Abstracts

Rationale: Intra- and inter-patient variability in drug absorption and clearance are recognized sources of variability in bioavailability during bioequivalence testing. Lot-to-lot variation in mg tablet content is potentially an important source of variation, too (Levy-J Pharm Pharmacol 1995;47:975), but capsule or tablet mg content and/or variability is not routinely analyzed, reported or considered in bioequivalence trials for test or reference products. Recently, clinical problems with the use of generic anti-epileptic drugs (AEDs) as it pertains to the management of epilepsy has been identified or alluded to (Besag-Drug Safety 2000,23:173; Crawford-Seizure 2006;15:165; Berg-Neurology 2007;68:1245) prompting the American Academy of Neurology to oppose generic substitution of AEDs without physician approval (Liow-Neurology 2007;68:1249). Yet, controversy prevails; one recent publication suggested that 5-7 % plasma level differences between branded vs. generic AED could be accounted for merely by batch-to-batch mg content variation in branded AED (Bialer-Epilepsia 2007;48:1825). We sought to determine the degree of lot-to-lot (inter-lot) variation in tablet mg content for branded enteric-coated, delayed-release and extended-release divalproex sodium, various strengths. Methods: The assay data for mg content of the tablet formulations above manufactured by Abbott--#926 batches total (#315 enteric-coated, #611 extended-release divalproex sodium), from April 2005 through 2007 according to the requirements outlined in each new drug application and current Good Manufacturing Practices, were reviewed. Results: Assay data for various tablet strengths, representing over 1.3 billion tablets for each formulation, were reported using these metrics: mean, standard deviation, relative standard deviation, maximum & minimum, as % of labeled mg amount. The composite mean (summary of all dosage strengths) for enteric-coated, delayed-release was 100.9%, and the extended-release divalproex sodium formulation was 100.5% of the labeled mg amount. The standard deviation for actual mg amount was between 1.0-1.5% when both formulations, all strengths were considered. The minimum and maximum % of labeled amount for all strengths, both formulations, never exceeded United States Pharmacopeia:National Formulary specifications of 90-110% for assay and 85-115% for content uniformity. Conclusions: The variability in lot-to-lot mg content and variability for content uniformity for both enteric-coated and extended-release divalproex sodium tablets (Abbott) is minimal. Hence, such factors are very unlikely to be a significant source of variation in bioequivalence studies or the source of a clinical problem in a patient with epilepsy, either as excessive dosage resulting in intermittent toxicity or inadequate dosage resulting in breakthrough seizures. The assayed potency is substantially tighter than the specification allowance per the USP:NF. Such manufacturing consistency helps ensure patient safety.