title: Control Strategies for Drug Product Continuous Direct Compression-State of Control, Product Collection Strategies, and Startup/Shutdown Operations for the Production of Clinical Trial Materials and Commercial Products.
abstract: Continuous manufacturing (CM) has emerged in the pharmaceutical industry as a paradigm shift with significant advantages related to cost, efficiency, flexibility, and higher assurance of quality. The inherent differences from batch processes justify examining the CM control strategy more holistically. This article describes the current thinking for the control and implementation of CM, using the example of a direct compression process and taking into consideration the ICH Q10 definition of "state of control" and process validation requirements. Statistical process control using control charts, sources of variation, process capability, and process performance is explained as a useful concept that can help assess the impact of variation within a batch and indicates if a process is in state of control. The potential for time-variant nature of startup and shutdown with CM is discussed to assure product quality while minimizing waste as well as different options for detection and isolation of non-conforming materials due to process upsets. While different levels of control are possible with CM, an appropriate balance between process control and end product testing is needed depending on the level of process understanding at the different stages of development from the production of clinical supplies through commercialization.
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana 46221. Electronic address: Almaya_ahmad@lilly.com.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Almaya
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Lawrence
authors.initials: L
authors.lastname: De Belder
authors.affiliation: Merck, Kenilworth, New York 07033.
authors.forename: Robert
authors.initials: R
authors.lastname: Meyer
authors.affiliation: Genentech, San Francisco, California 94080.
authors.forename: Karthik
authors.initials: K
authors.lastname: Nagapudi
authors.affiliation: Amgen, Thousand Oaks, California 91320.
authors.forename: Hung-Ren Homer
authors.initials: HH
authors.lastname: Lin
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana 46221.
authors.forename: Ian
authors.initials: I
authors.lastname: Leavesley
authors.affiliation: AbbVie, North Chicago, Illinois 60064.
authors.forename: Jayanthy
authors.initials: J
authors.lastname: Jayanth
authors.affiliation: Glaxo Smith Kline, Brentford, UK.
authors.forename: Gurjit
authors.initials: G
authors.lastname: Bajwa
authors.affiliation: Merck, Kenilworth, New York 07033.
authors.forename: James
authors.initials: J
authors.lastname: DiNunzio
authors.affiliation: Bristol-Myers Squibb, New York City, New York 10154.
authors.forename: Anthony
authors.initials: A
authors.lastname: Tantuccio
authors.affiliation: Pfizer, New York City, New York 10017.
authors.forename: Dan
authors.initials: D
authors.lastname: Blackwood
authors.affiliation: Bristol-Myers Squibb, New York City, New York 10154.
authors.forename: Admassu
authors.initials: A
authors.lastname: Abebe
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods / Q000592:standards*; D002986:Clinical Trials as Topic / Q000379:methods / Q000592:standards*; D003132:Commerce / Q000379:methods / Q000592:standards*; D004345:Drug Industry / Q000379:methods / Q000592:standards*; D006801:Humans; D011786:Quality Control
keywords: continuous manufacturing; control strategy; direct compression; process capability; state of control; statistical process control