated. However, Michels noted that these inspections are more time consuming and resource intensive, and that decisions will have to be made by FDA and congress to determine what additional resources are needed "to minimize the probability of fraudulent activities taking place."

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