Mab manufacturing today and tomorrow. Reducing risk, reducing cost. Reducing costs, informing decisions, insight for innovation.

Transcription

1 Mab manufacturing today and tomorrow. Reducing risk, reducing cost. Reducing costs, informing decisions, insight for innovation.

2 Summary Monoclonal antibodies are expensive to develop and to manufacture. There is a clear need to reduce costs and manufacturing risk in order to support new chronic indications and extend their reach in the developing world. BioSolve Process is used to study different process scales, products and facility operations (multi component, multi product). In this study it is used to address some fundamental questions relating to the large scale manufacture of an antibody at 5 tonnes per year: What can current stainless steel technology deliver? Modelling in BioSolve Process shows that for a traditional six pack stainless steel facility, a cost of goods per gram of $35 can be achieved with a capital investment of $352 million into the manufacturing plant. What is the potential for modular single-use facilities? BioSolve Process shows that a modular single-use facility can deliver a comparable cost of goods at $38/g but with a 30% reduction in capital investment at $250 million, achieved by shifting cost from fixed to variable costs. Combined with faster builds and easier reconfiguration, this allows adoption of a scaleout approach that significantly reduces overall manufacturing risk. What is the potential for continuous processing facilities? BioSolve Process finally reveals that combining continuous technology with modular single use technology has the potential to reduce the capital requirement to just $80 million and a resulting cost of goods of $32/g, with the potential for even greater reductions to around $15/g. Continuous technology has the potential to reduce costs and significantly reduce risk, making it easier to widen patient access and manufacture locally. Note that quality in process test costs have been excluded, and the analysis is based on a standard three-column chromatography process. In this paper, BioSolve Process is used to analyse the case of a large-scale single product but the tool can easily be applied for different scales, product types and multi-product facilities. Subsequent studies will return to this theme and look further at quality testing strategies and the quantification of risk. If you would like to be informed when these studies are published, please register at 2

3 Analysis The largest and fastest growing segment in biopharmaceuticals is monoclonal antibodies, which are typically used to address unmet acute conditions in the developed world. These novel antibodies are expensive to develop and manufacture and, as the biopharma industry seeks to develop them for chronic indications and to extend their use into the developing world, there is an increasing requirement to substantially reduce the cost to the patient. One significant component of this cost is manufacturing. In this study, we addressed three key questions regarding manufacturing cost: 1.What can current stainless steel technology deliver? 2.What is the potential for modular single-use facilities? 3.What is the potential for continuous processing facilities? Answering these questions provides insight into the current cost of bulk drug substance in today s large scale manufacturing facilities, while also exploring the potential for state-of-the-art technologies to have an impact on manufacturing costs, both now and in the future. In the creation of this study, we used the industry standard modelling software, BioSolve Process, to address these questions. The study focuses on very large scale processes in the region of five (5) tonnes per annum of bulk antibody, targeting a large patient population in the developing world. 3

4 1 What can current stainless steel technology deliver? The current state of the art manufacturing technologies for this scale are large six pack stainless steel facilities. Determining what these facilities can deliver in terms of cost is key; a question that depends greatly on factors including bioreactor size and titres. Using the multi variable analysis tools in BioSolve Process, it was possible to model three different options at around 5000 kg/yr throughput: Option 1 Option 2 Option 3 Bioreactor size 10,000L; 7g/L 15,000L; 5g/L 20,000L; 4g/L Cost of goods $34/g $35/g $38/g Capital investment $304 million $352 million $399 million All three options compare well with smaller throughputs, which typically see cost of goods in excess of several $100/g. From a manufacturing cost perspective, the option that best represents a state of the art titre is 5g/L. Option 2 represents the required facility in stainless steel to provide 5000 kg/yr.however, the capital investment and fixed operating costs required to achieve this are significant (note that the figures above only cover direct capital investment costs). Conclusion While compelling in terms of cost of goods, this approach locks the manufacturer into a fixed technology with large overheads. If the process is not certain and if it is not known whether the product will achieve the required sales, this becomes a high-risk approach. 4

5 2 What is the potential for modular single-use facilities? When looking at the potential of using the latest modular single use technologies, the key issue is one of scale. The maximum disposable bioreactor size is 2000L, so if a scale out approach is adopted, will it give the same cost outcomes? BioSolve Process is an ideal tool for doing this type of analysis as it can quickly execute multiple process comparison analyses and assess facility fit before users make a decision. Modelling in BioSolve Process shows that approximately L bioreactors are required to meet the target throughput, which can be built in modules of 15 bioreactors. The questions then become: What is the best harvest strategy? Should the outputs be pooled? If so, which configuration is optimal: one, three, five or 15 reactors? But this is not the whole story. The rapid analysis in BioSolve Process shows that the total capital investment is $250 million for two 15 bioreactor modules. This is a significant reduction from the $352 million capital investment required by the optimum approach with current stainless steel technology and represents a key decision-point from a risk management perspective. The scenario analysis capability of BioSolve Process can provide these answers quickly. By running these six scenarios, the lowest cost of goods was seen when the bioreactors are harvested in groups of three or five. In this case, a cost of goods of $38/g was achieved, which is interesting as it shows a similar result to the traditional large scale stainless steel plant. Conclusion A modular single use approach allows the facility to be rapidly turned around for new products for minimal cost compared to a traditional stainless steel facility. In addition: The capacity build can be phased in line with the demand profile The fixed running costs are less The upfront capital is significantly reduced by about 30% The build-time to bring new capacity on board is greatly reduced The key conclusion is that taking a small scale modular build out route can produce an equivalent cost of goods, while reducing scale and upfront capital, and greatly increasing operational flexibility. We will explore the financial implications of this in a later study. 5

6 3 What is the potential for continuous processing? The final step is to examine the potential of next generation of continuous processing technologies combined with modular design and single use systems. Using the continuous processing operations available in BioSolve Process, it was possible to model a 2000L single-use bioreactor operated in perfusion mode. In this case, the relative titre (comparing perfusion titre to traditional fed-batch) is important. The base case with perfusion titres was set at 1.0g/L compared to the 5g/L for fedbatch to represent legacy processes. Recognising the significant improvements achieved using high cell density devices and modern cell retention devices, the impact of improved titres up to 7.0g/L was considered. The cost of cell culture media, which is a major cost component in legacy perfusion processes, was also considered. Continuous processing can continue to be improved by targeting media cost reduction and also through recognition that titres are likely to improve significantly as cell line productivity and cell density in the bioreactor are increased. BioSolve Process enables examination of these factors in detail using the product s sensitivity analysis tools. In this case, titre improvements combined with reduced media costs were considered. This analysis shows that it should be realistic within a titre range of 2 g/l to achieve a target cost of goods in the $15/g to $20/g range at 5 tonnes per annum with continuous operations. In addition, there is a real opportunity to get between 10 to 15 g/l with titres above 4 g/l and optimised media costs. When looking at the legacy titre and the modular build, BioSolve Process shows that a cost of goods of $32/g can be achieved for an upfront capital investment of about $80 million. This is a significant improvement on the baseline stainless steel facility results, delivering a 10% reduction in cost of goods and a 73% reduction in upfront capital. More potential savings can be found when cost distribution by category is analysed, showing that media and resin costs dominate, representing 47% of the cost of goods. Conclusion Of course, for a new technology like continuous processing there are many unknowns, but BioSolve Process demonstrates the significant potential to be gained from marrying continuous technologies with portable modular build. This technology has the potential to radically change the nature of large-scale biomanufacturing. Access to this knowledge through BioSolve Process can make it easier for the industry to widen patient access and implement local manufacturing. 6

7 Background Biopharm has over 15 years experience in assessing the impact of new technologies and process options in the manufacture of biopharmaceuticals. We work with all the key stakeholders suppliers, innovators, academics and the major manufacturers. As a consequence, not only are we made aware of new innovative technologies early on, we have unparalleled insight into their impact on process and manufacturing from an operational and economic perspective. This experience has helped us shape our modelling package, BioSolve Process, and to embed in it our collective experience. BioSolve Process is accepted by the bioprocessing community as the standard for analysis of innovation. Our users feedback helps shape the product, making it more relevant with every update. BioSolve s modelling framework has demonstrated its flexibility as successive innovations have been readily incorporated in the platform. Milestone achievements include: All the major transgenic players have used Biopharm to model their technologies from corn and animals to eggs Alternatives to protein A were being explored by Biopharm as far back as 2005 Biopharm is recognised for supplying a coherent analysis of the impact of single use technology from 2002 until today Since investigations into the impact of continuous processing started in 2008 Biopharm has been working closely with many of the leading companies, users and suppliers During this period Biopharm has worked with users and suppliers to understand the implications of new process routes, Pichia, cell therapy, gene therapy, vaccines etc. In 2012 the industry recognised Biopharm founder Andrew Sinclair s contribution by nominating him for thought leader of the decade in the area of process knowledge management. In 2014 he was elected by his industry peers to become a Fellow of the Royal Academy of Engineering BioSolve software is now accepted by many leading companies as a means of ensuring a consistent approach to innovation and process analysis. This is achieved by using the platform s ability to standardise and control data sets and methods. Biopharm s experience and knowledge of the platform means we are able to analyse and assess technologies and processes in an efficient and cost effective manner. 7

8 Biopharm supports biopharma innovators across the globe. Here are 3 ways to connect with us: Tel: info@biopharmservices.com Copyright 2014 Biopharm Services Limited. All rights reserved. Biopharm, BioSolve and associated logos are trademarks of Biopharm Services Limited. All other trademarks are the property of their respective owners. All Biopharm products and services are subject to continuous development. We reserve the right to alter technical specifications without prior notice.