title: The regulatory framework for preventing cross-contamination of pharmaceutical products: History and considerations for the future.
abstract: Cross-contamination in multi-product pharmaceutical manufacturing facilities can impact both product safety and quality. This issue has been recognized by regulators and industry for some time, leading to publication of a number of continually evolving guidelines. This manuscript provides a historical overview of the regulatory framework for managing cross-contamination in multi-product facilities to provide context for current approaches. Early guidelines focused on the types of pharmaceuticals for which dedicated facilities and control systems were needed, and stated the requirements for cleaning validation. More recent guidelines have promoted the idea of using Acceptable Daily Exposures (ADEs) to establish cleaning limits for actives and other potentially hazardous substances. The ADE approach is considered superior to previous methods for setting cleaning limits such as using a predetermined general limit (e.g., 10 ppm or a fraction of the median lethal dose (LD50) or therapeutic dose). The ADEs can be used to drive the cleaning process and as part of the overall assessment of whether dedicated production facilities are required. While great strides have been made in using the ADE approach, work remains to update good manufacturing practices (GMPs) to ensure that the approaches are clear, consistent with the state-of-the-science, and broadly applicable yet flexible enough for adaptation to unique products and situations.
authors.affiliation: Rutgers University, United States. Electronic address: evsargent@gmail.com.
authors.forename: Edward V
authors.initials: EV
authors.lastname: Sargent
authors.affiliation: F. Hoffmann-La Roche Ltd, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Flueckiger
authors.affiliation: Novartis, Switzerland.
authors.forename: Ester Lovsin
authors.initials: EL
authors.lastname: Barle
authors.affiliation: Bristol-Myers Squibb, United States.
authors.forename: Wendy
authors.initials: W
authors.lastname: Luo
authors.affiliation: Mylan, United States.
authors.forename: Lance R
authors.initials: LR
authors.lastname: Molnar
authors.affiliation: SafeDose, Ltd, United States.
authors.forename: Reena
authors.initials: R
authors.lastname: Sandhu
authors.affiliation: Genentech, Inc., United States.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Weideman
mesh_terms: D000818:Animals; D004059:Diffusion of Innovation; D004340:Drug Contamination / Q000331:legislation & jurisprudence / Q000517:prevention & control*; D004345:Drug Industry / Q000266:history / Q000331:legislation & jurisprudence / Q000592:standards / Q000639:trends; D005544:Forecasting; D017408:Guidelines as Topic; D006291:Health Policy; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D019055:No-Observed-Adverse-Effect Level; D016273:Occupational Exposure / Q000009:adverse effects / Q000331:legislation & jurisprudence / Q000517:prevention & control* / Q000592:standards; D016272:Occupational Health / Q000266:history / Q000331:legislation & jurisprudence / Q000592:standards / Q000639:trends; D004364:Pharmaceutical Preparations / Q000032:analysis* / Q000145:classification / Q000592:standards; D011050:Policy Making; D011786:Quality Control; D018570:Risk Assessment; D018675:Toxicity Tests
chemical_list: D004364:Pharmaceutical Preparations
keywords: Acceptable daily exposure; Cleaning validation; Cross-contamination; GMP; Maximum allowable carryover; Maximum safe carryover; Permitted daily exposure; Pharmaceutical manufacturing; Risk assessment