Use of a Trinomial Distribution Probability Model in Development of a Tier-Testing Scheme for Content Uniformity Testing

Abstract

A trinomial distribution probability model was used to determine the rejection probabilities of various proposed tier-testing schemes for drug content uniformity testing of a unique drug product. The use of this probability model helped in defining a sampling plan and associated acceptance limits for uniformity of the constituted formulation that would assure an appropriate level of control for both releasing acceptable lots (those having desirable distributions of drug content) and rejecting unacceptable lots (those having undesirable distributions of drug content). The ATRIGEL® Delivery System with 10% doxycycline hyclate presents a challenge when testing for content uniformity because each product unit must be individually constituted just prior to application. This two-stage product is composed of doxycycline hyclate powder filled in one syringe and a liquid polymer formulation consisting of poly(DL-lactide) dissolved in N-methyl-2-pyrrolidone in another syringe. The drug substance and polymer formulation syringes are connected via Luer-Lok® fittings and the drug is blended with the delivery system by cycling the contents between the two syringes. The resulting constituted formulation is a viscous flowable mixture that is used to treat diseased tooth pockets in patients with periodontal disease.