Do Formulation Differences between the Reference Listed Drug and Generic Piperacillin-Tazobactam Impact Reconstitution? HaiAn Zheng, a James Truong, a Fred Carroll, b Manjunath P. Pai a Albany College of Pharmacy and Health Sciences, Albany, New York, USA a ; Pfred Pharma Consulting, LLC, East Lyme, Connecticut, USA b Pharmaceutical differences between the reference listed drug (RLD) and generic formulations of piperacillin-tazobactam may impact the reconstitution process for intravenous administration. This study evaluated the RLD against three generic formulations and measured their reconstitution times using a standardized process. The mean (standard deviation [SD]) reconstitution time for one generic formulation was 5.57 (1.49) min, which was 35% to 42% longer (P < 0.002) than that for the RLD and two other formulations. Observable microscopic differences in powder particle morphology may explain these findings. P iperacillin-tazobactam is a -lactam-and--lactamase-in- hibitor antibiotic combination for intravenous injection approved by the Food and Drug Administration in 1993 and marketed as Zosyn in the United States, which serves as the reference listed drug (RLD). The original formulation of Zosyn contained no excipients, but there were concerns after recon- stitution that resulting particulate matter might exceed the United States Pharmacopeia (USP) standards (1). Through a series of investigations, the manufacturer of this RLD identi- fied the primary contributors to these aberrant larger particu- lates to be related to the acidic pH and presence of metal cat- ions. These findings led to the reformulation of the RLD to include sodium citrate as a buffer agent and sodium edetate as a cation chelator (1). This revised formulation received U.S. Food and Drug Administration approval in 2005. In 2009, generic formulations of piperacillin-tazobactam were introduced into the U.S. market using the original no- excipient formulation, because the revised formulation of the reference listed drug (RLD) was still under patent protection (2). The regulatory approvals were made through a waiver for “exception excipient regulations,” which covers preservatives, buffers, and antioxidants used in parenteral drug products (3). Considering this known formulation differences between the products and a history of concerns regarding particulate matter formation (4, 5), this study was performed to investigate the pharmaceutical equivalence of these products during the re- constitution process. A total of 160 vials of 3.375 g of piperacillin-tazobactam for injection were purchased through Cardinal Health (Dublin, OH), from four manufacturers (manufacturing location): (i) Pfizer (It- aly) (the RLD), (ii) AuroMedics (India), (iii) APP (Italy), and (iv) Hospira (Austria) (40 per manufacturer). Sterile water for injec- tion (SWFI) USP (20-ml single-dose vials by Hospira) and 20-ml syringes with 20 gauge 1.5-in. needles (Becton Dickinson, Frank- lin Lakes, NJ), and 70% isopropanol swabs were also purchased from Cardinal Health. All reconstitution processes were per- formed in a certified horizontal laminar flow hood, similar to standard compounding practices within a hospital setting. Several compounding pharmacists were consulted in order to develop a standard operation procedure (SOP) for reconstitution to ensure consistency, clinical relevance, and compliance with the directions and regulatory guidelines of the manufacturers. Up to 10 vials per manufacturer were used to pilot and develop this SOP. The four formulations were not identical in physical appearance due to differences in the vial dimensions, label size, and content appearance (Fig. 1). During SOP development, we found that the reconstitution times varied significantly for the same-lot product, which were markedly affected by the swirling motion and the process of powder wetting and aggregation. Ex- tensive powder clumping due to aggregation at the bottom and sides of the vial increased both the length and variability in the reconstitution times (Fig. 1). To reduce both intra- and interbatch reconstitution variation, our final SOP included specifications to define swirling and tapping motions, which was consistent with a common approach used by compounding pharmacists. There- fore, tapping of the drug powder was tested and standardized in our SOP. To further reduce interoperator variability, a single in- vestigator (J. Troung) performed all of the reconstitution proce- dures after the SOP was defined. The controlled tests included the reconstitution of 30 vials per manufacturer based on the finalized SOP, as follows. The se- quence for the reconstitution of all 120 vials of products was ran- domized. To begin reconstitution, each vial was tapped three times by hand to loosen the dry powder. According to the routine practice, 15 ml of SWFI was injected rapidly at a 45° angle into the product vial while the vial was rotated circularly to distribute the SWFI and evenly wet the solid. The timer was started as soon as all SWFI was injected. Swirling was performed by hand in a circular motion at a rate of approximately 60 to 120 rpm. The operator swirled the vial for 10 s and then stopped to observe the vial for 5 s. If powder clumps were attached to the vial wall, the operator Received 15 October 2014 Returned for modification 6 November 2014 Accepted 7 December 2014 Published ahead of print 15 December 2014 Address correspondence to HaiAn Zheng, haian.zheng@acphs.edu, or Manjunath P. Pai, amit.pai@acphs.edu. Citation Zheng H, Truong J, Carroll F, Pai MP. 2015. Do formulation differences between the reference listed drug and generic piperacillin-tazobactam impact reconstitution? Antimicrob Agents Chemother 59:1767–1769. doi:10.1128/AAC.04563-14. Copyright © 2015, American Society for Microbiology. All Rights Reserved. doi:10.1128/AAC.04563-14 March 2015 Volume 59 Number 3 aac.asm.org 1767 Antimicrobial Agents and Chemotherapy on June 9, 2020 by guest http://aac.asm.org/ Downloaded from