SEPARATE ANDAs REQUIRED FOR EACH MANUFACTURING SITE, FDA's GENERIC DIVISION SAYS; PRODUCTION REQUIREMENTS FOR BIOEQUIVALENCE STUDIES UNDER REVIEW
FDA is looking into whether generic manufacturers have separate ANDAs for each product at each manufacturing site, FDA Generic Drugs Division Director Marvin Seife, MD, told the National Association of Pharmaceutical Manufacturers' annual meeting Jan. 19 at Dorado Beach, Puerto Rico. "In a mass-produced operation such as ours we have got to know where everything is done or we will be completely lost," FDA Generic Drugs Division Director Marvin Seife, MD, explained. "In the last year or so, with the proliferation of new plants by generic firms, as well as the large firms," Seife said. "We are gradually losing contact with what is going on." Accordingly, Seife stated, the generic division has decided to "retrench and find out what products" are being assigned to specific production facilities. Firms manufacturing the same product in more than one plant will be expected to have separate ANDAs for each site, Seife explained. That is "the only way we can keep track of this industry and all the facilities they have," the generic division director said. FDA's Seife noted that while the manufacturer has the option of obtaining separate ANDA approvals for different production sites, the generic division is generally encouraging firms to assign a particular product or a particular dosage strength to one facility. Generic Division ANDA Review Branch Chief Jack Meyer said that the division will generally allow a firm about six months to gear up production in the new facility. However, citing the example of moving production to a new facility in Puerto Rico, Meyer advised that "when you know what you are doing down in Puerto Rico, we expect you to stop making it back in the States." Meyer emphasized that firms should inform FDA where a drug will be made and the qualifications of those making it in the ANDA. In the context of the rapid expansion in the industry, Meyer stated, "it is important that we know where every step of the finished dosage form is being made . . . so that when the inspector does come to inspect the place he is not surprised." Meyer also advised ANDA applicants to inform contract manufacturers to expect a visit from FDA, "because as soon as you send in that application we are going to ask for an inspection." FDA Office of Drug Standards Director Peter Rheinstein, MD, explained at the NAPM meeting that cross-licensing arrangements between firms cannot obviate the need for separate ANDAs, which include separate bioequivalence studies, when a product is being manufactured by both firms. "The agency is worried about the proliferation of the different applications referring to a single bioequivalence study," Rheinstein said. In addressing the problem, the agency is taking the position that "a bioequivalence study, and hence an ANDA, represents the ability of a particular management group to produce a particular product in a particular factory," he noted. "That doesn't mean that on a case-by-case basis there won't be the usual ability to request a waiver of a bioequivalence study for a change of manufacturing site or for a change of ownership," Rheinstein told NAPM. However, Rheinstein noted that "when all the changes occur at once, as they do in a kind of cross-licensing agreement," FDA is going to ask for the extra testing as part of a separate ANDA. FDAers at the NAPM meeting also pointed to growing agency concern about the ongoing validity of bioequivalence studies for oral dosage forms in the context of production scale-up and formulation changes by the ANDA holder. "What we have noted," Rheinstein said, "is that several months into the marketing for any particular ANDA there is a fairly high possibility that we are going to receive a supplement for some change in the formulation." To the extent that those supplements are a result of the scale-up in production, Rheinstein continued, "we are wondering whether or not in some cases the larger batch should have been used to produce the materials used in the bioequivalence study." Bioequivalence Division staffer Frank Pelsor, PharmD, explained that the division's policy has been to require that the bioequivalence test product be obtained from a production-size batch or a batch produced on production equipment. In either case, Pelsor noted, his division has been requiring that the batches be "at least 100,000 dosage units, produced using tableting and encapsulating machines to be employed for production lots, and the same type of equipment as in production runs for operations such as blending, milling, drying and coating." However, in the context of the apparent need among ANDA holders for equipment and formulation changes following scale-up, Pelsor explained, the agency is evaluating "whether the current requirements are sufficient to assure that final production lots are adequately represented by the lots made for the bioequivalence study." While the policy review is taking place, Pelsor cautioned that FDA "will be taking a closer look at applications in order to ensure compliance with existing policy regarding production-size studies." Where an applicant's bioequivalence study report indicates that the study batch size is less than 100,000 units, Pelsor said, the bioequivalence division will label it a "pilot study" and return the submission to the Division of Generic Drugs without further review. Pelsor also advised ANDA applicants to conduct a careful in vitro evaluation of the reference product used in the bioequivalence study and to provide results of that evaluation in the study report. Pelsor also highlighted FDA concerns regarding food challenge studies for immediate release products. The food studies, he noted, "have become increasingly popular because many of the products coming off patent have references in the labeling to the effect of food on the absorption of the drug." In order to determine when a food challenge study is required, Pelsor advised the NAPM group, "you should determine whether the labeling for the listed drug product states that food does or does not have an effect on the absorption of the drug." If such a statement appears, Pelsor said, "the sponsor of the ANDA must conduct a food challenge study in addition to the fasting study which is required for the bioequivalence determination." As part of the agency's interest in automated data processing techniques for new drug submissions, the division of bioequivalence has recently issued a guidance for electronic submission of in vivo bioequivalence study data. Pelsor said at the NAPM meeting that the submission of data on a diskette "is on a voluntary basis and is in addition to the hard copy submission." Pelsor noted that his division will be developing guidance on electronic submissions of other information in the bioequivalence section of an ANDA, including dissolution and formulation information from the protocol study, summaries, and bioequivalence tables and graphs.
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