Pharmaceutical Biotechnology Syringe Filling of a High-Concentration mAb Formulation: Experimental, Theoretical, and Computational Evaluation of Filling Process Parameters That Influence the Propensity for Filling Needle Clogging Simon Hanslip 1 , Kashappa Goud Desai 2, * , Mark Palmer 3 , Ian Kemp 3 , Stephen Bell 1 , Paul Schofield 1 , Prashant Varma 4 , Frank Roche 1 , James D. Colandene 2 , Douglas P. Nesta 2 1 New Product Introduction, Global Manufacturing and Supply, GlaxoSmithKline, Harmire Road, Barnard Castle DL12 8DT, UK 2 Biopharmaceutical Product Sciences, GlaxoSmithKline, 1250 S Collegeville Road, Collegeville, Pennsylvania 19425 3 Product and Process Engineering, GlaxoSmithKline, Park Road, Ware SG12 0DP, UK 4 Downstream Process Development, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406 article info Article history: Received 19 July 2018 Revised 28 September 2018 Accepted 18 October 2018 Keywords: high-concentration mAb formulation syringe filling product drying meniscus instability needle clogging needle priming process capability (P pk ) abstract This article summarizes experimental, theoretical, and computational assessments performed to un- derstand the effect of filling and suck-back cycle factors on fluid behaviors that increase the propensity for filling needle clogging. Product drying under ambient conditions decreased considerably when the liquid front was altered from a droplet or meniscus at the needle tip to a point approximately 5 mm inside the needle. Minimizing the variation in size of product droplet formed after the fill cycle is critical to achieve a uniform meniscus height after the suck-back cycle. Several factors were found to contribute to droplet size variability, including filling and suck-back pump speed, suck-back volume, and product temperature. Filling trials and the computational fluid dynamics simulations showed that product meniscus stability during the suck-back cycle can be improved by reducing the suck-back flow rate. The computational fluid dynamics simulations also showed that a decrease in contact angle had the greatest effect in reducing meniscus stability. As the number of filling line stoppages increases, the product buildup at the needle increases. The interaction between stoppages and the number of dispenses be- tween stoppages was established to minimize product buildup at the filling needle. Improved suck-back control was shown to improve process capability of large-scale batches. © 2018 Published by Elsevier Inc. on behalf of the American Pharmacists Association. Introduction Syringe filling of high-concentration mAb products is often performed with peristaltic pumps and single-use presterilized filling assemblies (consisting of flexible tubing configurations for liquid flow from the pumps to the filling needles). 1 Peristaltic liquid filling mechanisms involve positive displacement, wherein the liquid is contained within a flexible tube that is fitted inside a cir- cular (rotary) pump casing (between a rotor and a stationary sur- face). 2,3 A rotor with several rollers attached to the external circumference compresses the flexible tube. As the rotor turns in a clockwise direction, the part of the tube under compression closes thus forcing the liquid to be pumped to move through the tube. 2,3 The syringe filling process involves multiple steps that include sy- ringe nest and filling needle alignment, insertion of filling needle into the syringe, product filling/fill cycle (peristaltic pumps com- plete the required number of rotations to dispense the selected volume of the product into the syringes), and suck-back/pump reversal. 1 After the fill cycle, the fluid stream detaches from the needle tip and a drop of the product remains hanging from the needle tip. During the suck-back cycle, a specific volume of product is The authors Simon Hanslip, Kashappa Goud Desai, Mark Palmer, and Ian Kemp contributed equally. This article contains supplementary material available from the authors by request or via the Internet at https://doi.org/10.1016/j.xphs.2018.10.031. * Correspondence to: Kashappa Goud Desai (Telephone: þ1-610-917-4799). E-mail addresses: kashappa-goud.x.desai@gsk.com, kghdesai@yahoo.com (K.G. Desai). Contents lists available at ScienceDirect Journal of Pharmaceutical Sciences journal homepage: www.jpharmsci.org https://doi.org/10.1016/j.xphs.2018.10.031 0022-3549/© 2018 Published by Elsevier Inc. on behalf of the American Pharmacists Association. Journal of Pharmaceutical Sciences xxx (2018) 1-9