The biopharmaceutical industry is driven by the need to increase production and reduce costs, while maintaining product quality – and has increasingly been focused on intensification of processes to accomplish this goal. In this article, European Pharmaceutical Review’s Hannah Balfour summarises the potential benefits of implementing continuous bioprocessing and manufacturing as a method of process intensification, the current state of continuous process implementation and some ongoing challenges.
BIOPHARMACEUTICALS are a $331 billion industry,1 known for their precision, innovativeness and life-changing potential; however, stringent regulations and complex bioproduction methods that result in high manufacturing and product costs continue to limit the growth of this otherwise thriving sector.
To cut expenditure and complexity, as well as enhance process efficiency for large-scale biologics manufacturing, the industry is investing in the R&D of intensified bioprocesses. One such method under development is continuous biomanufacturing – the production of finished biopharmaceuticals using an uninterrupted process, consisting of an integrated sequence of more than one unit operation.
Continuous bioprocessing is a single unit operation within biomanufacturing where raw materials are continuously loaded, processed and unloaded. This market was valued at just $82 million in 2020 but is expected to quadruple over the next few years, growing to almost $350 million by 2027 at an anticipated 23 percent compound annual growth rate (CAGR).2 Market research suggests the major factors encouraging this growth include the rising demand for biopharmaceuticals, technological developments in continuous bioprocessing, and various initiatives supporting its adoption, as well as the shift towards digitalisation and automation driven by Pharma 4.0.2
This report addresses the key factors shaping pharmaceutical formulation, including regulation, QC and analysis.
Access the full report now to discover the techniques, tools and innovations that are transforming pharmaceutical formulation, and learn how to position your organisation for long-term success.
What you’ll discover:
Key trends shaping the pharmaceutical formulation sector
Innovations leading progress in pharmaceutical formulation and how senior professionals can harness their benefits
Considerations and best practices when utilising QbD during formulation of oral solid dosage forms
Why develop and implement continuous manufacturing?
The biopharmaceuticals sector is inherently complex. While the rising adoption of personalised therapies, such as autologous cell therapies, calls for extremely small batches and manufacturing flexibility, increased demand for allogeneic products, therapeutic proteins such as antibodies and vaccines conversely necessitates large-scale production of quality products. While batch is a well-established manufacturing doctrine that provides process flexibility and requires less precise and robust controls, it is somewhat inefficient for the larger-scale production requirements of the modern-day biopharmaceutical industry, since it enhances complexity and thus costs. Continuous manufacturing, however, offers the benefit of streamlined processes and a reduced manufacturing facility footprint to produce vast volumes of low-cost, high-quality biopharmaceuticals. The potential benefits of continuous manufacturing are too numerous for complete examination, so here I review two of the key ones: process efficiency and cost, and product quality.
The continuous manufacturing price tag
The economic benefits of continuous manufacturing include reduced capital expenditures, smaller facility footprints and lower overall cost of goods.3 This has been confirmed in various studies and reviews – the key findings of several are outlined below
The economic benefits of continuous manufacturing include reduced capital expenditures, smaller facility footprints and lower overall cost of goods”
In a paper evaluating the cost of goods resulting from continuous manufacturing for liposomal formulations, Worsham et al. found that the continuous process produced 1,053 filled units/h, where the batch process only produced 125 units/h. This was an “8.4-fold increase in output for the same overhead costs based on units per hour and a 24-fold output increase for the same process preparation costs and single-use componentry costs.”3 However, they noted that this does not take into account costs needed to implement a continuous manufacturing setup. In terms of monoclonal antibody (mAb) production, Mahal et al. compared costs for single‑use and stainless-steel batch, single-use continuous and single-use hybrid (combining batch and continuous elements) bioprocessing setups across commercial scales of mAb production from 100 to 3,000 kg/year. They found that both single-use batch and continuous setups had an approximately 35 percent advantage in terms of cost of goods over stainless steel batch at 100 kg/year. Beyond production of 500 kg/year, single-use batch became less favourable, and from 1,000 kg/year the continuous facilities became at least as cost effective as stainless-steel batch, if not more (nine percent advantage at 3,000 kg/ year).4 They concluded that across the whole project lifecycle, end-to-end continuous facilities become more cost effective than stainless-steel batch facilities when accounting for costs from both drug development and commercial activities.
Quality benefits
Another potential benefit of continuous bioprocessing and manufacturing is that it can increase quality and consistency of the end product, primarily because it requires more stringent controls and monitoring. The implementation of process analytical technologies (PAT) provides operators with greater control of the cellular environment and metabolism, as well as the overall production environment, which should therefore increase control over final product quality.5 In a study comparing the impacts of fed batch and perfusion platforms on process and product attributes for immunoglobulin G1 (IgG1)- and G4 (IgG4)-producing cell lines, Walther et al. reported that perfusion (continuous) cultures decreased intra-lot heterogeneity. They showed that though fed batch produced product concentrations 2.5 times greater than perfusion, perfusion cultures had 7.5 times more productivity. Their study shows that not only is the batch process more variable in terms of environment and metabolism, but that the products were more likely to be exposed to extracellular enzymes that could degrade them. Overall, they found that the IgG1 perfusion product had higher purity and lower fragmentation (half‑antibody), though both processes had similar glycosylation.5 The numerous other potential advantages include:
Smaller equipment and manufacturing footprint
Reduced waste
Potential for real-time release of products
Faster time-to-market with reduced holding and processing times.
For more detail, a broad examination of the benefits was published by Chong Hock et al. in the Generics and Biosimilars Initiative Journal earlier this year.6
Which continuous bioprocessing technologies are currently in use?
Despite the evident benefits, the application of continuous processing – especially in full end-to-end continuous manufacturing setups – remains limited in the biopharmaceutical industry. In terms of application, continuous upstream processes are more established, with perfusion technologies having been on the market for decades and approximately 20 US Food and Drug Administration (FDA)-approved biologics currently manufactured using this process.7 The majority of these are antibodies and enzymes.
Despite the evident benefits, the application of continuous processing – especially in full end-to-end continuous manufacturing setups – remains limited in the biopharmaceutical industry”
Perfusion processes keep cell counts constant while the culture supernatants are refreshed at regular intervals, allowing for large product volumes to accumulate. In recent years, advances have enabled some systems to support 10-fold higher cell concentrations, over 100 × 106 cells/ml,8 and thus generate higher product titers. However, for the most part, culture media and additives preparation is still done in batches, and cumulative sales of leading alternating tangential flow (ATF) perfusion systems are relatively low after 15 years.9 The implementation of continuous downstream processes has lagged somewhat. This is primarily because it is more challenging to operate in this manner, since each downstream bioprocessing step uses only a fraction of the material from the step before, as the product becomes increasingly refined. However, some continuous chromatography solutions such as countercurrent chromatography have entered the market. These overcome the step issue by spatially separating the various processes (washing, elution, etc) into individual chromatography columns.7 In 2020, the 17th Annual Report and Summary of Biopharmaceutical Manufacturing Capacity and Production reported that 44.2 percent of biopharma professionals were evaluating upstream continuous processing or perfusion technologies and 40 percent downstream continuous purification or chromatography systems.10 The authors found that biomanufacturers were leading in terms of investigating continuous upstream bioprocessing, while contract manufacturing organisations (CMOs) led the charge on downstream process investigations. The two were almost equally matched (38.1 and 40 percent, respectively) in terms of their investigation of automating process controls and monitoring.10
Room for future development
To capitalise on the potential of continuous manufacturing, there are certain challenges that must be overcome, including clarification of regulations and facilitating flexibility, while also balancing environmental sustainability.11 The ICH recently released its draft Q13 guideline on Continuous Manufacturing of Drug Substances and Drug Products12 for public consultation. This guidance is anticipated to come into effect in late 2022 or early 2023 and provides “scientific and regulatory considerations for the development, implementation, operation and lifecycle management of continuous manufacturing”. The guidance is specifically aimed at small organic molecules and therapeutic proteins, yet may also be applicable to larger biological molecules.
With the publication of ICH Q13 on the horizon, and other regulatory efforts to encourage continuous biomanufacturing, the future seems bright for this exciting production approach”
Flexibility is essential in biopharmaceutical manufacturing, given the ever-changing supply demands for products. Flexibility enables manufacturers to cope with changes in need, such as the COVID-19 pandemic demand surges, or more typical changes to clinical trials or clinical adoption timelines. However, continuous bioprocessing facilities are not only found to be more efficient in single-product, high-volume manufacturing runs, but are also often made specifically to manufacture a single product, rather than adapt for different processes.11 These both limit flexibility; thus, to overcome them, R&D efforts are underway to intensify processes and create modular biomanufacturing platforms. Additionally, the implementation of single-use systems has been used to improve flexibility; allowing bioreactors, chromatography columns and filters to be disposed of after each run and enabling a simpler shift to a new product or process.11 However, there are some limitations, including their unsuitability for very high cell densities and substantial environmental impact.11 In terms of environmental sustainability, experts state that appropriate waste disposal procedures are crucial to adopting these systems and that, if done correctly, continuous bioprocessing could actually improve sustainability by requiring a smaller setup, limiting wastage, enhancing productivity and efficiency, and enabling automation.11
Final thoughts
The potentially transformative effect continuous bioprocessing and manufacturing could have on the biopharmaceutical industry is immense. Research has shown that end-to-end continuous bioprocessing could reduce cost of goods by 30 percent, minimise intra-product heterogeneity and increase quality, all within a smaller setup. However, to capitalise on these potential benefits, regulatory clarity and other technical considerations, including enhanced process flexibility, must be addressed. With the publication of ICH Q13 on the horizon, and other regulatory efforts to encourage continuous biomanufacturing, the future seems bright for this exciting production approach.
About the author
Hannah Balfour is the Assistant Editor of European Pharmaceutical Review
References
Infogence Global Research. Global Biopharmaceutical Market (2021-2026) by Product Type, Therapeutic Application, Geography, Competitive Analysis and the Impact of Covid-19 with Ansoff Analysis [Internet]. Infogence Global Research; 2021. Available from: https://www.researchandmarkets.com/reports/…
Meticulous Market Research Pvt. Ltd. Continuous Bioprocessing Market by Product (Filtration, Chromatography, Centrifuges, Consumables), Application (Commercial {Vaccines, Monoclonal Antibodies}, R&D), End User (Pharmaceuticals, Biotechnology, CROs), and Geography – Forecast to 2028 [Internet]. 2021. Available from: https://www.researchandmarkets.com/reports/5337908…
Worsham R, Thomas V, Farid S. Potential of Continuous Manufacturing for Liposomal Drug Products. Biotechnology Journal. 2018;14(2):1700740.
Mahal H, Branton H, Farid S. End‐to‐end continuous bioprocessing: Impact on facility design, cost of goods, and cost of development for monoclonal antibodies. Biotechnology and Bioengineering. 2021;118(9):3468-3485.
Walther J, Lu J, Hollenbach M, et al. Perfusion Cell Culture Decreases Process and Product Heterogeneity in a Head‐to‐Head Comparison With Fed‐Batch. Biotechnology Journal. 2018;14(2):1700733.
Hock S, Siang T, Wah C. Continuous manufacturing versus batch manufacturing: benefits, opportunities and challenges for manufacturers and regulators. Generics and Biosimilars Initiative Journal. 2021;10(1):44-56.
Clincke M, Mölleryd C, Zhang Y, et al. Very high density of CHO cells in perfusion by ATF or TFF in WAVE bioreactor™. Part I. Effect of the cell density on the process. Biotechnology Progress. 2013;29(3):754-767.
Langer E. Biomanufacturing: Demand for Continuous Bioprocessing Increasing – Bioprocess Development Forum [Internet]. Processdevelopmentforum.com. 2020 [cited 13 September 2021]. Available from: http://www.processdevelopmentforum.com/articles/biomanufacturing…
TOP 15 TRENDS IN BIOPHARMACEUTICAL MANUFACTURING, 2020 [Internet]. 17th ed. Rockville, Maryland: BioPlan Associates, Inc.; 2020 [cited 13 September 2021]. Available from: http://www.biopharma.com/TRENDS.pdf
Kumar A, Udugama I, Gargalo C, Gernaey K. Why Is Batch Processing Still Dominating the Biologics Landscape? Towards an Integrated Continuous Bioprocessing Alternative. Processes. 2020;8(12):1641.
CONTINUOUS MANUFACTURING OF DRUG SUBSTANCES AND DRUG PRODUCTS Q13 [Internet]. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH); 2021 [cited 13 September 2021]. Available from: https://database.ich.org/sites/default/…
This website uses cookies to enable, optimise and analyse site operations, as well as to provide personalised content and allow you to connect to social media. By clicking "I agree" you consent to the use of cookies for non-essential functions and the related processing of personal data. You can adjust your cookie and associated data processing preferences at any time via our "Cookie Settings". Please view our Cookie Policy to learn more about the use of cookies on our website.
This website uses cookies to improve your experience while you navigate through the website. Out of these cookies, the cookies that are categorised as ”Necessary” are stored on your browser as they are as essential for the working of basic functionalities of the website. For our other types of cookies “Advertising & Targeting”, “Analytics” and “Performance”, these help us analyse and understand how you use this website. These cookies will be stored in your browser only with your consent. You also have the option to opt-out of these different types of cookies. But opting out of some of these cookies may have an effect on your browsing experience. You can adjust the available sliders to ‘Enabled’ or ‘Disabled’, then click ‘Save and Accept’. View our Cookie Policy page.
Necessary cookies are absolutely essential for the website to function properly. This category only includes cookies that ensures basic functionalities and security features of the website. These cookies do not store any personal information.
Cookie
Description
cookielawinfo-checkbox-advertising-targeting
The cookie is set by GDPR cookie consent to record the user consent for the cookies in the category "Advertising & Targeting".
cookielawinfo-checkbox-analytics
This cookie is set by GDPR Cookie Consent WordPress Plugin. The cookie is used to remember the user consent for the cookies under the category "Analytics".
cookielawinfo-checkbox-necessary
This cookie is set by GDPR Cookie Consent plugin. The cookie is used to store the user consent for the cookies in the category "Necessary".
cookielawinfo-checkbox-performance
This cookie is set by GDPR Cookie Consent WordPress Plugin. The cookie is used to remember the user consent for the cookies under the category "Performance".
PHPSESSID
This cookie is native to PHP applications. The cookie is used to store and identify a users' unique session ID for the purpose of managing user session on the website. The cookie is a session cookies and is deleted when all the browser windows are closed.
viewed_cookie_policy
The cookie is set by the GDPR Cookie Consent plugin and is used to store whether or not user has consented to the use of cookies. It does not store any personal data.
zmember_logged
This session cookie is served by our membership/subscription system and controls whether you are able to see content which is only available to logged in users.
Performance cookies are includes cookies that deliver enhanced functionalities of the website, such as caching. These cookies do not store any personal information.
Cookie
Description
cf_ob_info
This cookie is set by Cloudflare content delivery network and, in conjunction with the cookie 'cf_use_ob', is used to determine whether it should continue serving “Always Online” until the cookie expires.
cf_use_ob
This cookie is set by Cloudflare content delivery network and is used to determine whether it should continue serving “Always Online” until the cookie expires.
free_subscription_only
This session cookie is served by our membership/subscription system and controls which types of content you are able to access.
ls_smartpush
This cookie is set by Litespeed Server and allows the server to store settings to help improve performance of the site.
one_signal_sdk_db
This cookie is set by OneSignal push notifications and is used for storing user preferences in connection with their notification permission status.
YSC
This cookie is set by Youtube and is used to track the views of embedded videos.
Analytics cookies collect information about your use of the content, and in combination with previously collected information, are used to measure, understand, and report on your usage of this website.
Cookie
Description
bcookie
This cookie is set by LinkedIn. The purpose of the cookie is to enable LinkedIn functionalities on the page.
GPS
This cookie is set by YouTube and registers a unique ID for tracking users based on their geographical location
lang
This cookie is set by LinkedIn and is used to store the language preferences of a user to serve up content in that stored language the next time user visit the website.
lidc
This cookie is set by LinkedIn and used for routing.
lissc
This cookie is set by LinkedIn share Buttons and ad tags.
vuid
We embed videos from our official Vimeo channel. When you press play, Vimeo will drop third party cookies to enable the video to play and to see how long a viewer has watched the video. This cookie does not track individuals.
wow.anonymousId
This cookie is set by Spotler and tracks an anonymous visitor ID.
wow.schedule
This cookie is set by Spotler and enables it to track the Load Balance Session Queue.
wow.session
This cookie is set by Spotler to track the Internet Information Services (IIS) session state.
wow.utmvalues
This cookie is set by Spotler and stores the UTM values for the session. UTM values are specific text strings that are appended to URLs that allow Communigator to track the URLs and the UTM values when they get clicked on.
_ga
This cookie is set by Google Analytics and is used to calculate visitor, session, campaign data and keep track of site usage for the site's analytics report. It stores information anonymously and assign a randomly generated number to identify unique visitors.
_gat
This cookies is set by Google Universal Analytics to throttle the request rate to limit the collection of data on high traffic sites.
_gid
This cookie is set by Google Analytics and is used to store information of how visitors use a website and helps in creating an analytics report of how the website is doing. The data collected including the number visitors, the source where they have come from, and the pages visited in an anonymous form.
Advertising and targeting cookies help us provide our visitors with relevant ads and marketing campaigns.
Cookie
Description
advanced_ads_browser_width
This cookie is set by Advanced Ads and measures the browser width.
advanced_ads_page_impressions
This cookie is set by Advanced Ads and measures the number of previous page impressions.
advanced_ads_pro_server_info
This cookie is set by Advanced Ads and sets geo-location, user role and user capabilities. It is used by cache busting in Advanced Ads Pro when the appropriate visitor conditions are used.
advanced_ads_pro_visitor_referrer
This cookie is set by Advanced Ads and sets the referrer URL.
bscookie
This cookie is a browser ID cookie set by LinkedIn share Buttons and ad tags.
IDE
This cookie is set by Google DoubleClick and stores information about how the user uses the website and any other advertisement before visiting the website. This is used to present users with ads that are relevant to them according to the user profile.
li_sugr
This cookie is set by LinkedIn and is used for tracking.
UserMatchHistory
This cookie is set by Linkedin and is used to track visitors on multiple websites, in order to present relevant advertisement based on the visitor's preferences.
VISITOR_INFO1_LIVE
This cookie is set by YouTube. Used to track the information of the embedded YouTube videos on a website.