Continuous Processing in the Biopharmaceutical Industry
Continuous processing is believed to be the next step for process intensification in the evolution of biopharmaceuticals.
The biopharmaceutical industry is seeing several changes including an increasing number of biosimilars and multiple therapies targeting the same indication. This increases the cost pressure but also reduces the required batch size and calls for a re-evaluation of manufacturing strategies. In addition, the expression levels for monoclonal antibodies could be increased by one order of magnitude over the last two decades which shift s the bottleneck further downstream requiring an intensified operation in downstream processing. These are market drivers that have accelerated the interest for continuous manufacturing principles.
This article provides an overview of the concepts of continuous processing and its level of adoption in the biopharmaceutical industry today. In addition, current challenges of process intensification are discussed.
From Batch to Continuous
Today's standard batch manufacturing is comprised of a cascade of processes where the product is routed through one unit operation at a time and is collected in hold containers in between. This can limit both facility utilization and productivity. Integrated processing on the other hand includes the use of continuous unit operations where product moves through a series of unit operations without interruption as shown in fi g. 1 (p. 14). This design allows reducing the size of unit operations which translates into buffer, resin and consumable savings, and enables larger processing scales to be handled with single-use technologies. The reduced size and number of hold tanks also leads to a shorter residence time of the product in the overall process.
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Advantages of continuous manufacturing are seen in unprecedented control over product quality, better agility and flexibility to respond to patient needs or reduced risk of scale-up through smaller equipment and facilities. In addition, a faster product release can target a timely response to patient needs. The potential in process economics and product quality control are at hand and development towards the implementation of integrated processes at end users, suppliers and the regulatory community can be seen to pick up speed and gain significance.
Fig. 1: Process sequence and timing of a typical batch process (top) and an integrated continuous
Continuous Bioprocessing in Industry today
Continuous upstream processing (USP) has been a reality for over a decade and multiple biopharmaceutical products from perfusionbased USP can be found on the market today. With integrated downstream processing (DSP), the situation is different: fully integrated DSP has been presented at process development scale by multiple companies including Bayer (Leverkusen, DE), Merck (Kenilworth, US) and MedImmune (Gaithersburg, US). As first biopharmaceutical company BiosanaPharma (Leiden, NL) has received regulatory approval in February 2019 to move to phase I clinical trials with a biosimilar monoclonal antibody originating from fully integrated manufacture3.
The majority of end users is seen to take smaller steps towards the implementation of novel technologies by evaluating hybrid processing modes. Hybrid processes represent a mix of batch technologies and novel integrated steps to address a bottleneck in production or a cost- and labour-intense operation. Continuous chromatography capture is thereby one of the most frequently implemented continuous processing steps in hybrid processing next to single-pass tangential flow applications for in-process volume reduction or concentration2. Data from hybrid processing evaluation at manufacturing scale have among others been presented by Sanofi Aventis (Frankfurt, DE), Merck (Kenilworth, US) or BMS (Devens, US).
Today, technologies for intensified processing are available from multiple suppliers and can cover the full process from USP to final filtration of bulk product in DSP. A variety of single-use solutions are available for process development scales and most technologies can be directly scaled to manufacturing anticipating batch sizes of up to 2'000 L. As continuous operation allows operating increasing volumes without significantly increasing the size of unit operations, the risk associated with scale-up is generally reduced. Regulatory agencies, especially the US FDA, have articulated the advantages of continuous manufacturing for biopharmaceuticals and have identified this as an emerging technology1. The Emerging Technologies Team ETT of the US FDA enables the pharmaceutical industry to receive guidance on continuous manufacturing principles. The European Medicines Agency EMA has similarly recognized the benefits and launched the Innovation Task Force ITF which among others supports continuous processing. The regulatory agencies are pro-active in this field as can be seen by recently shared guidelines on oral pharmaceuticals from continuous manufacture or projects supported in the field of parenteral biopharmaceuticals4,5.
Challenges of Continuous
Operation With the benefits in economics and product quality control at hand, it has also been stated that business challenges, technology gaps and regulatory uncertainties need to be addressed for continuous biomanufacturing to get fully accepted in the industry5.
Continuous operation offers significant economic drivers through reduction in operating expenses directly linked to the decreased size of unit operations, line sizes, buffer consumption and filter or media requirements. In addition, less labor or manual handling is required during operation and it is also expected that eff ort in quality control can be reduced. To the other end, it has to be considered that compared to batch operations, a continuous process typically comes with a higher investment upfront with increased capital and consumables cost. These need to be balanced with the savings in the backend of the process. Investments already made for a batch platform can thereby hinder a potential change towards a continuous process and continuous operation is primarily seen to be an option for new product developments.
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Economic calculations from manufacturers, contract manufacturers and suppliers suggest a beneficial balance especially for high titer and volume applications in commercial manufacture but also in a variety of clinical scenarios. The decision for or against a continuous process needs to be made on a case-to-case basis with regards to the business case.
While technologies for continuous processing have been widely tested and are at an advanced state already, gaps are to be found in analytics, automation and process control. Adequate automation and control is also an ongoing challenge for batch processes but gains importance in continuous operations where in-line or at-line monitoring and long-term sensor stability is adding significantly to the robustness of the platform. There, improvements are needed surrounding process analytical technologies (PAT) to allow real-time monitoring of critical process parameters.
To address regulatory uncertainties, strong support from regulatory communities, industry groups and suppliers is provided which have drafted different strategies for process validation. These strategies cover possible solutions for eg. control of bioburden, virus safety, lot definition, lot traceability or quality by design7. Collaborations such as a virus removal study for multicolumn chromatography from Amgen, Pall and the FDA keep investigating in novel solutions to address regulatory questions5.
Integration of continuous unit operations is described as one of the most promising means for process intensification DSP and the mentioned paradigm shift can be seen to gain importance.
The current market drivers with focus on flexibility, economic viability and intensification supports the implementation of single-use technologies for continuous processing. Several adopters have shown successful examples for both fully integrated and hybrid processing platforms and first steps towards regulatory approval have been taken. However, the decision for continuous technology has to be made on a case-to-case basis. It is recommended to perform risk assessments for the platform, the connections and the automation to meet cGMP requirements3. Ongoing developments are expected to advance integrated processing to general acceptance within the next 5-15 years.
... is Manager of Continuous Bioprocessing at Pall Biotech.
1 BiosanaPharma, "BiosanaPharma gets approval to start phase I clinical trial for a biosimilar version of omalizumab, the fi rst monoclonal antibody productd with a fully continuous biomanufacturing process," 21 February 2019. [Online]. Available: https://docs.wixstatic.com/ugd/3f142e_adbf792b6efa47ebb1aa1aa85770ca9c.pdf.
2 B. Manser, M. Glenz und M. Bisschops, "Single-use Downstream Processing for Biopharmaceuticals: Current State and Trends," in Single-Use Technology in Biopharmaceutical Manufacture, part II, 2019, ahead of publication.
3 U.S. FDA, "Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization Guidance for Industry," 2017. [Online]. Available: https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm478821.pdf.
4 U.S. Department of Health and Human Safety, FDA, CDER, "Quality considerations for continuous manufacturing," 2019.
5 M. Schofi eld, "Virus Clearance in Continuous Chromatography," in Th e Bioprocessing Summit, Boston, US, 2018.
6 C. Challenger, "Managing Uncertainty in Continuous Biomanufacturing," BioPharm International, pp. 12-17, 1 5 2018.
7 M. Bisschops und M. Krishnan, "Regulatory Aspects of Continuous Bioprocessing," 2018, ahead of publication.