Manufacturing classification system in the real world: factors influencing manufacturing process choices for filed commercial oral solid dosage formulations, case studies from industry and considerations for continuous processing

Johannes Khinast, Michael Leane, Kendal Pitt, Gavin K. Reynolds, Neil Dawson, Iris Ziegler, Aniko Szepes, Abina M. Crean, Rafaela Dall Agnol, Bianca Broegmann, Stuart Charlton, Conrad Davies, John Gamble, Michael Gamlen, Wen Kai Hsiao, Yaroslav Khimyak, Peter Kleinebudde, Chris Moreton, Mira Oswald, Susanne PageAmrit Paudel, Ranjita Sahoo, Stephen Sheehan, Howard Stamato, Elaine Stone

Research output: Contribution to journalReview article

Abstract

Following the first Manufacturing Classification System (MCS) paper, the team conducted surveys to establish which active pharmaceutical ingredient (API) properties were important when selecting or modifying materials to enable an efficient and robust pharmaceutical manufacturing process. The most commonly identified factors were (1) API particle size: small particle sizes are known to increase risk of processing issues; (2) Drug loading in the formulation: high drug loadings allow less opportunity to mitigate poor API properties through the use of excipients. The next step was to establish linkages with process decisions by identifying publicly-available proxies for these important parameters: dose (in place of drug loading) and BCS class (in place of particle size). Poorly-soluble API were seen as more likely to have controlled (smaller) particle size than more highly soluble API. Analysis of 435 regulatory filings revealed that higher doses and more poorly-soluble API was associated with more complex processing routes. Replacing the proxy factors with the original parameters should give the opportunity to demonstrate stronger trends. This assumption was tested by accessing a dataset relating to commercial tablet products. This showed that, for dry processes, a larger particle size was associated with higher achievable drug loading as determined by percolation threshold.
Original languageEnglish
Pages (from-to)964-977
Number of pages13
JournalPharmaceutical development and technology
DOIs
Publication statusPublished - 2018

Keywords

  • Drug product manufacturing processes
  • oral solid dosage forms
  • pharmaceutical development
  • quality by design
  • drug substance
  • continuous processing

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