title: Root Cause Analysis of Tungsten-Induced Protein Aggregation in Pre-filled Syringes.
abstract: Particles isolated from a pre-filled syringe containing a protein-based solution were identified as aggregated protein and tungsten. The origin of the tungsten was traced to the tungsten pins used in the supplier's syringe barrel forming process. A tungsten recovery study showed that the vacuum stopper placement process has a significant impact on the total amount of tungsten in solutions. The air gap formed in the syringe funnel area (rich in residual tungsten) becomes accessible to solutions when the vacuum is pulled. Leachable tungsten deposits that were not removed by the supplier's wash process are concentrated in this small area. Extraction procedures used to measure residual tungsten in empty syringes would under-report the tungsten quantity unless the funnel area is wetted during the extraction. Improved syringe barrel forming and washing processes at the supplier have lowered the residual tungsten content and significantly reduced the risk of protein aggregate formation. This experience demonstrates that packaging component manufacturing processes, which are outside the direct control of drug manufacturers, can have an impact on the drug product quality. Thus close technical communication with suppliers of product contact components plays an important role in making a successful biotherapeutic.
authors.affiliation: Drug Product and Device Development, Amgen Inc., Thousand Oaks, CA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Rob
authors.initials: R
authors.lastname: Swift
authors.forename: Gianni
authors.initials: G
authors.lastname: Torraca
authors.forename: Yasser
authors.initials: Y
authors.lastname: Nashed-Samuel
authors.forename: Zai-Qing
authors.initials: ZQ
authors.lastname: Wen
authors.forename: Yijia
authors.initials: Y
authors.lastname: Jiang
authors.forename: Aylin
authors.initials: A
authors.lastname: Vance
authors.forename: Anthony
authors.initials: A
authors.lastname: Mire-Sluis
authors.forename: Erwin
authors.initials: E
authors.lastname: Freund
authors.forename: Janice
authors.initials: J
authors.lastname: Davis
authors.forename: Linda
authors.initials: L
authors.lastname: Narhi
mesh_terms: D006801:Humans; D019999:Pharmaceutical Solutions; D019064:Product Packaging; D011506:Proteins; D060891:Root Cause Analysis; D012996:Solutions; D013594:Syringes; D014414:Tungsten; D014618:Vacuum
chemical_list: D019999:Pharmaceutical Solutions; D011506:Proteins; D012996:Solutions; D014414:Tungsten