title: Application of quality by design principles to the development and technology transfer of a major process improvement for the manufacture of a recombinant protein.
abstract: This study describes the application of quality by design (QbD) principles to the development and implementation of a major manufacturing process improvement for a commercially distributed therapeutic protein produced in Chinese hamster ovary cell culture. The intent of this article is to focus on QbD concepts, and provide guidance and understanding on how the various components combine together to deliver a robust process in keeping with the principles of QbD. A fed-batch production culture and a virus inactivation step are described as representative examples of upstream and downstream unit operations that were characterized. A systematic approach incorporating QbD principles was applied to both unit operations, involving risk assessment of potential process failure points, small-scale model qualification, design and execution of experiments, definition of operating parameter ranges and process validation acceptance criteria followed by manufacturing-scale implementation and process validation. Statistical experimental designs were applied to the execution of process characterization studies evaluating the impact of operating parameters on product quality attributes and process performance parameters. Data from process characterization experiments were used to define the proven acceptable range and classification of operating parameters for each unit operation. Analysis of variance and Monte Carlo simulation methods were used to assess the appropriateness of process design spaces. Successful implementation and validation of the process in the manufacturing facility and the subsequent manufacture of hundreds of batches of this therapeutic protein verifies the approaches taken as a suitable model for the development, scale-up and operation of any biopharmaceutical manufacturing process.
authors.affiliation: Pfizer Ireland Pharmaceuticals, Grange Castle International Business Park, Dublin 22, Ireland. mairead.looby@pfizer.com
authors.forename: Mairead
authors.initials: M
authors.lastname: Looby
authors.forename: Neysi
authors.initials: N
authors.lastname: Ibarra
authors.forename: James J
authors.initials: JJ
authors.lastname: Pierce
authors.forename: Kevin
authors.initials: K
authors.lastname: Buckley
authors.forename: Eimear
authors.initials: E
authors.lastname: O'Donovan
authors.forename: Mary
authors.initials: M
authors.lastname: Heenan
authors.forename: Enda
authors.initials: E
authors.lastname: Moran
authors.forename: Suzanne S
authors.initials: SS
authors.lastname: Farid
authors.forename: Frank
authors.initials: F
authors.lastname: Baganz
mesh_terms: D000818:Animals; D061249:Batch Cell Culture Techniques / Q000379:methods* / Q000592:standards; D001709:Biotechnology / Q000379:methods* / Q000592:standards; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011786:Quality Control; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D018581:Technology Transfer
chemical_list: D004364:Pharmaceutical Preparations; D011994:Recombinant Proteins