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<!DOCTYPE html><html lang="en"><head><meta charSet="utf-8"/><meta name="viewport" content="width=device-width,initial-scale=1"/><meta name="robots" content="max-image-preview:large"/><title>October 2024 Featured Report: Gene Therapies</title><meta name="description" content="A BioProcess International Featured Report exploring delivery of gene therapies including viral vector development"/><meta property="og:title" content="October 2024 Featured Report: Gene Therapies"/><meta property="og:description" content="A BioProcess International Featured Report exploring delivery of gene therapies including viral vector development"/><meta property="og:url" content="https://www.bioprocessintl.com/publications/featured-reports/october-2024-featured-report"/><meta property="og:type" content="article"/><meta property="og:image" content="https://www.bioprocessintl.com/build/_assets/bioprocessinternational-XJK2Q5PK.ico"/><link rel="canonical" href="https://www.bioprocessintl.com/publications/featured-reports/october-2024-featured-report"/><script type="application/ld+json">{"@context":"https://schema.org","@type":"BreadcrumbList","itemListElement":[{"@type":"ListItem","position":1,"name":"Home","item":"https://www.bioprocessintl.com"},{"@type":"ListItem","position":2,"name":"publications","item":"https://www.bioprocessintl.com/publications"},{"@type":"ListItem","position":3,"name":"Featured Reports","item":"https://www.bioprocessintl.com/publications/featured-reports"},{"@type":"ListItem","position":4,"name":"October 2024 Featured Report","item":"https://www.bioprocessintl.com/publications/featured-reports/october-2024-featured-report"}]}</script><link rel="preload" href="https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/blta7432b2a648c1f83/672a6eaef3d12eef430f8d1f/22-10-FR-Cover_wide.jpg?width=1280&auto=webp&quality=10&format=jpg&disable=upscale&blur=40" as="image"/><meta property="twitter:card" content="summary"/><script type="text/javascript">window.NREUM||(NREUM={});NREUM.init={distributed_tracing:{enabled:true},privacy:{cookies_enabled:true},ajax:{deny_list:["bam.eu01.nr-data.net"]}}; ;NREUM.loader_config={accountID:"3936348",trustKey:"3288925",agentID:"538600195",licenseKey:"NRJS-26ae6a3b09493bbcc87",applicationID:"538600195"}; ;NREUM.info={beacon:"bam.eu01.nr-data.net",errorBeacon:"bam.eu01.nr-data.net",licenseKey:"NRJS-26ae6a3b09493bbcc87",applicationID:"538600195",sa:1}; ;/*! 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data-testid="by-text">by</span><a class="Contributors-ContributorName" data-testid="contributor-name" data-discover="true" href="/author/dan-stanton">Dan Stanton</a></div></div></div><div class="VerticalCard-Footer"><span class="VerticalCard-Date" data-testid="vertical-card-date">Nov 21, 2024</span><div data-module="card-time" class="CardTime"><div data-component="article-read-time" class="ArticleReadTime ArticleReadTime_size_small CardTime-ReadTime"><span>3 Min Read</span></div></div></div></div></div></div></div></div></div></div></div></div></div></div><div class="MainMenu-SearchButtonWrapper"><button data-testid="mainMenu-SearchButton" aria-label="Open Search" class="MainMenu-SearchButton"><span data-component="icon" data-name="Search" class="MainMenu-SearchButtonIcon" 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class="TwoColumnLayout-Content"><div class="TwoColumnLayout-Body"><div class="PublicationWithEntries-Body"><div class="ContentPreview PublicationWithEntries-ContentItem PublicationWithEntries-ContentItem_first" data-module="content-preview" data-variant="small-has-summary"><div class="ListCardWithSummary"><div class="ListCardWithSummary-ImageAndTitleWrapper"><div class="ListCardWithSummary-ImageSection"><div class="ListCardWithSummary-ImageContainer"><div class="ListCardWithSummary-ImageAspectWrapper"><a data-discover="true" href="/gene-therapies/exploring-strategies-for-developing-robust-aav-platforms"><img data-component="image" class="ListCardWithSummary-Image" data-src="https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/blt47514fadaf97e7bc/671250f48ef5a2674e4d08e0/image_(2).jpg?width=300&auto=webp&quality=80&disable=upscale" src="https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/blt47514fadaf97e7bc/671250f48ef5a2674e4d08e0/image_(2).jpg?width=300&auto=webp&quality=80&disable=upscale" loading="lazy" alt="" title=""/></a></div></div></div><div class="ListCardWithSummary-TitleSection"><div class="ListCardWithSummary-KeywordWrapper"><a data-component="keyword" class="Keyword Keyword_variant_alternate Keyword_title_geneTherapies ListCardWithSummary-Keyword" data-discover="true" href="/therapeutic-modalities/gene-therapies">Gene Therapies</a></div><div class="ListCardWithSummary-TitleWrapper"><a class="ListCardWithSummary-Title ListCardWithSummary-Title_displayOption_default" data-testid="preview-default-title" data-discover="true" href="/gene-therapies/exploring-strategies-for-developing-robust-aav-platforms">Exploring Strategies for Developing Robust AAV Platforms</a><a class="ListCardWithSummary-Title ListCardWithSummary-Title_displayOption_mobile" data-testid="preview-mobile-title" data-discover="true" href="/gene-therapies/exploring-strategies-for-developing-robust-aav-platforms">Exploring Strategies for Developing Robust AAV Platforms </a></div></div></div><div data-testid="preview-card-summary" class="ListCardWithSummary-Summary">Gene therapies are emerging as promising treatments for previously untreatable genetic disorders, with adeno-associated viruses (AAVs) being the preferred vector for gene delivery. However, AAV-based gene therapies face challenges in production, including cost, complexity, and scalability. With the gene therapy market projected to grow significantly, drug developers are seeking platforms that streamline AAV production. Key factors include ensuring flexibility to accommodate different therapies, minimizing risks by understanding the entire process, and scaling production as projects progress. A well-designed AAV platform can enhance efficiency, quality, and regulatory compliance, ensuring safe delivery of therapies to patients.</div><div class="ListCardWithSummary-Footer"><span class="ListCardWithSummary-Date">Oct 18, 2024</span></div><div class="ListCardWithSummary-ContributorsWrapper"><div class="Contributors Contributors_variant_slimline Contributors_cardVariant_small Contributors_hasAvatar" data-component="contributors"><div class="Contributors-AvatarWrapper"><a class="Contributors-AvatarLink" aria-label="Xiaojun Liu" data-discover="true" href="/author/xiaojun-liu"><img aria-hidden="true" data-testid="contributor-avatar" data-component="image" class="Contributors-Avatar" data-src="https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/bltf573a3db8aace5de/653a7dfd8d60da0407d884d2/theme1_placeholder_avatar.png?width=100&auto=webp&quality=80&disable=upscale" src="https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/bltf573a3db8aace5de/653a7dfd8d60da0407d884d2/theme1_placeholder_avatar.png?width=100&auto=webp&quality=80&disable=upscale" loading="lazy" alt="Picture of Xiaojun Liu" title="Picture of Xiaojun Liu"/></a></div><div class="Contributors-InfoWrapper"><span class="Contributors-ByText" data-testid="by-text">by</span><a class="Contributors-ContributorName" data-testid="contributor-name" data-discover="true" href="/author/xiaojun-liu">Xiaojun Liu</a></div></div></div></div></div><div class="ContentPreview PublicationWithEntries-ContentItem" data-module="content-preview" data-variant="small-has-summary"><div class="ListCardWithSummary"><div class="ListCardWithSummary-ImageAndTitleWrapper"><div class="ListCardWithSummary-ImageSection"><div class="ListCardWithSummary-ImageContainer"><div class="ListCardWithSummary-ImageAspectWrapper"><a data-discover="true" href="/gene-therapies/the-complex-calculus-of-viral-vector-facility-design-considerations-for-commercial-gene-therapy-manufacturing"><img data-component="image" class="ListCardWithSummary-Image" data-src="https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/blta85c6836d5c63a7b/671191d7c4a37b6bb8135d52/22-10-FR-Bream-Hobmann-P1.jpg?width=300&auto=webp&quality=80&disable=upscale" src="https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/blta85c6836d5c63a7b/671191d7c4a37b6bb8135d52/22-10-FR-Bream-Hobmann-P1.jpg?width=300&auto=webp&quality=80&disable=upscale" loading="lazy" alt="Adobe Stock" title="Adobe Stock"/></a></div></div></div><div class="ListCardWithSummary-TitleSection"><div class="ListCardWithSummary-KeywordWrapper"><a data-component="keyword" class="Keyword Keyword_variant_alternate Keyword_title_geneTherapies ListCardWithSummary-Keyword" data-discover="true" href="/therapeutic-modalities/gene-therapies">Gene Therapies</a></div><div class="ListCardWithSummary-TitleWrapper"><a class="ListCardWithSummary-Title ListCardWithSummary-Title_displayOption_default" data-testid="preview-default-title" data-discover="true" href="/gene-therapies/the-complex-calculus-of-viral-vector-facility-design-considerations-for-commercial-gene-therapy-manufacturing">The Complex Calculus of Viral-Vector Facility Design: Considerations for Commercial Gene-Therapy Manufacturing</a><a class="ListCardWithSummary-Title ListCardWithSummary-Title_displayOption_mobile" data-testid="preview-mobile-title" data-discover="true" href="/gene-therapies/the-complex-calculus-of-viral-vector-facility-design-considerations-for-commercial-gene-therapy-manufacturing">The Complex Calculus of Viral-Vector Facility Design: Considerations for Commercial Gene-Therapy Manufacturing</a></div></div></div><div data-testid="preview-card-summary" class="ListCardWithSummary-Summary">Guided by standardized production and purification platforms, developers of monoclonal antibodies (mAbs) and other recombinant-protein therapeutics can take a relatively straightforward path when designing and establishing facilities for commercial-scale operations. By contrast, designing gene-therapy (GT) facilities involves a more complex calculus. Multiple approaches are available for producing transgene-bearing viral vectors at commercial scales. GT developers must choose carefully, knowing that each manufacturing strategy raises distinctive advantages and limitations for process scalability, equipment implementation, storage, material and personnel flow, and ultimately, facility output. The plurality of manufacturing strategies — and the possibility of further platform advancements — requires GT companies and their facility-design teams to be forward-thinking in their planning. All the while, GT facilities must be engineered for good manufacturing practice (GMP) operations and work with viral vectors...</div><div class="ListCardWithSummary-Footer"><span class="ListCardWithSummary-Date">Oct 17, 2024</span></div><div class="ListCardWithSummary-ContributorsWrapper"><div class="Contributors Contributors_variant_slimline Contributors_cardVariant_small Contributors_hasAvatar" data-component="contributors"><div class="Contributors-AvatarWrapper"><a class="Contributors-AvatarLink Contributors-AvatarLink_isMultiple" aria-label="Brian Gazaille" data-discover="true" href="/author/brian-gazaille"><img aria-hidden="true" data-testid="contributor-avatar" data-component="image" class="Contributors-Avatar" data-src="https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/bltf573a3db8aace5de/653a7dfd8d60da0407d884d2/theme1_placeholder_avatar.png?width=100&auto=webp&quality=80&disable=upscale" src="https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/bltf573a3db8aace5de/653a7dfd8d60da0407d884d2/theme1_placeholder_avatar.png?width=100&auto=webp&quality=80&disable=upscale" loading="lazy" alt="Picture of Brian Gazaille" title="Picture of Brian Gazaille"/></a><a class="Contributors-AvatarLink Contributors-AvatarLink_isMultiple" aria-label="Allan Bream" data-discover="true" href="/author/allan-bream"><img aria-hidden="true" data-testid="contributor-avatar" data-component="image" class="Contributors-Avatar" data-src="https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/bltf573a3db8aace5de/653a7dfd8d60da0407d884d2/theme1_placeholder_avatar.png?width=100&auto=webp&quality=80&disable=upscale" src="https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/bltf573a3db8aace5de/653a7dfd8d60da0407d884d2/theme1_placeholder_avatar.png?width=100&auto=webp&quality=80&disable=upscale" loading="lazy" alt="Picture of Allan Bream" title="Picture of Allan Bream"/></a><span class="Contributors-ContributorsCount" data-testid="contributors-count"><span> +1</span></span></div><div class="Contributors-InfoWrapper"><span class="Contributors-ByText" data-testid="by-text">by</span><a class="Contributors-ContributorName Contributors-ContributorName_showComma" data-testid="contributor-name" data-discover="true" href="/author/brian-gazaille">Brian Gazaille, </a><a class="Contributors-ContributorName" data-testid="contributor-name" data-discover="true" href="/author/allan-bream">Allan Bream</a><span class="Contributors-MoreText" data-testid="more-text">and 1 more</span></div></div></div></div></div><div class="ContentPreview PublicationWithEntries-ContentItem" data-module="content-preview" data-variant="small-has-summary"><div class="ListCardWithSummary"><div class="ListCardWithSummary-ImageAndTitleWrapper"><div class="ListCardWithSummary-ImageSection"><div class="ListCardWithSummary-ImageContainer"><div class="ListCardWithSummary-ImageAspectWrapper"><a data-discover="true" href="/gene-therapies/a-scale-up-down-platform-for-fast-paced-upstream-process-development-of-raav-based-gene-therapies"><img data-component="image" class="ListCardWithSummary-Image" data-src="https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/bltaa34860800f1a153/67216d9098779fe5915ceff4/22-10-FR-Pavlistova-F1.png?width=300&auto=webp&quality=80&disable=upscale" src="https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/bltaa34860800f1a153/67216d9098779fe5915ceff4/22-10-FR-Pavlistova-F1.png?width=300&auto=webp&quality=80&disable=upscale" loading="lazy" alt="" title=""/></a></div></div></div><div class="ListCardWithSummary-TitleSection"><div class="ListCardWithSummary-KeywordWrapper"><a data-component="keyword" class="Keyword Keyword_variant_alternate Keyword_title_geneTherapies ListCardWithSummary-Keyword" data-discover="true" href="/therapeutic-modalities/gene-therapies">Gene Therapies</a></div><div class="ListCardWithSummary-TitleWrapper"><a class="ListCardWithSummary-Title ListCardWithSummary-Title_displayOption_default" data-testid="preview-default-title" data-discover="true" href="/gene-therapies/a-scale-up-down-platform-for-fast-paced-upstream-process-development-of-raav-based-gene-therapies">A Scale-Up/-Down Platform for Fast-Paced Upstream Process Development of rAAV-Based Gene Therapies</a><a class="ListCardWithSummary-Title ListCardWithSummary-Title_displayOption_mobile" data-testid="preview-mobile-title" data-discover="true" href="/gene-therapies/a-scale-up-down-platform-for-fast-paced-upstream-process-development-of-raav-based-gene-therapies">A Scale-Up/-Down Platform for Fast-Paced Upstream Process Development of rAAV-Based Gene Therapies</a></div></div></div><div data-testid="preview-card-summary" class="ListCardWithSummary-Summary">The field of bioprocess development has witnessed remarkable advancements in recent years driven by increasing demand for biopharmaceuticals, including gene-therapy products such as recombinant adenoassociated virus (rAAV) vectors. To date, global regulatory bodies have approved several rAAV-based gene therapies, and multiple clinical trials are ongoing as forecasts project significant growth over the next five to 10 years (1) . The field of rAAV production continues to be dominated by platforms using human embryonic kidney (HEK) and insect cells. For instance, uniQure’s proprietary platform is based on insect-cell production and a baculovirus expression vector system (BEVS) (2–5) . As the gene-therapy clinical pipeline expands, ensuring efficient, cost-effective, and scalable processes for viral-vector production becomes critical (1) . Central to that endeavor are scale-down models and fast-paced scale-up. Scale-down models are small-scale representations that are designed to mimic key process paramet...</div><div class="ListCardWithSummary-Footer"><span class="ListCardWithSummary-Date">Oct 17, 2024</span></div><div class="ListCardWithSummary-ContributorsWrapper"><div class="Contributors Contributors_variant_slimline Contributors_cardVariant_small Contributors_hasAvatar" data-component="contributors"><div class="Contributors-AvatarWrapper"><a class="Contributors-AvatarLink Contributors-AvatarLink_isMultiple" aria-label="Tereza Pavlištová" data-discover="true" href="/author/tereza-pavli-tov-"><img aria-hidden="true" data-testid="contributor-avatar" data-component="image" class="Contributors-Avatar" data-src="https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/bltf573a3db8aace5de/653a7dfd8d60da0407d884d2/theme1_placeholder_avatar.png?width=100&auto=webp&quality=80&disable=upscale" src="https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/bltf573a3db8aace5de/653a7dfd8d60da0407d884d2/theme1_placeholder_avatar.png?width=100&auto=webp&quality=80&disable=upscale" loading="lazy" alt="Picture of Tereza Pavlištová" title="Picture of Tereza Pavlištová"/></a><a class="Contributors-AvatarLink Contributors-AvatarLink_isMultiple" aria-label="Maria João Alves Correia" data-discover="true" href="/author/maria-jo-o-alves-correia"><img aria-hidden="true" data-testid="contributor-avatar" data-component="image" class="Contributors-Avatar" data-src="https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/bltf573a3db8aace5de/653a7dfd8d60da0407d884d2/theme1_placeholder_avatar.png?width=100&auto=webp&quality=80&disable=upscale" src="https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/bltf573a3db8aace5de/653a7dfd8d60da0407d884d2/theme1_placeholder_avatar.png?width=100&auto=webp&quality=80&disable=upscale" loading="lazy" alt="Picture of Maria João Alves Correia" title="Picture of Maria João Alves Correia"/></a><span class="Contributors-ContributorsCount" data-testid="contributors-count"><span> +5</span></span></div><div class="Contributors-InfoWrapper"><span class="Contributors-ByText" data-testid="by-text">by</span><a class="Contributors-ContributorName Contributors-ContributorName_showComma" data-testid="contributor-name" data-discover="true" href="/author/tereza-pavli-tov-">Tereza Pavlištová, </a><a class="Contributors-ContributorName" data-testid="contributor-name" data-discover="true" href="/author/maria-jo-o-alves-correia">Maria João Alves Correia</a><span class="Contributors-MoreText" data-testid="more-text">and 5 more</span></div></div></div></div></div><div class="ContentPreview PublicationWithEntries-ContentItem PublicationWithEntries-ContentItem_borderless" data-module="content-preview" data-variant="small-has-summary"><div class="ListCardWithSummary"><div class="ListCardWithSummary-ImageAndTitleWrapper"><div class="ListCardWithSummary-ImageSection"><div class="ListCardWithSummary-ImageContainer"><div class="ListCardWithSummary-ImageAspectWrapper"><a data-discover="true" href="/gene-therapies/the-delivery-dilemma-looking-beyond-viral-vectors-for-gene-therapy"><img data-component="image" class="ListCardWithSummary-Image" data-src="https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/blt6686041652618a41/671188a2abcdb71174946b0f/AdobeStock_458992830.jpg?width=300&auto=webp&quality=80&disable=upscale" src="https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/blt6686041652618a41/671188a2abcdb71174946b0f/AdobeStock_458992830.jpg?width=300&auto=webp&quality=80&disable=upscale" loading="lazy" alt="Adobe Stock" title="Adobe Stock"/></a></div></div></div><div class="ListCardWithSummary-TitleSection"><div class="ListCardWithSummary-KeywordWrapper"><a data-component="keyword" class="Keyword Keyword_variant_alternate Keyword_title_geneTherapies ListCardWithSummary-Keyword" data-discover="true" href="/therapeutic-modalities/gene-therapies">Gene Therapies</a></div><div class="ListCardWithSummary-TitleWrapper"><a class="ListCardWithSummary-Title ListCardWithSummary-Title_displayOption_default" data-testid="preview-default-title" data-discover="true" href="/gene-therapies/the-delivery-dilemma-looking-beyond-viral-vectors-for-gene-therapy">The Delivery Dilemma: Looking Beyond Viral Vectors for Gene Therapy</a><a class="ListCardWithSummary-Title ListCardWithSummary-Title_displayOption_mobile" data-testid="preview-mobile-title" data-discover="true" href="/gene-therapies/the-delivery-dilemma-looking-beyond-viral-vectors-for-gene-therapy">The Delivery Dilemma: Looking Beyond Viral Vectors for Gene Therapy</a></div></div></div><div data-testid="preview-card-summary" class="ListCardWithSummary-Summary">The term gene therapy (GT) encompasses a range of strategies for modifying or influencing genetic information either to treat or to prevent disease. GTs include both systems that work by introducing, replacing, or altering the existing genetic material within a patient’s cells — often called gene-modified cell therapy when performed ex vivo — and those that use genetic material to influence or modulate the in vivo expression of genes. Probably for mechanistic reasons, other emerging therapies such as viral oncolytics sometimes are included in GT discussions. It’s helpful to understand that categorical statements regarding many aspects of GT can be difficult because of exceptions to some stated generalities about components and desired functions. Some GTs involve genetic engineering systems as clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9). The combination provides a powerful gene-editing tool for precise and permanent modification of DNA sequences...</div><div class="ListCardWithSummary-Footer"><span class="ListCardWithSummary-Date">Oct 15, 2024</span></div><div class="ListCardWithSummary-ContributorsWrapper"><div class="Contributors Contributors_variant_slimline Contributors_cardVariant_small Contributors_hasAvatar" data-component="contributors"><div class="Contributors-AvatarWrapper"><a class="Contributors-AvatarLink" aria-label="William Whitford" data-discover="true" href="/author/william-whitford"><img aria-hidden="true" data-testid="contributor-avatar" data-component="image" class="Contributors-Avatar" data-src="https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/bltf573a3db8aace5de/653a7dfd8d60da0407d884d2/theme1_placeholder_avatar.png?width=100&auto=webp&quality=80&disable=upscale" 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alt="" title=""/></a><a class="ContentSpotlight-IconWrapper" title="Link to all podcast" data-testid="content-spotlight-icon-link" data-discover="true" href="/podcasts"><span data-component="icon" data-name="Microphone" class="ContentSpotlight-Icon" style="mask-image:url(/build/_assets/Microphone-W4D26BPI.svg);-webkit-mask-image:url(/build/_assets/Microphone-W4D26BPI.svg);mask-repeat:no-repeat;-webkit-mask-repeat:no-repeat;-webkit-mask-position:center;-webkit-mask-size:contain"></span></a></div><div class="ContentSpotlight-ContentContainer ContentSpotlight-ContentContainer_textAlignment_center ContentSpotlight-ContentContainer_isSidebar" data-testid="content-spotlight-content-container"><p class="ContentSpotlight-ContentSummary" data-testid="content-spotlight-summary">Voices of Biotech</p><a data-discover="true" href="/bpi-podcasts/podcast-sustainability-is-about-health-equity-says-scaleready-and-germfree"><h2 class="ContentSpotlight-ContentHeading" data-testid="content-spotlight-heading">Podcast: Sustainability is about health equity, says ScaleReady and Germfree</h2></a><div class="ContentSpotlight-ContentBodyWrapper ContentSpotlight-ContentBodyWrapper_isSidebar"><p class="ContentSpotlight-ContentBody" data-testid="content-spotlight-body">ScaleReady and Germfree discuss the need to rethink sustainability and move towards a more standardized and simplistic manufacturing model to ensure health equity can be achieved.</p></div><div class="ContentSpotlight-ButtonContainer"><a data-testid="content-spotlight-button-link" data-discover="true" href="/bpi-podcasts/podcast-sustainability-is-about-health-equity-says-scaleready-and-germfree"><button data-component="button" data-testid="button_button" class="Button Button_size_medium Button_variant_darkOutlined" type="button"><span class="Button-ContentWrapper">Listen Now</span></button></a></div></div></article></div></div><div class="Sidebar-SidebarItem" data-testid="sidebar-item"><div 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These include the shortage of talent in the space, the element of many players still “figuring it out” as sustainability is not an individual issue but a collective one, and the issue of drug shortages."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"The pair ended the podcast with some thought-provoking statements regarding the need to rethink what sustainability means and urged how standardization is really the key to achieving better patient care and access."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"The latest episode can be found here or through the "},{"type":"text","marks":[{"type":"italic"}],"text":"BioProcess Insider Expression Platform"},{"type":"text","text":" at, "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://open.spotify.com/show/0Sh7c6SJOJ7nsFLNPuW7B0","target":"_blank","rel":null,"class":null}}],"text":"Spotify"},{"type":"text","text":", "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://podcasts.apple.com/fr/podcast/the-bioprocess-insider-expression-platform/id1549869188","target":"_blank","rel":null,"class":null}}],"text":"Apple iTunes"},{"type":"text","text":", "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://podcasts.google.com/feed/aHR0cHM6Ly9mZWVkLnBvZGJlYW4uY29tL2Jpb3Byb2luc2lkZXIvZmVlZC54bWw/episode/YmlvcHJvaW5zaWRlci5wb2RiZWFuLmNvbS8xODZhZGExNS1hNTQ4LTMyMGMtOGJhZi00YWM4ZWQxODdiMjk?sa=X\u0026ved=0CAUQkfYCahcKEwiosu2Xm_r3AhUAAAAAHQAAAAAQFg","target":"_blank","rel":null,"class":null}}],"text":"Google podcasts"},{"type":"text","text":", or wherever you get your podcasts."}]},{"type":"paragraph","attrs":{"textAlign":"left"}}],"articleSummary":"ScaleReady and Germfree discuss the need to rethink sustainability and move towards a more standardized and simplistic manufacturing model to ensure health equity can be achieved. 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However, AAV-based gene therapies face challenges in production, including cost, complexity, and scalability. With the gene therapy market projected to grow significantly, drug developers are seeking platforms that streamline AAV production. Key factors include ensuring flexibility to accommodate different therapies, minimizing risks by understanding the entire process, and scaling production as projects progress. A well-designed AAV platform can enhance efficiency, quality, and regulatory compliance, ensuring safe delivery of therapies to patients.","articleBodyJsonSummary":"","variant":"small-has-summary","categoryName":"Gene Therapies","categoryUrl":"/therapeutic-modalities/gene-therapies","timeRead":0,"paidGating":null,"articleBody":[{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Gene therapies have emerged rapidly as promising treatment options for genetic disorders that previously were considered untreatable, such as cancers, rare diseases, and neurological disorders "},{"type":"text","marks":[{"type":"bold"}],"text":"(1)"},{"type":"text","text":". Adenoassociated viruses (AAVs) are the preferred vector for gene delivery because they can be cultured to relatively high titers and show good long-term transgene expression in vivo "},{"type":"text","marks":[{"type":"bold"}],"text":"(2, 3)"},{"type":"text","text":". However, manufacturing AAV-based gene therapies is a complex process demanding cost-efficiency, flexibility, and speed in all aspects of production."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Below, I delve into the increasing necessity for carefully designed development platforms to deliver cutting-edge AAV therapies efficiently and safely to patients."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Growing Reliance on AAV-Production Platforms"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"The gene-therapy market is growing rapidly, with more than 2000 gene therapies (including genetically modified cell therapies) currently under development "},{"type":"text","marks":[{"type":"bold"}],"text":"(1)"},{"type":"text","text":". With the biopharmaceutical industry increasingly recognizing the potential of gene therapies, the global gene-therapy market is predicted to reach a value of US$23.9 billion by 2028 "},{"type":"text","marks":[{"type":"bold"}],"text":"(4)"},{"type":"text","text":"."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Despite the promise of effective, innovative gene therapies, their inaccessibility and high costs pose significant challenges. Lenmeldy (atidarsagene autotemcel), the world’s most expensive gene therapy, offers hope for metachromatic leukodystrophy patients but comes with a price tag of about $4.25 million"},{"type":"text","marks":[{"type":"bold"}],"text":" (5)"},{"type":"text","text":". Successfully providing gene therapies to patients relies on drug developers and manufacturers navigating the intricate balance of upholding quality standards while optimizing cost-effectiveness and expediting timelines. That challenge has prompted AAV-therapy developers to seek collaborations with contract development and manufacturing organizations (CDMOs) that offer robust platforms tailored to meet such needs."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Platform Approaches"},{"type":"text","text":" "},{"type":"text","marks":[{"type":"bold"}],"text":"To Overcome Complexity"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Despite the rapid expansion of the gene-therapy sector since the first approved therapy in 1990, drug companies have yet to establish a standard procedure for gene-therapy development and manufacturing "},{"type":"text","marks":[{"type":"bold"}],"text":"(6)"},{"type":"text","text":". This can be attributed to the many complexities associated with AAV production, which differ across products and processes. AAV manufacturing involves many steps, encompassing plasmid production, transient transfection/infection, upstream production, downstream processing, and fill–finish. The choice of upstream process and associated conditions depends on several factors such as the virus, host cell line, transfection reagents, and culture medium to be used. Decisions made during upstream production have a cascading effect on the selection of downstream processing methods. Adding to the complexity of AAV production, each of those processes requires optimization to ensure quality, safety, scalability, and cost-effectiveness. Therefore, a comprehensive understanding of how decisions in each stage affect subsequent processes and future scale-up is crucial."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Biotechnology companies with AAV programs also face pressure to accelerate manufacturing timelines. Such demand is driven not only by the need to demonstrate potential return on investment (RoI) to investors, but also by the desire to assist patients."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"With pressure to accelerate the complex production of AAV therapies, many developers and manufacturers are looking for a robust, established platform to simplify the process. By developing an AAV platform, developers can streamline production while lowering costs, reducing complexity, and forging a clear path to clinical phases and commercialization. However, designing and developing an AAV platform is no easy task and requires strategies that ensure built-in flexibility and scalability while minimizing risk."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Minimizing Risks:"},{"type":"text","text":" Although biotechnology companies with AAV programs face pressure to accelerate delivery, the inherent complexity of AAV-therapy development and manufacturing poses significant risks. Poor decision-making can cause costly delays to critical milestones."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"A comprehensive approach to developing AAV platforms can enable identification of potential risks early, leading to proactive solutions. To attain a holistic viewpoint, developers and manufacturers must possess a profound understanding of every step in the process while remaining adaptable to necessary adjustments. Developers and manufacturers with substantial experience in supporting various virotherapy projects will understand the unique needs of different drug modalities. Their intimate knowledge will help them to anticipate how such needs might evolve as projects progress toward commercialization and to account for those changes when developing the AAV platform."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Ensuring Flexibility:"},{"type":"text","text":" Candidate gene therapies are diverse, each one targeting a specific disease with a distinct, highly engineered viral vector of a specific serotype. Achieving commercial viability will require a flexible platform that can accommodate such diversity. Developers must leverage the most suitable technology, cell line, and process to optimize yield, quality, safety, and efficacy for each therapy. With flexibility built into the AAV platform, developers can tailor their approaches to each project’s requirements, enhancing the success of AAV-based therapies."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Designing AAV platforms with flexibility in mind is also critical to ensuring consistent regulatory compliance. The gene-therapy sector has experienced rapid advancements in methodologies and technologies, allowing developers to attain higher viral-vector yields, enhanced quality, and efficient project scaling. Consequently, regulators have had to adapt their guidelines. To ensure a continuous supply of advanced therapies, AAV-production platforms must be able to incorporate new technologies and advancements while maintaining compliance in a changing regulatory landscape."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Expertise in a broad spectrum of viral vectors is essential for developers and manufacturers to ensure platform flexibility. In-depth knowledge and understanding of each project’s complexities and requirements can help to identify potential risks during the process of developing AAV-based therapies. Producers can draw on their past experiences to find and address potential risks, leading to tailored, effective solutions."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Delivering Scalability:"},{"type":"text","text":" As AAV projects advance from preclinical to clinical phases and eventually commercialization, production needs will expand, with higher volumes required at each stage. Consequently, manufacturing processes must be adaptable and robust enough to ensure consistent product quality at each scale-up phase. Establishing an AAV platform requires developers and manufacturers to adopt a comprehensive, systematic approach, ensuring careful consideration of how project needs might change over time. A program should begin with small-scale screening of cell lines, reagents, and methods to identify optimal conditions. Developers and manufacturers then can use design of experiments (DoE) methodologies to optimize those conditions with the aim of maximizing yield and quality while minimizing costs. Once the process performs consistently in benchtop bioreactors, the project can advance to pilot-scale production."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Looking to the Future"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"As reliance on AAVs for gene therapies grows, needs also increase for carefully designed development platforms that can deliver AAV therapies to patients efficiently and safely. To do so, developers and manufacturers must navigate the complexity, cost, and scalability of AAV manufacturing. Robust platform approaches will play a critical role in overcoming complexity, minimizing risk, and ensuring flexibility in AAV development and manufacturing to continue delivering innovative therapies to the patients who need them."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"References"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"1"},{"type":"text","text":" Barrett D, et al. Gene, Cell, + RNA Therapy Landscape Report: Q4 2023 Quarterly Data Report. American Society of Gene + Cell Therapy, 2023; "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://www.asgct.org/global/documents/asgct-citeline-q4-2023-report.aspx","target":"_blank","rel":null,"class":null}}],"text":"https://www.asgct.org/global/documents/asgct-citeline-q4-2023-report.aspx"},{"type":"text","text":"."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"2"},{"type":"text","text":" Wang D, Tai PWL, Gao G. Adeno-Associated Virus Vector as a Platform for Gene Therapy Delivery. Nat. Rev. Drug Discov. 18(5) 2019: 358–378; "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://doi.org/10.1038/s41573-019-0012-9","target":"_blank","rel":null,"class":null}}],"text":"https://doi.org/10.1038/s41573-019-0012-9"},{"type":"text","text":"."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"3"},{"type":"text","text":" Lansford R. Engineering Viruses for CNS Studies. Encyclopedia of Neuroscience. Squire LR, Ed. Academic Press: Cambridge, MA, 2009: 1059–1068."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"4"},{"type":"text","text":" Gene Therapy Market Size by Type, Vector, Non-Viral, Therapeutic Area, Delivery Method, RoA, \u0026 Region — Global Forecast to 2028. MarketsandMarkets Research, 2023; "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://www.marketsandmarkets.com/Market-Reports/gene-therapy-market-122857962.html","target":"_blank","rel":null,"class":null}}],"text":"https://www.marketsandmarkets.com/Market-Reports/gene-therapy-market-122857962.html"},{"type":"text","text":"."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"5"},{"type":"text","text":" Package Insert — Lenmeldy. US Food and Drug Administration: Silver Spring, MD, 15 April 2024; "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/lenmeldy","target":"_blank","rel":null,"class":null}}],"text":"https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/lenmeldy"},{"type":"text","text":"."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"6"},{"type":"text","text":" Scheller EL, Krebsbach PH. Gene Therapy: Design and Prospects for Craniofacial Regeneration. J. Dent. Res. 88(7) 2009: 585–596; "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://doi.org/10.1177/002203","target":"_blank","rel":null,"class":null}}],"text":"https://doi.org/10.1177/002203"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"4509337480."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Corresponding author "},{"type":"text","marks":[{"type":"bold"}],"text":"Xiaojun Liu"},{"type":"text","text":" is director of AAV process development at ReciBioPharm; 650 Pleasant Street, Watertown, MA 02472; xiaojun.liu@arrantabio.com."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"}}]},{"contentType":"Journal","thumbnail":{"src":"https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/blta85c6836d5c63a7b/671191d7c4a37b6bb8135d52/22-10-FR-Bream-Hobmann-P1.jpg","alt":"Adobe Stock"},"contributors":[{"name":"Brian Gazaille","link":"/author/brian-gazaille","avatar":""},{"name":"Allan Bream","link":"/author/allan-bream","avatar":""},{"name":"Brita Hobmann","link":"/author/brita-hobmann","avatar":""}],"articleName":"The Complex Calculus of Viral-Vector Facility Design: Considerations for Commercial Gene-Therapy Manufacturing","mobileHeadline":"The Complex Calculus of Viral-Vector Facility Design: Considerations for Commercial Gene-Therapy Manufacturing","articleUrl":"/gene-therapies/the-complex-calculus-of-viral-vector-facility-design-considerations-for-commercial-gene-therapy-manufacturing","linkAttrs":{},"listPageUrl":"/journals","date":"Oct 17, 2024","webinarStartTime":"","articleSummary":"","articleBodyJsonSummary":"","variant":"small-has-summary","categoryName":"Gene Therapies","categoryUrl":"/therapeutic-modalities/gene-therapies","timeRead":0,"paidGating":null,"articleBody":[{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Guided by standardized production and purification platforms, developers of monoclonal antibodies (mAbs) and other recombinant-protein therapeutics can take a relatively straightforward path when designing and establishing facilities for commercial-scale operations. By contrast, designing gene-therapy (GT) facilities involves a more complex calculus. Multiple approaches are available for producing transgene-bearing viral vectors at commercial scales. GT developers must choose carefully, knowing that each manufacturing strategy raises distinctive advantages and limitations for process scalability, equipment implementation, storage, material and personnel flow, and ultimately, facility output. The plurality of manufacturing strategies — and the possibility of further platform advancements — requires GT companies and their facility-design teams to be forward-thinking in their planning. All the while, GT facilities must be engineered for good manufacturing practice (GMP) operations and work with viral vectors, including measures for segregating virus-positive areas and preventing cross-contamination."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Allan Bream (senior fellow in biopharmaceutical processes) and Brita Hobmann (process engineer) of facility-engineering firm CRB have over 40 combined years of experience with biopharmaceutical-facility design and construction, with a particular focus on sites for GTs and gene-modified cell therapies. This past summer, I corresponded with Bream and Hobmann to enumerate some of the many variables involved in establishing commercial GT capabilities. After describing implementation trends for production platforms and related equipment and operational requirements, the duo explore strategies for engineering contamination controls into a facility plan and for optimizing facility use and output. Our discussion also highlights considerations for GT companies that are deciding between establishing internal manufacturing capabilities or outsourcing vector production to contract service providers."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Laying a Foundation for Gene-Therapy Manufacturing"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"How would you describe the landscape of GT manufacturing? What production approaches currently prevail?"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Bream: "},{"type":"text","text":"Adenoassociated viruses (AAVs) remain the most common gene-delivery vehicles for in vivo gene therapy. Lentiviral vectors (LVVs), adenovirus vectors (AdVs), and retrovirus vectors (RVVs) are other available delivery systems. A key consideration is that AAVs do not integrate into a patient-cell’s genome, which makes them effective for in vivo applications but can limit treatment effectiveness over time. LVVs and RVVs do integrate into host-cell genomes and thus are ideal systems for ex vivo manipulation of dividing cells."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Triple transfection still leads the way for gene transfer into cells used to produce recombinant AAV. Three DNA plasmids are incubated in sequence with a production cell line, usually human embryonic kidney 293 (HEK293) cells. One plasmid contains a pair of essential AAV genes, the second has a transgene specific to the GT, and the third is a helper plasmid."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Hobmann:"},{"type":"text","text":" Common themes in GT manufacturing today include scalability of suspension cell culture, the need for single-use (SU) equipment, and the desire to balance in-house and outsourced activities. Typically, GTs are capping at 500-L production volumes in SU bioreactors. However, some companies are operating two 200-L bioreactors because production at that scale often results in more effective transduction than what is observed in 500-L systems."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"SU equipment continues to dominate the GT market. Such products require relatively small process volumes compared with those for traditional mAb production. SU enables quick cleaning of biosafety-level (BSL) materials through disposal of spent process-contacting materials. And SU technologies are conducive to speed to market, which is advantageous for contract development and manufacturing organizations (CDMOs) that are trying to attract clients or for start-ups that are producing clinical material."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Discussions continue around the “make or buy” question. GT developers must decide what to invest in now and what to outsource to save capital. Allan and I have found that many CDMOs in the GT market handle the entire process for their clients. An outsourced approach provides biotechnology companies with an option to make their viral vectors off site — e.g., to support production of genetically modified cell therapies, such as those based on chimeric antigen receptor (CAR) T cells."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Alternatively, particular aspects of GT production may be beneficial to outsource initially and then bring back in house. Solution preparation is among the most common activities to be outsourced initially. By purchasing preformulated medias and buffers from a qualified third-party supplier, GT developers can save space and commodities such as water for injection (WFI). When building their own manufacturing facilities, GT companies often have conversations about insourcing and outsourcing to customize investments for current and future process needs."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"How do different production approaches influence GT facility design?"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Bream: "},{"type":"text","text":"Suspension culture facilitates processing better than anchorage-dependent operations do. Operating suspension cell culture in a rocker or agitated bioreactor system also offers better gas and nutrient exchange, therefore providing cells with optimal growth conditions. But scale-up is limited by current SU bioreactor equipment. Some bioreactors work at volumes up to 4000 L. However, most commercial processes are capped at 1000 L."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Although suspension cell culture is relatively straightforward, having an effective transfection method is key. With higher cell densities and volumes, transfection efficiency decreases. As Brita explained, that factor often compels manufacturers to use two small production bioreactors instead of one large unit."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Hobmann:"},{"type":"text","text":" Regarding anchorage-dependent platforms, starting with an adherent process can bring some clinical advantages, but unfortunately those benefits often are overcome with disadvantages during larger, commercial-scale operations. Compared with the many available options for suspension bioreactors, choices for large-scale adherent-culture equipment remain limited. Thus, commercial-scale processes based on adherent platforms max out around 500 m2, and increasing capacity requires adding equipment to scale out. Harvest steps also may require dislodging cells from the culture surface between media exchanges. In that regard, adherent bioreactors act like perfusion processes, which require larger media volumes than do suspension processes operated in batch mode. Large media volumes entail significant solution-preparation demand and require ample space to make, store, and transfer those solutions."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Suspension-"},{"type":"text","text":" and adherent-cell platforms have their own pros and cons. Sometimes GT developers will have a business driver to develop flexibility for using both approaches. Doing that is achievable with strategic facility planning and foresight."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"What considerations do packaging/helper and producer cell lines present for materials use, equipment configuration, and facility layout?"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Hobmann: "},{"type":"text","text":"Historically, packaging/helper cell lines have dominated the viral-vector space, and stable producer cells have been an aspiration for GT companies. In a survey for CRB’s 2020 Horizons: Cell and Gene Therapy report, 65% of respondents said that their companies were developing or intended to develop stable producer cells because of the potential for lowering costs and improving scalability "},{"type":"text","marks":[{"type":"bold"}],"text":"(1)"},{"type":"text","text":". In processes based on producer cell lines, transgene conversion occurs earlier in the process, at the start of the growth cycle. That reduces the need for costly plasmids compared with quantities needed for processes based on packaging cell lines and triple transfection at large production volumes. Producer cell lines also could improve vector yield and batch consistency because they are pretransfected with the needed genetic elements, effectively eliminating the need for triple transfection. The challenge will be to scale up these “holy grail” cell lines to be commercially viable. Advancements in producer cells will be exciting to watch develop over the next few years."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Establishing Facility Controls"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Which biosafety requirements come with viral-vector manufacturing?"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Bream: "},{"type":"text","text":"Cleanroom classification for viral-vector manufacturing depends on whether a process is open or closed. Typically, inoculum preparation occurs in a biosafety cabinet within a grade-C room background (see opening photo). Closed upstream operations (e.g., cell-culture expansion and viral-vector propagation) are carried out in a grade-D environment. When transitioning to downstream operations, process volumes decrease, and the need for truly closed, small-scale operations drives the cleanroom classification to grade C."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Bulk viral-vector filling occurs within a grade-C space, then is transferred to drug-product filling within the same facility. Such areas are subject to EU GMP Annex 1 (2), and they often are segregated from drug-substance manufacturing areas. Small-batch, manual filling of vials requires a grade-A environment with a grade-B background. That, of course, drives the need for airlocks and gowning protocols that are compatible with aseptic operations. For large-scale operations, regulators prefer automated vial filling within a high-efficiency particulate air (HEPA)–filtered isolator system. Being closed systems, isolators allow for a grade-C room background."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"The 2023 update to EU GMP Annex 1 calls for manufacturers to implement contamination control strategies (CCSs) along with preuse, poststerilization integrity testing (PUPSIT) while following quality risk management (QRM) principles (2)."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Hobmann: "},{"type":"text","text":"Viral vectors typically are classified as BSL-2 materials because they are “agents associated with human disease and pose moderate hazards to personnel” (3). BSL-2 materials entail special handling considerations, such as safety-exhausting bioreactors, isolators, and cleanrooms. A GT manufacturer should perform a risk assessment to evaluate the likelihood and impact of viral-vector escape from a functionally closed system. For instance, what is the probability of a bioprocess bag leaking? What would be the effect of recirculating air from vector-positive to vector-free areas? Such questions should be discussed with the goal of establishing engineering controls to minimize risk."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Beyond closed process equipment, heating, ventilation, and air conditioning (HVAC) systems play a critical role in GT manufacturing, helping to protect personnel and the environment. Air-handling zoning, HEPA filters, and room pressurization are a few mechanical elements that provide another level of control when used properly. If a viral-vector breach occurs within a room or isolator, chemical decontamination is recommended using vaporized hydrogen peroxide or an equivalent agent. Decontamination approaches should be discussed early in facility design and as part of a risk assessment."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"How else can manufacturers ensure segregation of vector-positive areas?"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Bream: "},{"type":"text","text":"Several methods provide layers of protection to prevent cross-contamination."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"As in other biopharmaceutical facilities, personnel, materials, and waste airlocks serve as transitions into and out of process areas. However, for GT operations, unidirectional flows of personnel, materials, and waste are preferred rather than the bidirectional flows typically used in facilities for mAbs and other biopharmaceutical products."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"A two-corridor facility approach is typical, and that aids unidirectional flow. Personnel and materials enter into process areas through “supply” corridors, while waste exits and personnel return to locker rooms through a return corridor."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Host-cell expansion (before infection of a production bioreactor) is segregated from the viral suite."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Validated chemical sanitization/wipe-down and decontamination steps are performed at entry/exit points into/out of process suites."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Generally, viral-vector suite HVAC pressurization is negative relative to that in facility supply and return corridors, helping with containment and preventing risk of cross-contamination."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Hobmann: In addition to the methods that Allan mentioned, closed processing serves as another level of engineering control for vector containment. Luckily, closed-process technology is not new to the industry, and GT manufacturers can choose from a variety of SU offerings to maintain closure. Aseptic connectors, tubing welders, and preassembled manifolds are a few components that aid in maintaining closure for an SU-based platform. Specific steps might need to be functionally open, in which case operations should be handled in higher-classified areas such as grade-A isolators or biosafety cabinets."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"For small batch volumes, few options are commercially available for closed, GMP-grade equipment options. Already small GT production volumes are reduced further after downstream processing. Thus, purification steps in a GT manufacturing process might require high room classifications or secondary containment measures to mitigate risks associated with functionally open steps."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Forward-Thinking Facility Design"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"What kinds of mistakes do GT manufacturers make when establishing production facilities?"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Bream:"},{"type":"text","text":" Early stage GT companies feel pressure to produce enough material quickly to support clinical trials. Thus, companies often make process-development (PD) compromises. With not enough time to optimize a given process, companies are forced to into a decision: Aim for a “perfect” process or settle for an “adequate” manufacturing approach. The problem is that modifying a process later can be disruptive and expensive. As a program advances to phase 3 clinical trials, it might reach the point at which process changes cannot be made."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Problems also come from using process methods that cannot be scaled up. PD often begins with open processes in research-scale equipment that does not perform robustly. Mitigating such deficiencies in future processes can be expensive, though. For instance, if an open step cannot be closed, then it will need to be housed in a cleanroom with a high classification. That would increase both facility capital costs and operational expenses."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Effective technology transfer from a partner CDMO can be troublesome. At some point, a GT developer might want to transfer a process from its CDMO back to its own manufacturing facility. During that process, communication and documentation regarding the process and associated methods will be vital, as will details about the quality control (QC) testing approach. Clear goals, intermediate objectives, and regularly scheduled meetings with progress tracking will be key to success."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Hobmann: "},{"type":"text","text":"Commercial GT products are relatively new to the market compared with mAbs and traditional modalities. Thus, there is no “gold standard” for GT manufacturing, and each company is developing its own best practices. Those different approaches can lead to creative innovatives, but companies can run into obstacles along the way if they lack a forward-looking mindset. For instance, that takes us back to the question of whether to use an adherent- or suspension-based platform and to the importance of considering long-term success with each format. GT developers need to balance speed to market with scalability for future demand."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"The past five years have witnessed a significant increase in GT companies vying for established commercial facilities. From this surge comes industry best practices and expert guidance. When building a facility, look to such guidance and to experts who have seen these obstacles before."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"How can manufacturers ensure that they are optimizing facility use and output?"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Bream:"},{"type":"text","text":" There are myriad factors to consider, including flexibility and redundancy, process closure, risk tolerance, and issues related to SU technologies. Companies also need to consider the basic make-or-buy choice carefully."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Regarding flexibility, where possible, specify equipment that can support a breadth of process capabilities and product types. And whether for routine calibration, part replacement, or unexpected failure, process equipment requires periodic maintenance and will be taken out of service. Manufacturers need to establish strategies to ensure that equipment maintenance does not interrupt production significantly. That includes N + 1 redundancy for key equipment."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"In terms of make-or-buy decisions, early-stage and prerevenue companies have tight budgets for personnel and capital equipment. Such companies should consider outsourcing activities such as media and buffer preparation (which also would help to decrease storage requirements) and QC release testing. Of course, outsourcing will require added planning to ensure that a vendor can support given manufacturing requirements."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"GT companies should work with suppliers of SU technologies to ensure that such equipment can support a given manufacturing process and fit into a particular facility design. GT developers also should investigate how effectively equipment can interface with a facility’s process-control system."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Developing a closed process will enable parallel processing without prompting additional regulatory scrutiny."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"As far as risk tolerance, companies must explore how comfortable they are with risk concerning GMP process flows, HVAC capabilities, equipment redundancy, open processing, and so on. Managers should get key stakeholder buy-in as early as possible."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Hobmann: "},{"type":"text","text":"The key to optimizing facility efficiency and throughput is planning. That seems simplistic, but it is important that GT companies take time at the start to identify facility drivers and capacity goals, with key stakeholder buy-in. Initial planning will provide a road map throughout facility design, and detours should be addressed as a team."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Simulation modeling can be used to inform early facility-design stages by pressure-testing GMP flows, process schedules, and equipment use. Process simulations also can test ratios of upstream, downstream, and filling functions to prevent schedule bottlenecks and reduce equipment downtime. Other use cases include evaluation of parallel trains to achieve throughput projections and warehouse capacity modeling to support incoming consumables. Planning sets the framework for an optimized facility and heads off challenges associated with significant course-correction."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"How can GT manufacturers help to ensure that their facilities will address future needs?"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Bream:"},{"type":"text","text":" At early project stages (preferably during feasibility assessment or preconcept activities), defining facility-user requirements for future needs is essential. Process modeling and exploration of different facility approaches are important in that regard. Those activities enable testing of different facility conditions, capabilities, and concepts before serious design work begins. Performing site master planning alongside manufacturing assessment can be valuable as well, considering site amenities such as parking, administrative buildings, and other needed supports. A strategic approach to intra- and extra-building planning will enable streamlined, well-conceived expansions."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Hobmann: "},{"type":"text","text":"Continuous innovation in biomanufacturing technology and science means that change is inevitable in the GT industry. The key is to be adaptable to such advances throughout the life cycle of a manufacturing facility."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Flexibility has become an industry buzzword, and it means something different for each person. If we look at one production suite as an example, a number of approaches could make that suite “flexible” for future operations. Gas utilities, data connections, and electrical outlets could be standardized and spaced around the suite for different equipment configurations. Ceiling heights and room footprints could be designed to facilitate future scale-up/out."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"A GT developer should work with its suppliers and facility engineers to define what flexibility means for its own purposes. To prevent overdesign, the team should not deviate from that definition. GTs are the product of cutting-edge science, and they will continue to evolve and change as the science does. Being flexible — within defined goals — will be key to mitigating risk and extending facility longevity."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"References"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"1"},{"type":"text","text":" Maestre N, et al. Horizons: Cell and Gene Therapy, 2020. CRB: Cary, NC, 2020; "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://go.crbgroup.com/horizons-atmp-thanks-0","target":"_blank","rel":null,"class":null}}],"text":"https://go.crbgroup.com/horizons-atmp-thanks-0"},{"type":"text","text":"."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"2"},{"type":"text","text":" EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use: Annex 1 — Manufacture of Sterile Medicinal Products. European Commission: Brussels, Belgium, 2022; "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://health.ec.europa.eu/system/files/2022-08/20220825_gmp-an1_en_0.pdf","target":"_blank","rel":null,"class":null}}],"text":"https://health.ec.europa.eu/system/files/2022-08/20220825_gmp-an1_en_0.pdf"},{"type":"text","text":"."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"3"},{"type":"text","text":" Biosafety in Microbiological and Biomedical Laboratories (sixth edition). Meechan PJ, et al., Eds."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"US Centers for Disease Control and Prevention: Atlanta, GA, 2020; https://www.cdc.gov/labs/pdf/SF__19_308133-A_BMBL6_00-BOOK-WEB-final-3.pdf. "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://www.cdc.gov/labs/pdf/SF__19_308133-A_BMBL6_00-BOOK-WEB-final-3.pdf","target":"_blank","rel":null,"class":null}}],"text":"https://www.cdc.gov/labs/pdf/SF__19_308133-A_BMBL6_00-BOOK-WEB-final-3.pdf"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Brian Gazaille,"},{"type":"text","text":" PhD, is managing editor of BioProcess International; brian.gazaille@informa.com; 1-212-600-3594. Allan Bream, MSChE, is senior fellow in biopharmaceutical processes, and Brita Hobmann, EIT, is a process engineer, both with CRB."}]}]},{"contentType":"Journal","thumbnail":{"src":"https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/bltaa34860800f1a153/67216d9098779fe5915ceff4/22-10-FR-Pavlistova-F1.png","alt":""},"contributors":[{"name":"Tereza Pavlištová","link":"/author/tereza-pavli-tov-","avatar":""},{"name":"Maria João Alves Correia","link":"/author/maria-jo-o-alves-correia","avatar":""},{"name":"Alejandro Molina Gil","link":"/author/alejandro-molina-gil","avatar":""},{"name":"Edina Ljubovic-Couteau","link":"/author/edina-ljubovic-couteau","avatar":""},{"name":"Bas van de Waterbeemd","link":"/author/bas-van-de-waterbeemd","avatar":""},{"name":"Mathieu Streefland","link":"/author/mathieu-streefland","avatar":""},{"name":"Hugo F. Cueto-Rojas","link":"/author/hugo-f-cueto-rojas","avatar":""}],"articleName":"A Scale-Up/-Down Platform for Fast-Paced Upstream Process Development of rAAV-Based Gene Therapies","mobileHeadline":"A Scale-Up/-Down Platform for Fast-Paced Upstream Process Development of rAAV-Based Gene Therapies","articleUrl":"/gene-therapies/a-scale-up-down-platform-for-fast-paced-upstream-process-development-of-raav-based-gene-therapies","linkAttrs":{},"listPageUrl":"/journals","date":"Oct 17, 2024","webinarStartTime":"","articleSummary":"","articleBodyJsonSummary":"","variant":"small-has-summary","categoryName":"Gene Therapies","categoryUrl":"/therapeutic-modalities/gene-therapies","timeRead":0,"paidGating":null,"articleBody":[{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"figure","attrs":{"figcaption":"Graphical Abstract: We discuss our development of a robust, fast-paced, and high-throughput (HT) process-development platform for production of recombinant adenoassociated virus (rAAV) vectors using insect cells and a baculovirus expression vector system (BEVS). Based on theoretical regime analysis, we redesigned upstream operations to generate bench and HT scale-down models that were representative of a large-scale process. Data collected during experimental validation showed that productivity levels and measured critical quality attributes (CQAs) matched across scales, demonstrating scalability from HT to commercial scale. Our findings can facilitate process characterization for rAAV production processes. As shown below, our data also suggest the possibility of bypassing intermediate scales during process development, effectively shortening timelines and decreasing costs for such activities. Solid lines in the image represent a traditional, linear development pathway, whereas the dashed, red lines indicate our propose development paths (RSD = relative standard deviation)."},"content":[{"type":"image","attrs":{"textAlign":"left","src":"https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/blt25eb47a5bf65c257/670e581e881bc36d50dcb396/22-10-FR-Pavlistova-GraphicalAbstract.jpg","alt":null,"title":null,"style":{"float":"left","display":"inline-block","margin":"0","width":"auto","max-width":"auto","text-align":"left"}}},{"type":"text","text":"Graphical Abstract: We discuss our development of a robust, fast-paced, and high-throughput (HT) process-development platform for production of recombinant adenoassociated virus (rAAV) vectors using insect cells and a baculovirus expression vector system (BEVS). Based on theoretical regime analysis, we redesigned upstream operations to generate bench and HT scale-down models that were representative of a large-scale process. Data collected during experimental validation showed that productivity levels and measured critical quality attributes (CQAs) matched across scales, demonstrating scalability from HT to commercial scale. Our findings can facilitate process characterization for rAAV production processes. As shown below, our data also suggest the possibility of bypassing intermediate scales during process development, effectively shortening timelines and decreasing costs for such activities. Solid lines in the image represent a traditional, linear development pathway, whereas the dashed, red lines indicate our propose development paths (RSD = relative standard deviation)."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"The field of bioprocess development has witnessed remarkable advancements in recent years driven by increasing demand for biopharmaceuticals, including gene-therapy products such as recombinant adenoassociated virus (rAAV) vectors. To date, global regulatory bodies have approved several rAAV-based gene therapies, and multiple clinical trials are ongoing as forecasts project significant growth over the next five to 10 years "},{"type":"text","marks":[{"type":"bold"}],"text":"(1)"},{"type":"text","text":"."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"The field of rAAV production continues to be dominated by platforms using human embryonic kidney (HEK) and insect cells. For instance, uniQure’s proprietary platform is based on insect-cell production and a baculovirus expression vector system (BEVS) "},{"type":"text","marks":[{"type":"bold"}],"text":"(2–5)"},{"type":"text","text":". As the gene-therapy clinical pipeline expands, ensuring efficient, cost-effective, and scalable processes for viral-vector production becomes critical"},{"type":"text","marks":[{"type":"bold"}],"text":" (1)"},{"type":"text","text":". Central to that endeavor are scale-down models and fast-paced scale-up."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Scale-down models are small-scale representations that are designed to mimic key process parameters, conditions, and challenges encountered at production scale "},{"type":"text","marks":[{"type":"bold"}],"text":"(6)"},{"type":"text","text":". Such models are instrumental in providing insights into process performance, identifying potential bottlenecks, and enabling process improvements without the need for large-scale, resource-intensive trials. Thus, scale-down models have become an indispensable tool in the biotechnology industry for developing, understanding, optimizing, and validating bioprocesses"},{"type":"text","marks":[{"type":"bold"}],"text":" (7, 8)."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Multiple bioreactor systems have demonstrated consistent scalability across bench, pilot, and commercial production scales for biopharmaceuticals, including cell and gene therapy (CGT) products "},{"type":"text","marks":[{"type":"bold"}],"text":"(9–12)"},{"type":"text","text":". The availability of such equipment shows that scaling up from benchtop to commercial manufacturing is not only possible, but also well-established in the industry."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Fast-paced scale-up refers to bridging the gap between laboratory-scale experiments and full-scale production in the shortest time frame. Several biopharmaceutical companies have adopted that philosophy as a result of implementing learnings from the successful deployment of SARS-CoV-2 vaccines in record times "},{"type":"text","marks":[{"type":"bold"}],"text":"(13, 14)"},{"type":"text","text":". A fast-paced approach is possible largely due to abundant internal know-how, platform-based approaches "},{"type":"text","marks":[{"type":"bold"}],"text":"(7, 15)"},{"type":"text","text":", and high-throughput experimentation and analytics."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"In that respect, high-throughput miniaturized bioreactors offer a cutting-edge solution to the problem of data generation toward expediting process development. Herein, we explore the pivotal role of such systems in scaling up processes, optimizing gene-therapy production, and streamlining biomanufacturing processes based on insect cells. Our objective is to establish a representative scale-down model of our current production bioreactor to support a platform capable of hastening commercial manufacturing of potentially lifesaving and life-transforming therapies. We propose a relatively unconventional approach to process development by providing data that support the possibility of bypassing small-scale studies and scaling up directly from minibioreactors to pilot/commercial scales for rAAV production."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Materials and Methods"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Regime Analysis:"},{"type":"text","text":" In the context of gene-therapy scale-up/-down, the regime-analysis approach serves as a fundamental tool for assessing and characterizing the behavior of bioprocesses at different scales, mainly the production-scale bioreactor, which is the target operation to be studied ("},{"type":"text","marks":[{"type":"bold"}],"text":"16–18"},{"type":"text","text":"). This analytical approach facilitates comprehension of both critical time constants and the influences of different parameters and operating conditions on process performance. It guides efforts to scale down processes into benchtop and high-throughput bioreactors while helping process engineers to select optimal operating spaces at commercial and intermediate production scales."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Several critical time constants are used during model characterization to ensure accurate representation of bioreactor performance at a larger scale "},{"type":"text","marks":[{"type":"bold"}],"text":"(8)"},{"type":"text","text":". Key parameters to address during model design include power input per unit volume ("},{"type":"text","marks":[{"type":"italic"}],"text":"P"},{"type":"text","text":"/"},{"type":"text","marks":[{"type":"italic"}],"text":"V"},{"type":"text","marks":[{"type":"subscript"}],"text":"L"},{"type":"text","text":"), impeller-tip speed ("},{"type":"text","marks":[{"type":"italic"}],"text":"v"},{"type":"text","marks":[{"type":"subscript"}],"text":"tip"},{"type":"text","text":"), superficial gas velocity ("},{"type":"text","marks":[{"type":"italic"}],"text":"v"},{"type":"text","marks":[{"type":"subscript"}],"text":"sg"},{"type":"text","text":"), and rate of overlay gas flow ("},{"type":"text","marks":[{"type":"italic"}],"text":"f"},{"type":"text","marks":[{"type":"subscript"}],"text":"ov"},{"type":"text","text":"). We conducted a literature survey to gather sufficient empirical correlations for performing a regime analysis, and we selected the most appropriate time constants for model design and testing"},{"type":"text","marks":[{"type":"bold"}],"text":" (4, 8–12, 16–36)."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Scaling up cell-culture processes in stirred-tank bioreactors (STRs) requires careful consideration of equipment capabilities in terms of mass, temperature, and momentum transfer — which can be characterized using the well-documented oxygen mass-transfer coefficient ("},{"type":"text","marks":[{"type":"italic"}],"text":"k"},{"type":"text","marks":[{"type":"subscript"}],"text":"L"},{"type":"text","marks":[{"type":"italic"}],"text":"a"},{"type":"text","text":"), heat-transfer coefficient ("},{"type":"text","marks":[{"type":"italic"}],"text":"U"},{"type":"text","text":"), and mixing time (θ"},{"type":"text","marks":[{"type":"subscript"}],"text":"m"},{"type":"text","text":"), respectively "},{"type":"text","marks":[{"type":"bold"}],"text":"(19–21)"},{"type":"text","text":". In addition, process engineers need a fair understanding of a host cell line’s biological properties, such as its shear resistance, death rate ("},{"type":"text","marks":[{"type":"italic"}],"text":"k"},{"type":"text","marks":[{"type":"subscript"}],"text":"D"},{"type":"text","text":"), and growth rate (µ"},{"type":"text","marks":[{"type":"subscript"}],"text":"max"},{"type":"text","text":") "},{"type":"text","marks":[{"type":"bold"}],"text":"(22–24, 26"},{"type":"text","text":"). One consideration for processes involving BEVs is that host cells are known to undergo physiological changes after baculovirus infection "},{"type":"text","marks":[{"type":"bold"}],"text":"(4, 25, 27, 37)"},{"type":"text","text":". An additional complication for scale-up design is that many of the variables described above have interdependencies (Figure 1). For example, media composition influences cell performance, which in turn can affect STR capacity for mass transfer."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"figure","attrs":{"figcaption":"Figure 1: A regime analysis mapping potential interactions among the main variables that influence cell-culture performance during production of recombinant adenoassociated virus (rAAV); Di: impeller diameter, imp.: impeller, kD: cell death rate, kLa: oxygen mass-transfer coefficient, P/VL: power per unit volume, PID: proportional–integral–derivative, Pr: Prandtl number, Re: Reynolds number, Sc: Schmidt number, θm: mixing time, U: heat-transfer coefficient, µmax: cell growth rate"},"content":[{"type":"image","attrs":{"textAlign":"left","src":"https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/bltaa34860800f1a153/67216d9098779fe5915ceff4/22-10-FR-Pavlistova-F1.png","alt":"22-10-FR-Pavlistova-F1.png","title":null,"style":{"float":"left","display":"inline-block","margin":"0","width":"auto","max-width":"auto","text-align":"left"}}},{"type":"text","text":"Figure 1: A regime analysis mapping potential interactions among the main variables that influence cell-culture performance during production of recombinant adenoassociated virus (rAAV); Di: impeller diameter, imp.: impeller, kD: cell death rate, kLa: oxygen mass-transfer coefficient, P/VL: power per unit volume, PID: proportional–integral–derivative, Pr: Prandtl number, Re: Reynolds number, Sc: Schmidt number, θm: mixing time, U: heat-transfer coefficient, µmax: cell growth rate"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Cell Expansion in Shake Flasks: "},{"type":"text","text":"The insect cell line used throughout this study was cultivated in single-use shake flasks with working volumes ranging from 125 mL to 2 L. We applied standard conditions reported in literature "},{"type":"text","marks":[{"type":"bold"}],"text":"(4, 5, 38, 39)."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Cell Growth and rAAV Production in STRs:"},{"type":"text","text":" We performed different studies to establish STR operating conditions for our scale-down models. Specifically, we investigated settings for dissolved-oxygen–concentration (%DO"},{"type":"text","marks":[{"type":"subscript"}],"text":"sat"},{"type":"text","text":") cascade and proportional–integral–derivative (PID) control parameters to match performance in terms of cell growth and rAAV production across scales. Published experimental conditions for growing insect cells and producing rAAV in STRs served as a starting point for process optimization "},{"type":"text","marks":[{"type":"bold"}],"text":"(38–40)"},{"type":"text","text":". We assessed cell growth experimentally at high-throughput (\u003c0.5 L), benchtop (\u003c5 L), and technology-transfer scales (\u003c100 L). Different iterations in operational parameters were selected based on our earlier regime analysis, with data obtained at pilot scale (\u003e100 L) serving as our target for optimization. After selecting successful conditions, we challenged the rAAV production process at all scales to validate its scalability, demonstrating similar performance in the form of statistically comparable (95% confidence in a "},{"type":"text","marks":[{"type":"italic"}],"text":"t"},{"type":"text","text":" test) product yield and main product critical quality attributes (CQAs), namely, infectivity and empty to full capsid ("},{"type":"text","marks":[{"type":"italic"}],"text":"E"},{"type":"text","text":":"},{"type":"text","marks":[{"type":"italic"}],"text":"F"},{"type":"text","text":") ratios."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Results and Discussion"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Selection of scale-up/-down factors is a critical aspect of bioprocess development because that process ensures successful transition from systems such as high-throughput (milliliter-scale) and benchtop (liter-scale) bioreactors to vessels of larger scales (e.g., hectoliter scale). During technology transfer from benchtop- (\u003c5 L) to commercial-scale (\u003e200 L) rAAV production, determination of biological and operational factors becomes paramount."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"We needed data about STR geometry (e.g., tank diameter and impeller number and diameter), physiochemical properties (density and heat capacity), operating conditions (stirring and aeration rates), and cell-inoculation density to compare our operational regime across scales. Key process parameters such as oxygen mass transfer and power consumption were calculated using empirical correlations that we found during our literature survey. Our choice of scaling factors was guided, on one hand, by the theoretical assessment provided by the regime analysis and, on the other, by experimental validation. Parameter selection hinged on results from different experimental iterations, and experiments were guided largely by findings from the regime analysis and learnings obtained during performance matching across scales (based on cell growth and rAAV production). Although we did not leverage such tools, we encourage use of artificial intelligence (AI) and machine learning (ML) to speed up scale-down endeavors and decrease the experimental workload — e.g., by using approaches outlined in Alavijeh et al. "},{"type":"text","marks":[{"type":"bold"}],"text":"(41)."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"That said, empirical confirmation of operational conditions and predictions from the regime analysis was an essential part of our process. For instance, experimental results highlighted concerns relating to bioreactor control, specifically the selection of nonscalable PID control parameters. Consideration of such factors was critical to ensuring performance matching (Figure 2). We performed PID tuning and validation using a mix of empirical testing and traditional tuning methods and modeling, as discussed by Harcum et al. "},{"type":"text","marks":[{"type":"bold"}],"text":"(42)."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"figure","attrs":{"figcaption":"Figure 2: Influence of proportional–integral–derivative (PID) parameters on cell expansion; the trends below show the critical role of PID parameters during performance-matching experiments between bench- (yellow and green lines) and technology-transfer (TT)–scale bioreactors (black line). The bench-scale bioreactor operated with PID set 2 (green line) more closely matched the performance of the TT bioreactor than did the reactor using PID set 1 (yellow line)."},"content":[{"type":"image","attrs":{"textAlign":"right","src":"https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/blt94979af7e461b2b9/67216fa27389343f56c5ef08/22-10-FR-Pavlistova-F2.png","alt":"22-10-FR-Pavlistova-F2.png","title":null,"style":{"float":"right","display":"inline-block","margin":"0","width":"auto","max-width":"auto","text-align":"right"}}},{"type":"text","text":"Figure 2: Influence of proportional–integral–derivative (PID) parameters on cell expansion; the trends below show the critical role of PID parameters during performance-matching experiments between bench- (yellow and green lines) and technology-transfer (TT)–scale bioreactors (black line). The bench-scale bioreactor operated with PID set 2 (green line) more closely matched the performance of the TT bioreactor than did the reactor using PID set 1 (yellow line)."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Cell Proliferation at Different Scales: "},{"type":"text","text":"After selecting scalable operational conditions, we monitored insect-cell growth during STR cultivation with the goal of demonstrating similar performance across scales, measured as a statistically similar growth rate (95% confidence interval in a "},{"type":"text","marks":[{"type":"italic"}],"text":"t"},{"type":"text","text":" test) (Figure 3). The obtained data suggest that specific growth rates were calculated with \u003c5% deviation between scales, confirming that the selected operating conditions provided a similar environment for cell proliferation."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"figure","attrs":{"figcaption":"Figure 3: Cell-growth profiles across scales; similar growth rates were achieved across technology-transfer (TT), bench, and high-throughput (HT) scales when using stirred-tank bioreactor (STR) operational conditions that were selected based on regime analysis and empirical testing. For HT-scale experiments, different vessel geometries underwent testing and showed no impact on cell proliferation."},"content":[{"type":"image","attrs":{"textAlign":"left","src":"https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/bltd06a2c9186785cae/670e597d923a095fb995cdad/22-10-FR-Pavlistova-F3.jpg","alt":"22-10-FR-Pavlistova-F3.jpg","title":null,"style":{"float":"left","display":"inline-block","margin":"0","width":"auto","max-width":"auto","text-align":"left"}}},{"type":"text","text":"Figure 3: Cell-growth profiles across scales; similar growth rates were achieved across technology-transfer (TT), bench, and high-throughput (HT) scales when using stirred-tank bioreactor (STR) operational conditions that were selected based on regime analysis and empirical testing. For HT-scale experiments, different vessel geometries underwent testing and showed no impact on cell proliferation."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"We observed some minor differences in dead-cell counts. In practical terms, those differences did not influence cell growth and rAAV production, but we performed additional experiments to identify potential root causes. We attribute the differences in cell-death profiles mainly to the presence of a microsparger in the larger-scale cultivation vessel, as opposed to an L-shaped sparger in the benchtop and high-throughput vessels ("},{"type":"text","marks":[{"type":"bold"}],"text":"11"},{"type":"text","text":")."}]},{"type":"figure","attrs":{"figcaption":"Figure 4: Cell-viability profile in the absence and presence of microsparger (MSP)–based control of dissolved oxygen. Adding O2 through a ring sparger generated cultures with lower cell-viability levels than did using MSP control."},"content":[{"type":"image","attrs":{"textAlign":"right","src":"https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/blt9de1eb543d39953c/670e59af870878446f78fa42/22-10-FR-Pavlistova-F4.jpg","alt":"22-10-FR-Pavlistova-F4.jpg","title":null,"style":{"float":"right","display":"inline-block","margin":"0","width":"auto","max-width":"auto","text-align":"right"}}},{"type":"text","text":"Figure 4: Cell-viability profile in the absence and presence of microsparger (MSP)–based control of dissolved oxygen. Adding O2 through a ring sparger generated cultures with lower cell-viability levels than did using MSP control."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Small, high-energy bubbles are known to influence cell-viability levels during cultivation "},{"type":"text","marks":[{"type":"bold"}],"text":"(43–45)"},{"type":"text","text":". Figure 4 shows the experimental demonstration confirming our hypothesis that differences in the dead-cell counts can be attributed to hydrodynamic stress generated when oxygen is added through a microsparger for %DO"},{"type":"text","marks":[{"type":"subscript"}],"text":"sat"},{"type":"text","text":" control. The higher viability observed with the microsparger-equipped vessel (the orange line in Figure 4) is associated with cell lysis due to hydrodynamic stress. Dead cells are unable to repair their biological structures, making them prone to lysis and less detectable than needed using traditional cell-counting methods. On the other hand, the vessel equipped with a ring sparger showed lower cell viability. Our data suggest that a ring sparger kept dead cells intact because it exerted lower hydrodynamic stress than did the microsparger. These results accord with literature reporting that small bubbles are linked to high-energy explosions that result in cell damage and concomitant cell death "},{"type":"text","marks":[{"type":"bold"}],"text":"(46)."}]},{"type":"figure","attrs":{"figcaption":"Figure 5: Performance comparison of three products based on recombinant adenoassociated virus (rAAV) vectors; our experimental data suggest nonsignificant variability obtained across high-throughput (HT), bench, and technology-transfer (TT) scales. (E:F = ratio of empty to full rAAV capsids)"},"content":[{"type":"image","attrs":{"textAlign":"right","src":"https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/blt2e0846baebda9c81/670e59ddd623b97aaa1e4b9e/22-10-FR-Pavlistova-F5.jpg","alt":"22-10-FR-Pavlistova-F5.jpg","title":null,"style":{"float":"right","display":"inline-block","margin":"0","width":"auto","max-width":"auto","text-align":"right"}}},{"type":"text","text":"Figure 5: Performance comparison of three products based on recombinant adenoassociated virus (rAAV) vectors; our experimental data suggest nonsignificant variability obtained across high-throughput (HT), bench, and technology-transfer (TT) scales. (E:F = ratio of empty to full rAAV capsids)"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"rAAV Production at Different Scales:"},{"type":"text","text":" After implementing operational conditions that matched cell-proliferation levels across the small (high-throughput, benchtop, and technology-transfer) and pilot/commercial scales, we further challenged our scale-down model to investigate whether production of different rAAV targets would result in similar performance. Figure 5 plots relative values for productivity (viral genomes per milliliter, vg/mL) and "},{"type":"text","marks":[{"type":"italic"}],"text":"E"},{"type":"text","text":":"},{"type":"text","marks":[{"type":"italic"}],"text":"F"},{"type":"text","text":" ratios for three rAAV products processed at high-throughput, benchtop, and technology-transfer scales, with results from the high-throughput processes set at 100%. We observed nonsignificant variability (95% confidence, "},{"type":"text","marks":[{"type":"italic"}],"text":"t"},{"type":"text","text":" test) across scales."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Similarly, we tracked the performance of a single rAAV product from high-throughput to pilot/commercial scale, assessing relative values for productivity (vg/mL), "},{"type":"text","marks":[{"type":"italic"}],"text":"E"},{"type":"text","text":":"},{"type":"text","marks":[{"type":"italic"}],"text":"F"},{"type":"text","text":" ratios, and infectivity (genome copies per infectious unit, gc/IU) with high-throughput values set as 100%. Results were consistent with our previous data, with nonsignificant variability across all scales (Figure 6). Thus, we confirmed that operational conditions selected for the different small-scale bioreactors accurately represented those for the pilot/commercial scale."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"figure","attrs":{"figcaption":"Figure 6: Performance comparison across scales for the same recombinant adenoassociated virus (rAAV) product; relative productivity (LEFT), relative ratios of empty to full rAAV capsids (E:F) (CENTER), and relative infectivity levels (RIGHT) all showed nonsignificant variability across commercial (COMM), technology-transfer (TT), bench (BEN), and high-throughput (HT) scales."},"content":[{"type":"image","attrs":{"textAlign":"left","src":"https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/blt5c5b287697a710ce/670e5b32f60eb073d89bf072/22-10-FR-Pavlistova-F6.jpg","alt":"22-10-FR-Pavlistova-F6.jpg","title":null,"style":{"float":"none","display":"inline-block","margin":"0","width":"auto","max-width":"auto","text-align":"none"}}},{"type":"text","text":"Figure 6: Performance comparison across scales for the same recombinant adenoassociated virus (rAAV) product; relative productivity (LEFT), relative ratios of empty to full rAAV capsids (E:F) (CENTER), and relative infectivity levels (RIGHT) all showed nonsignificant variability across commercial (COMM), technology-transfer (TT), bench (BEN), and high-throughput (HT) scales."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"The above results enable us to propose a new development pathway toward shortening timelines for rAAV production. Traditional approaches rely on small-scale experiments followed by confirmatory studies in different iterations at a larger scale. In our proposed workflow, initial studies can be performed at a high-throughput scale, then move directly to technology-transfer scale and further to pilot testing. Bypassing bench-scale and technology-transfer confirmation studies could shorten the development pathway by up to 20% — from 20 to 16 weeks — with significant decreases in development costs (Figure 7)."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"figure","attrs":{"figcaption":"Figure 7: Technoeconomic assessment of a traditional and proposed workflow for production of recombinant adenoassociated virus (rAAV) vectors; the size of each chart reflects the total development costs of its associated workflow. Each pie-chart fraction represents a work package related to developing a new rAAV product. The weeks listed refer to the time needed per work package, and listed percentages refer to the cost of a work package relative to total development costs. The new workflow represents a cost savings of 23%."},"content":[{"type":"image","attrs":{"textAlign":"left","src":"https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/blt0a12584517d1d7d7/670e5a8dec4a2f59ac3ef46d/22-10-FR-Pavlistova-F7.jpg","alt":"22-10-FR-Pavlistova-F7.jpg","title":null,"style":{"float":"left","display":"inline-block","margin":"0","width":"auto","max-width":"auto","text-align":"left"}}},{"type":"text","text":"Figure 7: Technoeconomic assessment of a traditional and proposed workflow for production of recombinant adenoassociated virus (rAAV) vectors; the size of each chart reflects the total development costs of its associated workflow. Each pie-chart fraction represents a work package related to developing a new rAAV product. The weeks listed refer to the time needed per work package, and listed percentages refer to the cost of a work package relative to total development costs. The new workflow represents a cost savings of 23%."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Conclusions"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Typical challenges to scaling cell-culture processes include defining and understanding the key phenomena that match performance across scales. Our work suggests that a good starting point is applying a combination of rational and empirical approaches. On one hand, the classical tool of regime analysis and other mathematical models helped us to constrain the design space of our cell-culture operation. On the other hand, empirical approaches for tuning PID controllers and matching bioreactor performance were essential to the endeavor of developing and validating a scale-down model based on the performance of a large-scale STR."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"The data presented suggest that operational conditions selected for high-throughput and bench scales achieved similar outcomes in larger-scale (technology-transfer and pilot/commercial) bioreactors, as shown by the statistically insignificant variability in productivity levels, "},{"type":"text","marks":[{"type":"italic"}],"text":"E"},{"type":"text","text":":"},{"type":"text","marks":[{"type":"italic"}],"text":"F"},{"type":"text","text":" ratios, and infectivity levels of different rAAV products."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"We believe that developing well-characterized and validated scale-down models at high-throughput scale (mL) will be essential to establishing a platform approach to process development and to accelerating time to market for rAAV products. The possibility of testing many conditions in a design-of-experiments (DoE) format in combination with empirical validation of scalability — and using no additional studies at intermediate bioreactor scales — would account for much of the substantial reductions in timelines and development costs."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Acknowledgments"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Experimental support, cell-growth data, and rAAV production data at technology-transfer scale were kindly provided by Sara Botas Sanmartin, Jeroen Verbruggen, Joyce Ijspelder, Maaike Steenkamp, Marsha Haneveld, Giorgio Rainone, Milja Pesic, Rupali Desai, Yang Jiang, and Tangir Ahamed, all part of the process development team of uniQure B.V. in Amsterdam, the Netherlands. Pilot-scale and (semi)commercial data were shared by the manufacturing science and technology (MSAT) team at uniQure Inc. in Lexington, MA, USA. Monika Golinska, Nasser Sadr, and their teams supported scalability assessment with analysis of the rAAV product and process intermediates. "}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Author Contributions"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Pavlištová performed data analysis and drafted the manuscript. Correia and Molina Gil performed critical experiments and supported them with data analysis. Van de Waterbeemd, Ljubovic-Couteau, and Streefland challenged and reviewed the experimental data and manuscript content. Cueto-Rojas designed experiments, challenged and reviewed data, and drafted this manuscript."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"References"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"1"},{"type":"text","text":" Jiang Z, Dalby PA. Challenges in Scaling Up AAV-Based Gene Therapy Manufacturing. 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Rep. 7(1) 2017: 15102; "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://doi.org/10.1038/s41598-017-14531-5","target":"_blank","rel":null,"class":null}}],"text":"https://doi.org/10.1038/s41598-017-14531-5"},{"type":"text","text":"."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Corresponding author "},{"type":"text","marks":[{"type":"bold"}],"text":"Tereza Pavlištová"},{"type":"text","text":" is a junior scientist in the Drug Substance Development department at uniQure B.V., Paasheuvelweg 25A, 1105BP, Amsterdam, the Netherlands; T.Pavlistova@uniqure.com. "},{"type":"text","marks":[{"type":"bold"}],"text":"Maria João Alves Correia"},{"type":"text","text":" is a senior bioprocess technologist, "},{"type":"text","marks":[{"type":"bold"}],"text":"Alejandro Molina Gil"},{"type":"text","text":" is a biotechnologist, "},{"type":"text","marks":[{"type":"bold"}],"text":"Edina Ljubovic-Couteau"},{"type":"text","text":" is senior director of global drug substance development, "},{"type":"text","marks":[{"type":"bold"}],"text":"Bas van de Waterbeemd"},{"type":"text","text":" is director of drug substance development, and "},{"type":"text","marks":[{"type":"bold"}],"text":"Mathieu Streefland"},{"type":"text","text":" is vice president, all in the Global Process Development department of uniQure B.V. Now with Koppert Biological Systems, "},{"type":"text","marks":[{"type":"bold"}],"text":"Hugo F. Cueto-Rojas"},{"type":"text","text":" was associate director and team lead of drug-substance development at uniQure at the time of writing."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"}}]},{"contentType":"Journal","thumbnail":{"src":"https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/blt6686041652618a41/671188a2abcdb71174946b0f/AdobeStock_458992830.jpg","alt":"Adobe Stock"},"contributors":[{"name":"William Whitford","link":"/author/william-whitford","avatar":""}],"articleName":"The Delivery Dilemma: Looking Beyond Viral Vectors for Gene Therapy","mobileHeadline":"The Delivery Dilemma: Looking Beyond Viral Vectors for Gene Therapy","articleUrl":"/gene-therapies/the-delivery-dilemma-looking-beyond-viral-vectors-for-gene-therapy","linkAttrs":{},"listPageUrl":"/journals","date":"Oct 15, 2024","webinarStartTime":"","articleSummary":"","articleBodyJsonSummary":"","variant":"small-has-summary","categoryName":"Gene Therapies","categoryUrl":"/therapeutic-modalities/gene-therapies","timeRead":0,"paidGating":null,"articleBody":[{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"The term gene therapy (GT) encompasses a range of strategies for modifying or influencing genetic information either to treat or to prevent disease. GTs include both systems that work by introducing, replacing, or altering the existing genetic material within a patient’s cells — often called gene-modified cell therapy when performed ex vivo — and those that use genetic material to influence or modulate the in vivo expression of genes. Probably for mechanistic reasons, other emerging therapies such as viral oncolytics sometimes are included in GT discussions. It’s helpful to understand that categorical statements regarding many aspects of GT can be difficult because of exceptions to some stated generalities about components and desired functions."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Some GTs involve genetic engineering systems as clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9). The combination provides a powerful gene-editing tool for precise and permanent modification of DNA sequences within cells. Oligonucleotide therapy, alternatively, delivers short DNA or RNA sequences (oligos) that generally modulate gene expression or correct a patient’s abnormal RNA function. Such products include antisense oligos (ASOs), small interfering RNA (siRNA), messenger RNA (mRNA), and others."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"There are two basic approaches to GT: in vivo and ex vivo therapies. In vivo GT introduces genetic or gene-altering materials directly into a patient’s body, with the therapeutic effect thus occurring within a living organism. In ex vivo GTs, patient or donor cells are collected, genetically modified in culture, often expanded in numbers, and then reintroduced into a patient (autologous therapy) or patients (allogeneic therapy)."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Viral vectors — e.g., adenovirus vectors (AdVs), adeno associated virus vectors (AAVs), and lentivirus vectors (LVVs) such as human immunodeficiency virus (HIV) — have proved to be the most GT popular delivery agents to date. They play a crucial role in packaging, protecting, stabilizing, and delivering gene-altering materials into cells "},{"type":"text","marks":[{"type":"bold"}],"text":"(1, 2)"},{"type":"text","text":". That said, other delivery methods are under exploration and development. Researchers are interested in identifying specific features (new advantages) and incremental benefits over viral vectors and alleviating known limitations of existing viral delivery methods. One advantage to nonviral vectors (NVVs) is their relative safety due to the absence of immunogenic viral proteins."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Viral-Vector Concerns"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Viral vectors can evoke immune responses in recipients, creating safety concerns. For example, viral-vectored GTs can be immunogenic when administered to individuals who have preexisting immunity to the specific type of virus used. An immunological response upon initial dosing could limit treatment effectiveness or, worse, endanger the patient. Viral-vectored products also can be immunostimulatory, inducing a response upon first administration that obviates their future use. In such cases, patients cannot receive the same product again (or others that use the same viral vector) in the future."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"In some systems, integration of viral DNA into the host genome might disrupt normal gene expression — e.g., through insertional mutagenesis — and even mediate disease "},{"type":"text","marks":[{"type":"bold"}],"text":"(3)"},{"type":"text","text":". Although vector viruses are engineered to be replication deficient, a slight risk of recombination remains and could result in undesired viral replication. Achieving specific targeting of viral vectors to desired tissues or cells can be difficult, and each virus has its own limitations in capacity for carrying large genes or therapeutic payloads. Some experts are concerned especially about the potential of low frequency, late-onset side effects "},{"type":"text","marks":[{"type":"bold"}],"text":"(1)"},{"type":"text","text":". And some concern remains regarding the spread of payloads to unintended tissues or organs — and even the potential for horizontal gene transfer to other organisms."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"In terms of design and customization to particular applications, viral vectors can be limited in flexibility and available options. Many researchers prefer to tailor drug-delivery systems to specific cargoes, therapeutic needs, and target cell types. When the delivery agent is a closed viral system, that can limit the adjustment of some parameters (e.g., inserted oligonucleotide size). Depending on the vector and type of GT being considered, viral genetic material could be introduced into a host genome in a nonengineered way, which raises concerns about insertional mutagenesis. NVVs lack the machinery to affect the integration of unintended genetic material into a host genome, which reduces the risk of potentially dangerous genetic alterations."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Producing viral vectors at scale with consistent quality is complex and costly, posing challenges for widespread therapeutic use. It involves complex biological systems, including cell cultures and viral replication cycles that require precise conditions to ensure vector stability and functionality "},{"type":"text","marks":[{"type":"bold"}],"text":"(4)"},{"type":"text","text":". Maintaining consistency and purity across batches of viral vectors is difficult, especially considering the risk of contamination by other viruses, mycoplasma, and unwanted cellular byproducts. Viral-vector production is labor intensive, and volumetric yields can be low, especially for lenti- and retroviruses. Scaling up can be quite complex and inflexible."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Benefits of Nonviral Vectors"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"My interest in delivery vectors began in the late 1970s while I was working in the laboratory of Demetrios Papahadjopoulos at Roswell Park Memorial Institute in Buffalo, NY. At the time, he was showing that liposomes could deliver entrapped drugs and vaccines to cells and thus eliminate some problems related to “raw” drug dosing. It wasn’t long before the idea arose for using liposomes to deliver DNA, which since then has culminated in the current idea of using such synthetic vesicles in GT and genetic immunization. All GT cargo carriers, including viral vectors, play a crucial role in protecting, stabilizing, and delivering genetic material to target cells."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Many different approaches now are in development for nonviral (mostly synthetic) delivery of cargo to treat genetic and acquired disorders with GT "},{"type":"text","marks":[{"type":"bold"}],"text":"(5)"},{"type":"text","text":". A renowned example of in vivo therapy using a nonviral delivery vector is mRNA COVID-19 vaccine technology. The SARS-CoV-2 spike protein is encoded in mRNA encapsulated within lipid nanoparticles (LNPs), which create a lipid bilayer to protect fragile mRNA from degradation and facilitate its functional delivery into recipients’ cells. Those cells then express the encoded protein, which induces a prophylactic immune response."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"With respect to the risk of immediate adverse immune reactions, NVVs typically are safer and less immunostimulatory than viral vectors. And as for vector flexibility, some NVVs can accommodate aspects of vector design, targeting, and customization to particular applications that are not possible with viral systems. Some researchers tailor lipid or polymeric nanoparticles (as well as other NVVs) to suit specific nucleic-acid cargoes, therapeutic needs, and target cell types. And some NVVs have the capacity for larger payloads than viral vectors can carry. That can support delivery of larger oligonucleotide sequences and even multiple therapeutic agents at once, making NVVs suitable for delivering complex therapeutic payloads."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"More versatile NVVs can be used to develop platforms for delivering an array of nucleic acids. Such adaptability enables NVV developers to design approaches for a range of GT initiatives. Engineering to enhance tissue targeting and specificity is a current concern for many GT programs. NVVs often can provide a breadth of possibilities for improving the precision of gene delivery to desired tissue or cell types. Such methods have been investigated for both in vitro and in vivo applications, with some more advanced for one than the other."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Note that scale considerations can constitute a significant factor in viral-vector manufacturing. Some NVVs are easier and less expensive to transfer into production and manufacture at scale by comparison. That facility can reduce the cost of at-scale manufacturing — savings that could help to reduce costs for payers and patients — while improving the effectiveness of GT treatments."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"So the advantages of nonviral vectors include reduced risk of inflammation, toxicity, and other immune-related complications "},{"type":"text","marks":[{"type":"bold"}],"text":"(5, 6)"},{"type":"text","text":". Because they elicit lower immune responses, most can be administered multiple times without losing effectiveness, which is especially beneficial for chronic conditions that require ongoing treatment. NVVs — especially those made from biodegradable materials — present a reduced risk of insertional mutagenesis and can be less toxic. Chemically based vectors are typically easier and less expensive to produce at large scale compared to viral vectors, often with less variation between batches. Nonviral vectors can be designed with specific targeting ligands that enhance delivery to specific tissues or cell types, thus improving therapeutic efficacy and making them less likely to affect unintended tissues or organs."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Nonviral Technologies in Development"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"A number of nonviral vector systems are in different stages of development. These include virus-like particles (VLPs), lipid nanoparticles (LNPs), exosomes, polysaccharide macromolecules, cell-penetrating peptides (CPPs), inorganic nanoparticles, electroporation technologies, ultrasound methods, and polymer hydrogels "},{"type":"text","marks":[{"type":"bold"}],"text":"(7–10)"},{"type":"text","text":"."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"VLPs"},{"type":"text","text":" are noninfectious particles that mimic the structure of viruses but lack any viral genetic material. They can be engineered to carry and deliver therapeutic nucleic acids. Possible approaches to producing VLPs include mammalian, yeast, insect cell, bacterial, and plant cell-based expression systems."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"LNPs"},{"type":"text","text":" currently are the most popular alternative to viral vectors. Lipid structures of about 20–200 nm in diameter can serve as carriers or delivery vectors for nucleic acids such as mRNA, siRNA, and other oligonucleotides. Other related nanoparticles made from biocompatible polymers such as polyethylenimine (PEI) and poly(lactic-co-glycolic acid) (PLGA), and also can be used for nucleic-acid delivery."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Exosomes"},{"type":"text","text":" are naturally occurring extracellular vesicles with a lipid bilayer structures by which they encapsulate and protect biomolecules within them. Exosomes can be engineered to carry many different types of cargo and show reduced immunogenicity compared with LNPs and VLPs. The precision and efficiency of gene delivery is promoted by an ability to display specific targeting molecules on the exosome surface. These structures are relatively stable and have the ability to permeate such thresholds as the blood–brain barrier."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Exosomes"},{"type":"text","text":" can present many advantages over other vector options "},{"type":"text","marks":[{"type":"bold"}],"text":"(11)"},{"type":"text","text":". Being naturally derived from cells makes them inherently biocompatible and less likely to trigger an immune response or cause cytotoxicity. Because the biomimetic membrane composition of even engineered exosomes resembles that of target cells, the exosomes can fuse with recipient cells efficiently, which facilitates uptake and delivery of their cargo. They can be engineered to express specific surface proteins or ligands that enable targeted delivery to particular cell types or tissues. Exosomes tend to be more stable in circulation than many other vectors, protecting their cargo from degradation by enzymes. They can carry a variety of biological molecules — proteins, RNA (such as mRNA, miRNA, siRNA), and DNA — without affecting a recipient’s genome."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"image","attrs":{"textAlign":"left","src":"https://eu-images.contentstack.com/v3/assets/blt0a48a1f3edca9eb0/blt538e697df5de8783/670e4f464ebca25e6c9499fb/2G81R50.jpg","alt":"2G81R50.jpg","title":null,"style":{"max-width":"337px","width":"337","height":"auto"}}}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Polysaccharide macromolecules "},{"type":"text","text":"such as chitosan and cyclodextrin are promising for their biocompatibility, enhanced cellular uptake, and versatility. Highly branched poly(β-amino esters) (HPAEs) offer versatility in synthesis, biocompatibility, and an ability to be functionalized with targeting ligands such as antibodies or peptides to improve the specificity of drug delivery."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Cell-Penetrating Peptides"},{"type":"text","text":" (CPPs) are short sequences of amino acids that have the ability to cross cell membranes and facilitate the delivery of various cargos (12). They have shown promise in delivering small molecules, proteins, nucleic acids, and nanoparticles. CPPs typically enter cells through endocytosis or direct translocation across membranes. Depending on their design and the nature of their cargo, CPPs can release cargo in either the cytoplasm or in specific organelles. A versatile tool for drug delivery that is less toxic than other options, CPPs can be modified to target specific cell types or tissues. However, they are susceptible to degradation (e.g., by proteases), which limits their effectiveness and could lead to toxicity or limited target specificity. Some CPPs have been observed to accumulate in endosomes, limiting cytoplasmic delivery."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Inorganic Nanoparticles:"},{"type":"text","text":" Jet-injection devices and “gene guns” are physical (nonchemical) methods for delivering nucleic acids directly into living tissue. Jet injection forces high-pressure streams of oligo-containing buffers directly into tissue. Gene guns use high-velocity particles such as porous platinum pellets and carbon nanotubes to deliver their genetic cargo."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"These more “mechanical” methods of gene delivery derive some distinct advantages from not being biologically directed mechanisms "},{"type":"text","marks":[{"type":"bold"}],"text":"(13, 14)"},{"type":"text","text":". However, they do demonstrate some significant limitations, especially in therapeutic application. For example, they lack precision in targeting specific cell types and can cause significant damage to the target cells or tissue. They can also exhibit inconsistent delivery efficiency and have more limited cargo capacity compared with other options. The depth of penetration into tissue is limited for particles and globules, which restricts the use of such methods to tissue surfaces and cell monolayers."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Electroporation"},{"type":"text","text":" applies electric pulses to create temporary pores or small holes in cell membranes. Simply formulated oligos then can enter the cells through those openings."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Ultrasound"},{"type":"text","text":" can be used alternatively to enhance the permeability of cell membranes for nucleic-acid delivery. This is one of the most noninvasive NVV options and has been investigated for both in vitro and in vivo applications."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Hydrogels "},{"type":"text","text":"are three-dimensional (3D) networks of hydrophilic polymers that carry buffers and genetic cargo. These structures can be designed for controlled release of nucleic acids and offer particular utility for localized in vivo delivery."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Many Means to an End"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"GT research is ongoing as NVV alternatives to viral vectors are continually refined and improved. The choice of delivery method for a given product will depend on factors such as the specific therapeutic application, target cells, and biophysical/biochemical characteristics of the nucleic acids to be delivered."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"Over a dozen GT products have been approved so far to treat both genetic and acquired diseases — and clinical trials continue to be initiated for new product candidates. Some type of vector will be required to focus and deliver every GT cargo to target cells, whether in vivo or ex vivo. Engineered viruses currently comprise the majority of vectors in use, but they each have limitations. Developers have many diverse GT delivery tools to consider that could provide relief from those limitations, or provide additional benefit, with cost and scale benefits coming as potential and welcome side effects."}]},{"type":"paragraph","attrs":{"textAlign":"left"}},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"References"}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"1"},{"type":"text","text":" Lundstrom K. Viral Vectors in Gene Therapy: Where Do We Stand in 2023? Viruses 15(3) 2023: 698; "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://doi.org/10.3390/v15030698. ","target":"_blank","rel":null,"class":null}}],"text":"https://doi.org/10.3390/v15030698."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"2"},{"type":"text","text":" Zhao Z, Anselmo AC, Mitragotri S. Viral Vector-Based Gene Therapies in the Clinic. Bioeng. Transl. Med. 7(1) 2022: e10258; "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://doi.org/10.1002%2Fbtm2.10258.","target":"_blank","rel":null,"class":null}}],"text":"https://doi.org/10.1002%2Fbtm2.10258."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"3"},{"type":"text","text":" Kumar SRP, Duan D, Herzog RW. Immune Responses to Muscle-Directed Adeno-Associated Viral Gene Transfer in Clinical Studies. Human Gene Ther. 34 (9–10) 2023; "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://doi.org/10.1089/hum.2023.056.","target":"_blank","rel":null,"class":null}}],"text":"https://doi.org/10.1089/hum.2023.056."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"4"},{"type":"text","text":" Jiang Z, et al. Challenges in Scaling Up AAV-Based Gene Therapy Manufacturing. 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Technological Advances in the Use of Viral and Non-Viral Vectors for Delivering Genetic and Non-Genetic Cargos for Cancer Therapy. Drug Deliv. Transl. Res. 13, 2023: 2719–2738; "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://doi.org/10.1007/s13346-023-01362-3.","target":"_blank","rel":null,"class":null}}],"text":"https://doi.org/10.1007/s13346-023-01362-3."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"7"},{"type":"text","text":" Ledesma-Feliciano C, et al. Improved DNA Vaccine Delivery with Needle-Free Injection Systems. Vaccines 11(2) 2023: 280;"},{"type":"text","marks":[{"type":"link","attrs":{"href":" https://doi.org/10.3390/vaccines11020280. ","target":"_blank","rel":null,"class":null}}],"text":" https://doi.org/10.3390/vaccines11020280."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"8"},{"type":"text","text":" Lemprière S. 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Recent Advances in Selective and Targeted Drug/Gene Delivery Systems Using Cell-Penetrating Peptides. Arch. Pharm. Res. 46, 2023: 18–34; "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://doi.org/10.1007/s12272-022-01425-y.","target":"_blank","rel":null,"class":null}}],"text":"https://doi.org/10.1007/s12272-022-01425-y."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"11"},{"type":"text","text":" Koh HB, et al. Exosome-Based Drug Delivery: Translation from Bench to Clinic. Pharmaceutics 15(8) 2023: 2042; "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://doi.org/10.3390/pharmaceutics15082042.","target":"_blank","rel":null,"class":null}}],"text":"https://doi.org/10.3390/pharmaceutics15082042."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"12"},{"type":"text","text":" Sun Z, et al. Cell-Penetrating Peptide-Based Delivery of Macromolecular Drugs: Development, Strategies, and Progress. Biomedicines 11, 2023: 1971; "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://doi.org/10.3390/biomedicines11071971.","target":"_blank","rel":null,"class":null}}],"text":"https://doi.org/10.3390/biomedicines11071971."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"13 "},{"type":"text","text":"Oelkrug C. Analysis of Physical and Biological Delivery Systems for DNA Cancer Vaccines and Their Translation to Clinical Development. Clin. Exp. Vacc. Res. 13(2) 2024: 73–82; "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://doi.org/10.7774/cevr.2024.13.2.73. ","target":"_blank","rel":null,"class":null}}],"text":"https://doi.org/10.7774/cevr.2024.13.2.73."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"14"},{"type":"text","text":" Shchaslyvyi AY, et al. Current State of Human Gene Therapy: Approved Products and Vectors. Pharmaceuticals 16, 2023: 1416; "},{"type":"text","marks":[{"type":"link","attrs":{"href":"https://doi.org/10.3390/ph16101416","target":"_blank","rel":null,"class":null}}],"text":"https://doi.org/10.3390/ph16101416."}]},{"type":"paragraph","attrs":{"textAlign":"left"},"content":[{"type":"text","text":"BPI editorial advisor "},{"type":"text","marks":[{"type":"bold"}],"text":"William Whitford"},{"type":"text","text":" is an independent consultant based in Logan, UT, who most recently served as life-sciences strategic solutions leader at Arcadis and can be reached at williamg.whitford@gmail.com."}]},{"type":"paragraph","attrs":{"textAlign":"left"}}]}]},"metadata":{"type":"publication issue","sourceType":"List of Entries","uid":"blt0ac4ef6929fdee7e","aid":"420426","reg":"anonymous","pterm":{"main":"BPI Issue Archive","parent":"","grandparent":{"title":""},"additional":[]},"contributor":[],"gatedWithExternalForm":false,"gatedWithSiteReg":false,"paidGating":false,"sponsorName":""},"schema":[{"@context":"https://schema.org","@type":"BreadcrumbList","itemListElement":[{"@type":"ListItem","position":1,"name":"Home","item":"https://www.bioprocessintl.com"},{"@type":"ListItem","position":2,"name":"publications","item":"https://www.bioprocessintl.com/publications"},{"@type":"ListItem","position":3,"name":"Featured Reports","item":"https://www.bioprocessintl.com/publications/featured-reports"},{"@type":"ListItem","position":4,"name":"October 2024 Featured Report","item":"https://www.bioprocessintl.com/publications/featured-reports/october-2024-featured-report"}]}]}},"actionData":null,"errors":null}};</script><script type="module" async="">import "/build/manifest-1DDC3B48.js"; import * as route0 from "/build/root-EIFOE2ED.js"; import * as route1 from "/build/routes/publications.$slug.$issue-HVOPFRJZ.js"; window.__remixRouteModules = {"root":route0,"routes/publications.$slug.$issue":route1}; import("/build/entry.client-IJHKMLWO.js");</script><script async="" defer="" src="https://connect.facebook.net/en_US/sdk.js#xfbml=1&version=v3.2"></script><script async="" defer="" src="https://www.instagram.com/embed.js"></script></body></html>