QC LAB DATA MUST BE KEPT AND INVESTIGATIONS DOCUMENTED, FDAer VOGEL TELLS PDA WORKSHOP; INDUSTRY REPS URGE FDA FLEXIBILITY IN INTERPRETING BARR DECISION

FDA expects firms to retain all quality control laboratory test results, even if the results are determined by the firm's investigation to be invalid. The need for preserving all QC lab testing data was highlighted by FDA Division of Manufacturing and Product Quality Director Paul Vogel at a Sept. 10 forum on retesting and laboratory investigations held at the Bethesda, Md. headquarters of the Parenteral Drug Association (PDA). Vogel cautioned the PDA workshop that a QC lab "should not discount or ignore suspect data without scientific justification that the results are not representative of the material." However, "even when this is established," he asserted, "the initial results ...must be kept" along with the justification for invalidating those results. Vogel emphasized that "section 211.94 of the GMP regulations requires laboratory records to include complete data derived from all tests." The evaluation of out-of-specification laboratory data has been a focal point of industry and FDA attention in the wake of the February ruling by the Newark federal court in the case of U.S. v. Barr Labs ("The Pink Sheet" Feb. 8, T&G-1). Judge Alfred Wolin's 80-page ruling, which rested heavily on the court's interpretation of cGMP requirements for laboratory testing and failure investigations, as provided support for a strengthened FDA compliance program in the QC lab practice area. FDA field office management prepared a summary of the court ruling that was issued to the district offices for reference purposes this spring. Relevant aspects of the decision were also incorporated into a revision of FDA's "Guide to Inspections of Pharmaceutical Quality Control Laboratories" released in August. Reflecting the ruling, the new draft indicates agency expectations for conducting failure investigations and the use of retesting, averaging and blend analysis. Vogel pointed to the lab data evaluation issues as critical to FDA's assessment of a firm's GMP compliance status. He emphasized that "the inadequate response to out-of-specification results is a common theme of many of the major enforcement actions taken by FDA over the past two-to-three years." The compliance official cautioned that the practice of ignoring or discounting these results "without adequate rationale or scientific justification" may occur in the evaluation and release of raw materials, in-process materials, and finished product, and in ongoing stability study of marketed products. Warner-Lambert is among firms that have faced serious enforcement action following FDA findings in this area. The firm's handling of stability data was a key problem cited during the inspections which led to a court-adjudicated consent decree in August ("The Pink Sheet" Aug. 23, p. 10). Inadequate lab investigations also have been a common thread in a rash of GMP warning letters issued recently to other major brandname firms, including Ciba-Geigy, Sandoz, Merck, Lilly and AHP's Whitehall Labs ("Tbe Pink Sheet" Aug. 16, T&G-II). Vogel pointed out that the FDA compliance actions and the Barr decision have stimulated debate on the topic "throughout the industry, legal profession, and regulatory bodies" and "many differing opinions have been expressed." However, he cited general agreement that out-of-spec results are "significant indicators that the material represented by the test article does not comply with specifications," and "cannot simply be ignored or discounted without an adequate basis to overcome the initial indication of material." These GMP principles have been affirmed by the experts and the federal courts, Vogel emphasized, "because they are basic to good science and control." Wyeth-Ayerst Labs QC Associate Director Kenneth Dilloway urged FDA to pay careful attention in directing agency investigators how to apply the principles outlined in Barr. The "problem industry faces," Dilloway maintained, is that FDA investigators tend to "take things literally." Other industry participants at the workshop commented that some inspectors appear to be taking a checklist" rather than a situation-specific approach recently in conducting lab audits. Former FDA compliance official Joel Davis cautioned that overzealous or inflexible application by the agency of Barr principles could actually result in a reduction in QC testing programs. Firms may "back off" from extra in-process or product testing not required for product release "to make sure [the additional results] are not misinterpreted" by FDA investigators, Davis said. Industry participants at the meeting expressed concern, in particular, with FDA placing overly tight strictures on the use of retesting and resampling, "outlier" tests and averaging. Pointing to the constraints placed on the use of retesting and resampling in Barr and subsequent FDA guidances, Wyeth-Ayerst's Dilloway commented that they may be used by firms, not simply to override or invalidate the original test results, but to conduct a more thorough and accurate follow-up investigation. For example, he noted, resampling may help identify problems with the original sample, container, or sampling procedure that otherwise would not be detected. Responding to the industry comments, Vogel noted that FDA's main concern is that the firm is doing a "quality investigation." He added that "the agency will look at what you do in context." Vogel further acknowledged that "you are never going to have absolute certainty" in investigating lab data. However, he cautioned, FDA will expect firms to have a "reasonable basis" for conclusions that are drawn. That rationale "is what investigators are going to look at," he said. The FDA compliance official identified resampling and the use of averaging when assaying for potency as issues which will got further attention at his office. The agency is also interested in "learning more" from proponents on the use of outlier tests Vogel said, "especially when applied to chemical tests designed to measure uniformity." The FDA panelists at the PDA workshop emphasized generally that firms should have written procedures that detail how evaluation techniques are going to be applied, and documentation showing that the procedures were followed in a consistent fashion. When problem results are not "clearly assignable" to lab error, Vogel maintained, a full investigation into the cause and scope of those results "must be conducted" in a timely fashion. This full investigation is necessary, he emphasized, regardless of whether the firm decides to reject, rework or destroy the material represented by the test article. The immediate problem indicated by the results, the FDA official explained, "may have an impact on past and/or future production, which cannot be addressed without determining its cause." Dilloway asserted the need for PDA and the Pharmaceutical Manufacturers Association to put together a proposal for USP consideration on handling of out-of-spec results. USP in the past has resisted addressing batch release criteria in the compendia. However, Dilloway maintained that inclusion of additional information on evaluating chemical test results would help resolve regulatory and legal disputes over the issues involved. The information could be included as a modification of the chapters on dissolution and content uniformity, he suggested. FDA Division of Manufacturing and Product Quality staffer David Barr reported that his office has begun working on a guideline addressing the handling of out-of-spec laboratory results. He predicted the guideline would not be available before the spring of 1994. PMA also has a technical committee focusing on statistical issues raised by the Barr decision. A report from that committee is expected to be released in six to nine months.