{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T08:11:02Z","timestamp":1791015062229,"version":"4.1.0"},"reference-count":107,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T00:00:00Z","timestamp":1705017600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Biotech &amp; Bioengineering"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>A demand for process intensification in biomanufacturing has increased over the past decade due to the ever\u2010expanding market for biopharmaceuticals. This is largely driven by factors such as a surge in biosimilars as patents expire, an aging population, and a rise in chronic diseases. With these market demands, pressure upon biomanufacturers to produce quality products with rapid turnaround escalates proportionally. Process intensification in biomanufacturing has been well received and accepted across industry based on the demonstration of its benefits of improved productivity and efficiency, while also reducing the cost of goods. However, while these benefits have been shown empirically, the challenges of adopting process intensification into industry remain, from smaller independent start\u2010up to big pharma. Traditionally, moving from batch to a process intensification scheme has been viewed as an \u201call or nothing\u201d approach involving continuous bioprocessing, in which the factors of complexity and significant capital costs hinder its adoption. In addition, the literature is crowded with a variety of terms used to describe process intensification (continuous, periodic counter\u2010current, connected, intensified, steady\u2010state, etc.). Often, these terms are used inappropriately or as synonyms, which generates confusion in the field. Through a detailed review of current state\u2010of\u2010the\u2010art systems, consumables, and process intensification case studies, we herein propose a defined approach in the implementation of downstream process intensification through a standardized nomenclature and viewing it as distinct independent levels. These can function separately as intensified single\u2010unit operations or be built upon by integration with other process steps allowing for simple, incremental, cost\u2010effective implementation of process intensification in the manufacturing of biopharmaceuticals.<\/jats:p>","DOI":"10.1002\/bit.28641","type":"journal-article","created":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T04:25:04Z","timestamp":1705033504000},"page":"877-893","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Reviewing the process intensification landscape through the introduction of a novel, multitiered classification for downstream processing"],"prefix":"10.1002","volume":"121","author":[{"given":"Louis","family":"Crowley","sequence":"first","affiliation":[{"name":"Sartorius Stedim North America Inc Bohemia New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Cashen","sequence":"additional","affiliation":[{"name":"Sartorius Stedim Biotech GmbH Goettingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Noverraz","sequence":"additional","affiliation":[{"name":"Sartorius Stedim Biotech GmbH Goettingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Lobedann","sequence":"additional","affiliation":[{"name":"Sartorius Stedim Biotech GmbH Goettingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3186-5149","authenticated-orcid":false,"given":"Piergiuseppe","family":"Nestola","sequence":"additional","affiliation":[{"name":"Sartorius Stedim Biotech GmbH Goettingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,12]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.18609\/cgti.2020.138"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acssuschemeng.1c01435"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chroma.2015.02.046"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/biot.201800061"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2019.07.016"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jctb.6686"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/biot.201500481"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.24252"},{"key":"e_1_2_8_10_1","unstructured":"BiosanaPharma(2021). BiosanaPharma announces successful phase I of omalizumab biosimilar. [Press Release].https:\/\/www.biosanapharma.com\/news\/Press-releases\/4"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/membranes9120159"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.27733"},{"key":"e_1_2_8_13_1","unstructured":"Busse R. A. Grunenberg M. Kuchemueller K. B. Toeppner K. Adametz P. &Thom V.(2022). Sartobind\u00ae Rapid A: Comparable high product quality as protein a resins at high productivity.Sartorius Stedim Biotech GmbH.https:\/\/www.sartorius.com\/download\/1289864\/sartobind-rapid-a-comparability-to-resin-application-note-en-1--data.pdf"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/9783527699902.ch2"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chroma.2021.462604"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/biot.202100351"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/9783527699902.ch15"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.27690"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.27670"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.25529"},{"key":"e_1_2_8_21_1","unstructured":"Cytiva. (2020).Data sheet CY7145\u201008Apr20\u2010DF \u201cHiTrap\u2122 Fibro PrismA and HiScreen\u2122 Fibro PrismA units.\u201d"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.27267"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.28234"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/btpr.3378"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1089\/gen.35.14.05"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/btpr.2862"},{"key":"e_1_2_8_27_1","unstructured":"Enright M.(2020). Amgen's new $200M next\u2010gen biologic plant a first in U.S.Providence Business News.https:\/\/pbn.com\/amgens-new-200m-next-gen-biologic-plant-a-first-in-u-s\/"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.27688"},{"key":"e_1_2_8_29_1","unstructured":"European Medicines Agency. (2007).Guideline on comparability of biotechnology \u2010derived medicinal products after a change in the manufacturing process.Non\u2010clinical and clinical issues.https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/guideline-comparability-biotechnology-derived-medicinal-products-after-change-manufacturing-process_en.pdf"},{"key":"e_1_2_8_30_1","unstructured":"European Medicines Agency. (2022).ICH Guideline Q5A(R2) on viral safety evaluation of biotechnology products derived from cell lines of human or animal origin \u2010 Scientific guideline.https:\/\/www.ema.europa.eu\/en\/ich-guideline-q5ar2-viral-safety-evaluation-biotechnology-products-derived-cell-lines-human-animal"},{"key":"e_1_2_8_31_1","unstructured":"Federal Food and Drug Administration. (2018).Postapproval changes to drug substances guidance for industry.https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/postapproval-changes-drug-substances-guidance-industry"},{"key":"e_1_2_8_32_1","unstructured":"Federal Food and Drug Administration. (2023):ICH Q13 guidelines for the continuous manufacturing of drug substances and drug products \u2013 Guidance for industry.https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/q13-continuous-manufacturing-drug-substances-and-drug-products#:~:text=and%20Drug%20Products- Q13%20Continuous%20Manufacturing%20of%20Drug%20Substances%20and Guidance%20for%20Industry%20March%202023&text=This%20guidance%20describes%20scientific%20and of%20continuous%20manufacturing%20(CM)"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.27232"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibtech.2018.08.008"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/biot.201700718"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/9783527673681.ch04"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2021.02.010"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiotec.2015.04.026"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiotec.2016.12.005"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiotec.2015.06.393"},{"key":"e_1_2_8_41_1","unstructured":"Gore. (2022).Data sheet: GORE\u00ae protein capture devices.https:\/\/www.gore.com\/resources\/data-sheet-gore-protein-capture-devices-DD?from=%5B%22industries%3A671%22%2C%22industries%3A711%22%2C%22industries%3A716%22%2C%22industries%3A671%22%2C%22industries%3A711%22%2C%22industries%3A716%22%5D"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiotec.2015.08.015"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/btpr.3108"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/biot.202100219"},{"issue":"6","key":"e_1_2_8_45_1","first-page":"26","article-title":"Scale\u2010up of complex biologics","volume":"29","author":"Hernandez R.","year":"2016","journal-title":"BioPharm International"},{"issue":"16","key":"e_1_2_8_46_1","article-title":"Supplement: Integrated continuous manufacturing of biologics","volume":"37","author":"Hernandez R.","year":"2017","journal-title":"Genetic Engineering & Biotechnology News"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/biot.201700665"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2019.05.009"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibtech.2013.05.011"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.copbio.2017.12.015"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/biot.202000524"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines9010003"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ces.2015.10.029"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cep.2016.01.002"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiotec.2015.06.388"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.24268"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.3390\/pr8121641"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2022.09.008"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcyt.2020.03.389"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chroma.2020.461855"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trac.2020.116051"},{"issue":"4","key":"e_1_2_8_62_1","first-page":"1","article-title":"Monoliths in the mRNA vaccine purification process\u2010The silica resin and other composite materials: The carbon content","volume":"11","author":"Luisetto M.","year":"2022","journal-title":"Virology and Mycology"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.28402"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seppur.2022.120949"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.27774"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.27292"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics14071346"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2022.1020174"},{"key":"e_1_2_8_69_1","unstructured":"Modor Intelligence. (2023):Biopharmaceutical industry size & share analysis \u2010 Growth trends & forecasts(2023\u20132028).https:\/\/www.mordorintelligence.com\/industry-reports\/global-biopharmaceuticals-market-industry."},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.28531"},{"issue":"9","key":"e_1_2_8_71_1","first-page":"12","article-title":"Monoclonal antibody manufacturing: Cost benefits of hybrid disposable systems","volume":"9","author":"Monge M.","year":"2011","journal-title":"Bioprocess International"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.1002\/9781119126942.ch20"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cep.2021.108727"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2017.06.015"},{"key":"e_1_2_8_75_1","unstructured":"National Institute for Innovation in Manufacturing Biopharmaceuticals. (2022).N\u2010mAb: A case study to support development and adoption of integrated continuous bioprocesses for monoclonal antibodies. Version 1."},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chroma.2023.463784"},{"key":"e_1_2_8_77_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biotechadv.2013.12.001"},{"key":"e_1_2_8_78_1","unstructured":"Pollard D. Brower M. Abe Y. Lopes A. &Sinclair A.(2016). Standardized economic cost modeling for next\u2010generation mAb production.Bioprocess International."},{"issue":"1","key":"e_1_2_8_79_1","first-page":"26","article-title":"EASY: A disruptive mAb purification process to reduce cost of goods","volume":"34","author":"Prouzeau T.","year":"2021","journal-title":"BioPharm International"},{"key":"e_1_2_8_80_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.28384"},{"key":"e_1_2_8_81_1","doi-asserted-by":"publisher","DOI":"10.1002\/jssc.201800963"},{"key":"e_1_2_8_82_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.28235"},{"key":"e_1_2_8_83_1","doi-asserted-by":"publisher","DOI":"10.1021\/ie2006752"},{"key":"e_1_2_8_84_1","volume-title":"Report and survey of biopharmaceutical manufacturing capacity and production CDC. A study of biotherapeutic developers and contract manufacturing organizations","author":"Schmidt S. R.","year":"2023"},{"key":"e_1_2_8_85_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.27689"},{"key":"e_1_2_8_86_1","unstructured":"Siemens. (2015). Continuous manufacturing \u2013 Moving towards real\u2010time release (VRPH\u2010B10001\u201000\u20107600).https:\/\/assets.new.siemens.com\/siemens\/assets\/api\/uuid:b482e362a8e3b074acde17f469f4a045a7e40947\/continuous-manufacturing-moving-towards-real-time-release.pdf"},{"key":"e_1_2_8_87_1","unstructured":"Singh R. Boukouvala F. Jayjock E. Ramachandran R. Lerapetritou M. &Muzzio F. (2012). Flexible multipurpose continuous processing of pharmaceutical tablet manufacturing process.GMP News European Compliance Academic (ECE)."},{"key":"e_1_2_8_88_1","doi-asserted-by":"publisher","DOI":"10.1002\/cite.202200133"},{"key":"e_1_2_8_89_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2020.00758"},{"key":"e_1_2_8_90_1","unstructured":"Tosoh. (2018).Protein A chromatography \u2013 The process economics driver in mAb manufacturing.Application Note No. A15P28A (A15P28A)."},{"key":"e_1_2_8_91_1","unstructured":"U.S. Department of Transportation. (2018).Preparing for the future of transportation: Automated vehicles3."},{"key":"e_1_2_8_92_1","unstructured":"U.S. Food and Drug Administration. (1996). Guidance for industry for the submission of chemistry manufacturing and controls information for a therapeutic recombinant DNA\u2010derived product or a monoclonal antibody product for in vivo use.https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/guidance-industry-submission-chemistry-manufacturing-and-controls-information-therapeutic"},{"key":"e_1_2_8_93_1","unstructured":"U.S. Food and Drug Administration. (2001). Guidance for industry Q7A good manufacturing practice guidance for active pharmaceutical ingredients.https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/guidance-industry-q7a-good-manufacturing-practice-guidance-active-pharmaceutical-ingredients"},{"key":"e_1_2_8_94_1","unstructured":"U.S. Food and Drug Administration. (2020). Chemistry manufacturing and control (CMC) information for human gene therapy investigational new drug applications (INDs)."},{"key":"e_1_2_8_95_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2020.119194"},{"key":"e_1_2_8_96_1","doi-asserted-by":"publisher","DOI":"10.3390\/pr10091868"},{"key":"e_1_2_8_97_1","unstructured":"Vuksanaj K.(2019).First MAB produced via fully continuous biomanufacturing.Edited by GEN \u2010 Genetic Engineering and Biotechnology News.https:\/\/www.genengnews.com\/news\/first-mab-produced-via-fully-continuous-biomanufacturing\/"},{"key":"e_1_2_8_98_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiotec.2015.05.010"},{"key":"e_1_2_8_99_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2019.09.006"},{"key":"e_1_2_8_100_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.24584"},{"key":"e_1_2_8_101_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2021.08.009"},{"key":"e_1_2_8_102_1","doi-asserted-by":"publisher","DOI":"10.1002\/9783527827343.ch4"},{"key":"e_1_2_8_103_1","doi-asserted-by":"publisher","DOI":"10.18609\/cgti.2020.053"},{"key":"e_1_2_8_104_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiotec.2015.04.020"},{"key":"e_1_2_8_105_1","doi-asserted-by":"publisher","DOI":"10.3389\/fninf.2022.907942"},{"key":"e_1_2_8_106_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2017.07.002"},{"key":"e_1_2_8_107_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.iecr.8b04717"},{"key":"e_1_2_8_108_1","doi-asserted-by":"publisher","DOI":"10.18609\/cgti.2022.192"}],"container-title":["Biotechnology and Bioengineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bit.28641","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T22:43:48Z","timestamp":1760049828000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/bit.28641"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,12]]},"references-count":107,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2024,3]]}},"alternative-id":["10.1002\/bit.28641"],"URL":"https:\/\/doi.org\/10.1002\/bit.28641","archive":["Portico"],"relation":{},"ISSN":["0006-3592","1097-0290"],"issn-type":[{"value":"0006-3592","type":"print"},{"value":"1097-0290","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,12]]},"assertion":[{"value":"2023-08-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-01-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}