STABILITY TESTING SHOULD COME BEFORE BIOEQUIVALENCE STUDIES, FDA's ISE RECOMMENDS; FDAer ALSO CAUTIONS ABOUT EARLY DISSOLUTION TEST SUBMISSIONS

Bioequivalence studies should be delayed until the stability of a drug formulation has been assured, FDA Bioequivalence Division Deputy Director Charles Ise advised attendees of the National Association of Pharmaceutical Manufacturers' annual meeting at Cerromar Beach, Puerto Rico on Jan. 20. "I strongly recommend that before embarking upon a full definitive bioequivalence study, the sponsor firm should evaluate the formulation to be marketed with regard to stability and ensure that it meets all the stability criteria," Ise said. "A bioequivalence study should be undertaken only when the formulation of a drug product is shown to be stable under usual conditions of stability testing." Ise noted that recently several firms have conducted bioequivalence testing first and then run into problems with the stability of the formulation used in the bioequivalence study. After conducting bioequivalence testing, the generic manufacturers "discovered that the formulation [was] not stable," Ise noted. "These firms have then come to the division and asked for help. The only answer we can give is that there is nothing we can do and the firm must conduct another study on a stable formulation." Another problem FDA has encountered with bioequivalence study submissions is premature filings of dissolution data to FDA, Ise observed. He said "many firms submit their dissolution data for all [dosage] strengths months before submission of the in vivo bioequivalence study." Ise explained that the problem arises when the company submits its bioequivalence study for the drug product, possibly long after FDA has informed the firm that the dissolution data is acceptable. "I must inform you that the reviewer of the in vivo bioequivalence study may not be aware of the acceptance of your earlier dissolution data, and he/she will recommend acceptance of only that dosage strength submitted in the bioequivalency study," the FDAer stated. "At the time of approval, [the Generic Drugs Division] can only approve the dosage strength recommended in our evaluation." Ise suggested that manufacturers "submit dissolution data prior to submission of the bioequivalence study; however, at the time of submission of your in vivo bioequivalency study you should resubmit the same dissolution data for all dosage strengths with the bioequivalency study." The FDAer said a complete bioequivalence package for a drug product with multiple strengths should also include "dissolution testing data on each strength comparing it with the respective strength of the pioneer product"; "formulation (amount of drug and excipients) for all the strengths"; and "a letter requesting waiver of in vivo bioequivalence studies for strength[s] not undergoing bioequivalence study." Generic Drugs Division Deputy Director Kent Johnson also offered advice at the NAPM meeting on how to avoid problems in ANDA applications. Although the listing of an inactive ingredient in the labeling of oral dosage forms is voluntary, Johnson said, "if you do choose to list it, it must be correct." The generic division is continuing to have "problems with the listing when it is not complete, or when ingredients are not cited by their established name." Dyes, including those found in the tablet coating and in capsules should be included in the listing, Johnson emphasized. Johnson recommended that firms submit this type of labeling as a supplement rather than as an item in a periodic report. Filing a supplement allows FDA to comment upon the copy and, Johnson asserted, "represents an efficiency and cost saving measure for you." The generic division's labeling review staff "puts forth considerable effort to respond to these supplements quickly," Johnson added. In addition, Johnson cautioned firms that the generic division will focus particular attention on inactive ingredient labeling following two recent Federal Register notices dealing with the subject. One notice stated that the presence of FD&C Yellow 6 (Sunset Yellow) must be included on labels; a second, that sulfites must be acknowledged in the insert with a defined warning. The FDA staffer also pointed out that new submission requirements covering changes to approved applications are causing problems for both applicants and FDA. One problem results when "information submitted by the firm does not adequately describe or support the change and we must therefore go to the firm and request more information," Johnson said. "In fact, several pieces of correspondence may issue before the change is found satisfactory." For supplements submitted at the time a change is implemented, or for changes described in a periodic report, Johnson observed that there is often a period of time when an implemented procedure is under question and a firm in limbo. "We are especially concerned when some of the manufacturing and control revisions which have been implemented are concluded [by the agency] to be non-supportable," Johnson said. Johnson again emphasized that clearing a change with the agency through a supplemental filing, even when not required, may be advantageous in the long run. Supplement submissions and approval letters in the applications for these changes "are like bookmarks which are always easily found and the letters clearly define the change," Johnson maintained. "As the years pass and reviewers change, it will become increasingly more difficult to find these changes proposed in periodic reports, and determine if the reviewer really in fact addressed and found these various changes satisfactory."