August 22, 2022
SUTs such as Biosafe RAFT bags in
combination with Biosafe ports enhance sterility assurance in aseptic processing
A long-time editorial advisor for BPI, Miriam Monge is head of marketing for fluid-management technologies (FMT) at Sartorius, where she works to develop sustainable growth strategies for single-use bioprocessing. Over the past 20 years, she has played a significant role in championing development, promotion, analysis, and adoption of single-use technologies (SUTs). We asked her to share her experiences and to offer additional thoughts about current and future industry trends.
Science and Technology
From a technological perspective, without a doubt, I cite the implementation of SUTs in bioprocess development and manufacturing. Those technologies are gradually replacing stainless steel or glass pretty much throughout bioprocesses and are making an impact on the industry in so many ways. The industry had been stuck in a rut for such a long time operating massive stainless-steel facilities that were slow to build, required massive capital expenditure, and created huge utility requirements. Operations lacked flexibility, which is so important when you bear in mind the drug attrition rate.
SUTs have radically changed the way the biomanufacturing community operates. The benefits are well known and understood by the industry today. Originally used mostly for monoclonal antibody (MAb) manufacturing, SUTs now are being implemented for cell and gene therapy processes as well.
At no other time was the value of SUTs more obvious than during the COVID pandemic. If we think about what happened during the pandemic — the rapid development and implementation of new processes to manufacture COVID vaccines — that achievement would not have been possible in such a short timeframe without SUTs. Science also has played very much in favor of the switch to single-use processes because titer improvements have enabled manufacturing in much smaller scales. In addition, we have seen a move away from the blockbuster drug model to a demand that is more in the 100–300 kg range for a large number of MAbs.
What scientific and technical developments have surprised you the most over the past 20 years? I was a pioneer of SUTs (beginning with Stedim Biosystems). The first 10 years of launching and implementing them were pretty tough. We had a huge amount of convincing to do on the scientific, regulatory, technical, and economic fronts. Everything we did when proposing SUTs to the industry in the early 2000s was heavily scrutinized — amid a lot of skepticism. Clients used to call me that bag lady!
What helped the industry start to think differently was when Andrew Sinclair (Biopharm Services) and I started investigating bioprocess economic modeling. [Editor’s note: Please see Sinclair’s article on that topic on page 63.] Using case studies, we provided direct comparisons of processes based on stainless steel and single use, working through in detail what those new technologies could mean to the industry. We asked where it did make sense to apply single-use from the standpoints of productivity, cost of goods (CoG), scale, and sustainability; where it did not make sense; and at what scale it could make sense to switch to a hybrid approach.
Sustainability: As we thought about how SUTs could change our perspective about water and energy use in bioprocessing, sustainability already was on our minds when in November 2008 we wrote a paper with Lindsay Leveen from Genentech entitled “The Environmental Impact of Disposable Technologies.” We asked whether disposables reduce a facility’s environmental footprint (1). The coauthors and I concluded that the greatest impact of disposables was in reducing water requirements. In stainless-steel–based facilities, water use is one of the most significant contributors to the carbon footprint (excluding driving to work). The key consequence of the extensive use of disposables, therefore, is the removal of significant requirements for high-quality water by eliminating clean-in-place (CIP) operations.
By using modeling tools, we demonstrated scientifically the true value of SUTs compared with more traditional manufacturing methods. Sinclair and I went on to publish multiple papers based on client case studies in which we modeled their processes, comparing single-use applications to their current setups. The first publication that made significant noise in the industry was in ISPE’s Pharmaceutical Engineering in May–June 2002 issue (exactly 20 years ago!). The paper was entitled “Quantitative Economic Evaluation of Single-Use Disposables in Bioprocessing” (2).
In that paper, we noted how we could apply discrete event-modeling techniques to simulate the entire operation of a bioprocess manufacturing system. That capability allowed us to quantify at a macro level the impact of emerging operations with disposable single-use bags compared with use of traditional stainless-steel vessels. We demonstrated that a new installation for a 2,000-L MAb process using disposable-bag technologies would reduce capital requirements by around 20%, which in turn resulted in an 8% reduction in the CoGs. The great benefit lay in reducing capital spent early in a product life cycle.
When we considered substituting stainless-steel vessels with bags in an existing operation, the situation became more complex. The net benefit very much depends on what is limiting production. Many biomanufacturers face problems related to insufficient utility capacity, CIP capacity, and/or floor space. In such cases, application of disposable bags can increase production throughput. The exact increase depends upon individual plant circumstances.
In the case that we presented, we saw a throughput improvement of about 7% that equated to an 8% reduction in COGs. In a fixed-vessel model, water-for-injection (WFI) generation capacity is set at 950 L/hr. We know that to operate without WFI constraint, a fixed-vessel model requires a WFI generation capacity of 1,500 L/hr. In the 2002 paper, we reviewed the impact of substituting fixed vessels with bags and assessed the overall impact of that substitution on CoG. We showed how introducing disposables increased the production rate from 15.3 kg/year to 16.4 kg/year. Introduction of SUTs reduced the CIP requirement enough that the reduced water demands could be met by existing utility systems. That reduction in requirements could allow production to proceed at a desired rate.
We noted that actual improvement percentages are case dependent, and situations do arise where that production increase can be significantly higher. In our study, the capital charge difference was zero, and the capital used in both production lines was approximately the same. The resulting increase in throughput achieved through introduction of disposable bags provided for a more efficient operation and resulted in a net reduction in CoG of about 8%. We noted that the increased consumables cost was more than offset by labor efficiencies and reduced utilities and indirect costs.
Environmental Impact: An often-stated concern about the use of disposable bag technology is the environmental impact of the additional consumption of the single-use bags. Those are a tangible and visible manifestation of waste, so it often is assumed that their use will result in greater environmental damage compared with use of stainless-steel vessels. Although it was not the aim of the above exercise to carry out a full environmental-impact comparison of the two process options, we were able to gain an insight into likely environmental damage/benefits based on material consumption and capital requirements. The study compared results between the two models based on differences in material used per batch. The disposable model required approximately 100 disposable plastic bags with associated tubing per batch, amounting to ~200 kg of plastic waste. In a number of facilities, that material either is sent off site for incineration or into landfills. But the commonly held view that adoption of disposable bags creates an adverse environmental impact compared with use of stainless-steel vessels is not necessarily true. Although not an objective of the study, our analysis showed that increased consumption of plastic is offset by large reductions in water and CIP chemical requirements while also reducing capital requirements for new facilities. Our conclusion was that stainless-steel–based processes had a greater environmental impact, although we recommended a rigorous environmental audit to compare the two options fully.
That paper started the industry debating and discussing application of SUTs in a way that hadn’t happened previously. In 2004 and 2005, Sinclair and I published a two-part series in Bioprocess International: “Biomanufacturing for the 21st Century: Designing a Concept Facility Based on Single-Use Systems” (3). The intention of that study was to develop a leading-edge design for a concept facility that exploited fully the benefits of disposable technologies. By comparing that concept facility with a traditional facility based on reusable equipment, we sought to identify the benefits of disposable technologies, thereby stimulating further industry discussion. We looked at how qualitative benefits translated through to quantifiable savings in terms of capital, time to build, and cost of goods.
Beginning in 2008, Sinclair and I wrote a monthly column called Disposables Advisor (4). Many of the topics we wrote about still are highly relevant today:
∙ early mitigation of the risks of single-use supplier dependency
∙ rapid-response manufacturing — could SUT manufacturing match the pace of a pandemic?
∙ end-to-end deployment of SUTs in aseptic filling — presenting a success story about efficiency and risk reduction (from an interview with Nigel Bell of GlaxoSmithKline on Christmas Eve as he was boarding a plane to Egypt)
∙ a cost-model for evaluating SUTs and user viewpoints on implementing disposable technologies.
After working past those initial hurdles, I actually have been surprised at the rate at which the industry has moved toward full integration of SUTs. In particular, the past 10 years have brought an unprecedented acceleration of SUT adoption and implementation all the way through to commercial manufacturing.
Regulation
20 years ago, very few regulatory references were available that directly applied to SUT. At that time, existing regulatory requirements were extrapolated from the device regulations for container-closure systems to SUT process applications. Since that time, three major topics corresponding to major identified risks have been challenged deeply among users applying SUTs to biomanufacturing for injectables: extractables/leachables (E&L), integrity loss, and particulate contamination.
The US Pharmacopeial Convention (USP) has been particularly proactive in the study of E&L, and the industry is looking forward to the release of USP chapters related to SUS (<665> and <1665>). Industry associations and organizations such as ASTM, BioPhorum, BPSA, ISPE, and PDA have helped also to leverage standards and practices and share the knowledge on each topic. My company has been serving and continues to serve as a key player in regulatory organizations and associations through subject-matter-expert (SPE) participation. The company hopes to drive a regulatory evolution toward reducing risks related to E&L, loss of integrity, and particle contamination. Examples of the work of these groups include the following:
E&L: USP <665> and USP <1665> provide a process-risk–analysis approach focusing on E&L and presenting a protocol for extractable evaluation (5, 6).
Two best-practices guides from BioPhorum address “Extractables Testing of Polymeric Single-Use Components Used in Biopharmaceutical Manufacturing” and “Evaluating Leachables Risk from Polymeric Single-Use Components” (7, 8)
Integrity: ASTM E3244-20 addresses “Standard Practice for Integrity Assurance and Testing of Single-Use Systems”; and ASTM E3251-20 presents a “Standard Test Method for Microbial Ingress Testing on Single-Use Systems” (9, 10).
Business
Speaking of pure strategy, I think the number of companies outsourcing to contract development and manufacturing organizations (CDMOs) is constantly on the rise. During the pandemic, CDMOs have played a significant role through their manufacturing networks to supply COVID vaccines. Leveraging those networks certainly helped to reduce business risks. Also, the number of virtual companies has grown substantially. Beyond supply-chain/pandemic-related risks, the continued emergence of new therapeutic modalities and the general lack of in-house process expertise also are key reasons for increased outsourcing to CDMOs.
Another important development has been the uptake in modular/non-stickbuilt expansion driven by the need for rapid deployment of manufacturing capacity and the advent of low-dose therapeutic modalities. This coincides with a step back from the “globalization” of bioprocessing and renewed focus on developing internal/domestic bioprocessing capabilities especially in developing markets. That shift will help position those markets for success in the event of future emergencies that once again threaten to disrupt all kinds of supply chains.
Looking Ahead
Although we have been talking about continuous biomanufacturing for many years, probably since around 2005 when Konstantin Konstantinov first presented and published widely on this subject, the industry has moved pretty slowly into this direction. It’s still taking baby steps. But we talk now more about intensified bioprocessing, by which companies seek to optimize a specific process step rather than developing a fully continuous automated bioprocess operation with on-line, at-line sensing. I attended a workshop back in 2018 hosted by the US Food and Drug Administration (FDA) and the Biomedical Advanced Research and Development Authority (BARDA) at the National Academy of Sciences. The FDA had invited ~80 industry experts to address this question: How can we collectively drive forward implementation of intensified and continuous biomanufacturing? Both the FDA and BARDA considered the rate of implementation to be too slow and wanted to understand the barriers. There is a strong push from the FDA to implement continuous processing (CP), especially to derisk the complicated global supply chains of the industry and move to more localized production.
Process analytical technologies (PAT), automation, and data analytics are key factor that will enable CP to move forward. There is consensus that CP will lead to better product quality. An increased level of process understanding will lead to faster, more widespread implementation. Key here is the development of new PAT tools and associated data analytics, improved automation, and effective small-scale models.
Although many companies and organizations are testing intensified processing methodologies and integrating those methodologies to some degree, CP hasn’t had the level of rapid uptake I anticipated. We know that clear benefits are linked not only to productivity, costs, and product quality, but also to sustainability with regard to electricity and water use because intensified processing enables a much smaller facility footprint, significantly reducing heating, ventilation, and air-conditioning (HVAC) requirements. CP has yet to drive disruptive change at the pace that the FDA would like to have seen. And it is important to note that CP methodologies can be applied not only to MAbs, but to new modalities as well: The same need to intensify processes applies across the board with the opportunity to miniaturize facilities.
What do you hope that the industry will accomplish in the next five, 10, or even 20 years? How can the industry make that happen? We need to move forward to drive higher productivity and lower costs in MAb biomanufacturing. Many clients talk about a target CoG of US$10/g for a MAb, so I hope that we will manage that truly disruptive change toward fully continuous biomanufacturing. Such a shift can enable strong cost reductions with direct knock-on effects on the prices that patients pay for such drugs.
Likewise but of a different order in the cell and gene therapy arena, there is much to do to design processes that make such therapies truly affordable. Using intensified methodologies also is key here: The question about who pays for a “cure” that may cost more than US$1 million is critical to address. We suppliers are on the front line to design truly innovative processes that can drive CoG down and make those therapies accessible for the patients who need them. In addition, part of the innovation challenge is to design our technologies and manufacturing processes with sustainability in mind.
In that context, returning to the topic of environmental sustainability and SUT, the many factors to consider include climate impact, material circularity, and water use. As part of the innovation challenge, we need to design our technologies and overall manufacturing processes to minimize environmental impact along the product life cycle: from raw material through manufacturing, distribution, use, and end of life. Examples include minimizing quantities of plastic and packaging and evaluating how to improve plastic circularity. Sartorius, for example, makes single-use bags using a recyclable film. Advances in facility design that minimize carbon footprints will directly reduce HVAC requirements, water requirements, and so on.
Those are some of my wishes for the next few years. To those changes — notably, toward increased sustainability — the industry and its related working groups and associations need to work together to reach a consensus on industry standards for recycling methodologies.
The Next Potential Disruption: Finally, a number of academics have been adamant that protein replacement through RNA ultimately will replace MAb therapies during the next 10 years A current Moderna clinical study involves an RNA-derived vascular endothelial growth factor (VEGF) that might replace MAb therapy (11). Using mRNA technology for therapeutic antibody production could disrupt the traditional MAb template thanks to
∙ improved glycosylation patterns (posttranslational modifications in vivo rather than in a bioreactor)
∙ targeted action thanks to dedicated lipid nanoparticle (LNP) formulation and route of administration (increased efficacy and decreased side effects)
∙ increased safety for patients thanks to the in vitro nature of the manufacturing process.
Those advancements will require further delving into formulation issues; the association between mRNA(s) and lipids remains an unexplored field. Companies promoting the modular facility concept can get traction but should be focusing on multiproduct/multimodal designs to maximize the return on investment (RoI) and adapt to constant changes in new therapeutic modalities (mRNA, siRNA, miRNA) as well as another potential surge demand in the face of extraordinary circumstances such as COVID-19.
References
1 Sinclair A, et al. The Environmental Impact of Disposable Technologies. BioPharm Int. 21(7 supp.) 2008: 4–15; https://www.biopharminternational.com/view/environmental-impact-disposable-technologies.
2 Sinclair A, Monge M. Quantitative Economic Evaluation of Single-Use Disposables in Bioprocessing. Pharm. Eng. 22 (2002): 20–34.
3 Sinclair A, Monge M. Biomanufacturing for the 21st Century: Designing a Concept Facility Based on Single-Use Systems (Part 1). BioProcess Int. 2(9) 2004: 26–31; https://bioprocessintl.com/wp-content/uploads/2014/05/2-9_sup_monge_76568a.pdf; and Concept Facility Based on Single-Use Systems, Part 2: Leading the Way for Biomanufacturing in the 21st Century. BioProcess Intl. 3(9) 2005: 51–56; http://www.bioprocessintl.com/wp-content/uploads/bpi-content/0309su07_78595a.pdf.
4 Topic: Disposables Advisor. BioPharm Int.; https://www.biopharminternational.com/topic/disposables-advisor.
5 USP-NF <665> (draft revision). Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products. United States Pharmacopeia: Rockville, MD, 2022; https://www.uspnf.com/notices-665-nitr-20220225.
6 USP-NF <1665>. Characterization and Qualification of Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products. United States Pharmacopeia: Rockville, MD, 2022; https://doi.org/10.31003/USPNF_M11136_02_01.
7 Best Practices Guide for Extractables Testing of Polymeric Single-Use Components Used in Biopharmaceutical Manufacturing. BioPhorum Operations Group: London, UK, 2020; https://www.biophorum.com/wp-content/uploads/Best-practices-guide-for-extractables-testing-April-2020.pdf.
8 Leachables: A Best Practices Guide for Evaluating Leachables Risk from Polymeric Single-Use Systems. BioPhorum: London, UK, 2021; https://www.biophorum.com/download/best-practices-guide-for-evaluating-leachables-risk-from-polymeric-single-use-systems.
9 ASTM E3244-20. Standard Practice for Integrity Assurance and Testing of Single-Use Systems. ASTM International: West Conshohocken, PA, April 2020.
10 ASTM E3251-20. Standard Test Method for Microbial Ingress Testing on Single-Use Systems. ASTM International: West Conshohocken, PA, May 2020.
11 Anttila V, et al. Synthetic mRNA Encoding VEGF-A in Patients Undergoing Coronary Artery Bypass Grafting: Design of a Phase 2a Clinical Trial. Mol. Ther. Meth. Clin. Dev. 18, 2020: 464–472; https://doi.org/10.1016/j.omtm.2020.05.030.
BPI editorial advisor Miriam Monge is head of marketing for fluid-management technologies (FMT) at Sartorius; [email protected].
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