Solutions To Today's Biomanufacturing Challenges
by John Ward, Vice President of Engineering at Patheon, part of Thermo Fisher Scientific
Biopharmaceutical companies take on a lot of risk developing new large molecule drugs.
With more complex molecules in development, changing capacity needs, uncertain forecasts and increased competition, the market demands flexibility and innovative approaches to address today’s new challenges.
Current and future challenges
The biopharmaceutical pipeline is currently growing at double2 the rate of the small-molecule market, and now represents the fastest-growing sector of the pharmaceutical industry. Analysts forecast that by the end of 2016, 50% of the top 100 drugs on the market will be biologics. Currently more than 900 biologic drugs are in development.3 The number of new biological approvals is steadily increasing, with 13 new therapeutic biologics approved in 2015, up by two from 20144, and 16 new biologics approved by the FDA in 2016, accounting for 35% of all approvals. While the outlook for the growth of biologics market looks promising, the industry continues to need improved productivity and efficiency.
This significant increase in complex large molecules in the industry pipeline brings changes in pipeline composition, size and production requirements. Increasing numbers of biologics are competing to be first to market for narrower therapeutic classes, such as orphan indications, specialized medicines and personalized treatments. These niche and targeted therapies call for smaller-scale, more diverse types of production. Advances in cell lines continue to drive different capacity demands than those seen with blockbuster biologics. In addition, it is estimated that 60% to 90% of all new compounds entering development will need specialized manufacturing and/or molecular profile modification.5
These changes have resulted in new production challenges, with increased pressure to reduce development cycle times. Advances in cell line titers and upstream and downstream biopharmaceutical processing have led to changes in the types of capacity the market demands. Increased competition has also driven increasing demand fluctuation and has made speed a critical attribute for biopharma companies. As a result, the market requires new expertise, versatile capabilities, more automated platforms and innovative technologies, as well as flexible business models, production scales and approaches that enable increased speed to market.
While speed is a critical factor for biopharmaceutical production, the cost and time to bring a molecule to market continues to increase. Biopharmaceutical companies looking to outsource seek creative ways to decrease development timelines and costs, as well as reduce supply chain complexity. To achieve these efficiencies and provide high-quality, robust process development and manufacturing of even the most complex recombinant proteins and monoclonal antibodies, they seek expertise, versatile capabilities, flexible capacity and integrated services.
Sponsors also seek innovative approaches to solve for capacity, worldwide demand and market fluctuation, including multiplexing and a global network. Multiplexing, the use of multiple bioreactors in a series for upstream processing, allows for multiple 2,000-liter bioreactors to be run at once for higher volumes, leveraging single-use technologies. This allows the lines to flex based on the required volumes needed. The changing nature of pipelines, based on narrower indications such as orphan and personalized medicines, may require customized business solutions, such as custom manufacturing platforms and production time reservations to allow for the right capacity and capabilities when required.
Biopharmaceutical APIs, which are hundreds of times larger than small molecules, often lack well-defined glycol structures and have inherent structural instability, which poses challenges for production processes. As a result, the manufacturing process is more complex and costly to develop, operate and maintain than the chemical process for small molecules. State-of-the-art facilities and expertise are necessary for successful biomanufacturing.
Changing capacity calls for flexible solutions
The significant growth of complex large molecules in the industry pipeline and advances in cell lines are driving new capacity demands for biopharmaceutical companies and their CDMOs. The attractiveness of marketed biologics, advances in manufacturing technologies and increased productivity due to significantly higher titers have led to significant changes in capacity requirements. Innovative, highly efficient, flexible approaches and facilities to meet challenging capacity demands have become imperative.
The shift in capacity needs is based on changes in therapeutic targets in the pipeline, which have been narrowing to orphan indications, specialized and personalized medicines. Narrower indication targets are driving increasing numbers of biologics competing to be first to market for certain therapeutic classes. Advances in upstream and downstream processing have also driven changes in capacity requirements and facility designs.
Higher titers from cell lines are driving the need for smaller-volume bioreactors, allowing for supply platform flexibility in smaller systems, which solves many potential issues and presents opportunities. In many countries, regulatory agencies require local manufacturing, driving smaller-scale production. For companies manufacturing in multiple countries, producing smaller volumes in each country can have tax advantages compared to running larger batches at a single site.
The types of capacity offered are also changing, based on new process platforms such as flexible, modular and disposable technologies and continuous manufacturing. Mammalian cell culture product types have grown as well, antibody drug conjugates, vaccines, gene therapy and cell therapy have also impacted capacity needs. There is a need to link the new process platforms with each new product category.
Increased yields from upstream and downstream processing have diminished the need for large-scale bioreactors. About 60% to 70% of the large-molecule pipeline can now be produced in bioreactors under 2,000 liters for what previously required a 20,000-liter vessel. Large molecules can more easily utilize mid-scale bioreactors with the ability to scale. As the industry gradually shifts to smaller-scale production, flexibility in operational capabilities and production scales, as well as multiple-product operations are significant advantages.
Continuous bioprocessing is emerging as a critical trend in biopharmaceutical manufacturing, an even more important trend than single-use systems and downstream processing.1 Continuous bioprocessing, with perfusion as the leading technology upstream technology, is gaining increasing adoption, especially for downstream processes.
There are many major advantages of perfusion over fed-batch bioreactors. With perfusion, cell culture lives in consistent, ideal conditions with a constant flow of media and no accumulation of waste products. Expressed proteins are rapidly removed and available for purification, a significant advantage with proteins prone to instability. High cell density can be achieved and operated for extended periods for higher volume productivity, and the product is harvested continuously. Other advantages of perfusion bioreactors are their smaller size, culturing cells at smaller concentrations, and making perfusion more amenable to single-use applications. In addition, less equipment, space, utilities and labor are generally needed, saving considerable costs.
The effective management of capacity constraints requires specialized expertise and experience in the development and manufacturing of complex drug substances. To facilitate speed to market, continuous manufacturing improves scalability while lowering costs. Process analytical testing improves process understanding, and single-use/disposable systems can increase flexibility and reduce lead times while lowering capital investments and energy requirements. Multiplexing batches into a downstream not only saves the high costs of stainless steel reactors, but also saves labor costs, a major component of downstream processing. Having both single-use and stainless steel technologies, custom manufacturing suites for unique biologics, and multiplexing capabilities, as well as flexible capacity and a global network enable solutions that flex as demand fluctuates.
Leveraging outsourcing to address the challenges of demand forecasting
The single most important factor that influences pharmaceutical and bio-pharmaceutical manufacturing decisions is demand forecasting. Drug forecasts influence decisions regarding capital cost, outsourcing for product commercialization, and many other critical aspects of production.
However, achieving accurate forecasts remains extremely challenging, with countless factors influencing product demand. As demand forecasts are made during the initial phase of drug development, there is little information on which to base sales projections. Companies must build capacity and inform manufacturing commitments as many as four to five years before launch, while the label may arrive only six to nine months prelaunch6. The larger the scale, the longer it will take. In that time span, variables and market conditions change, and competing products may enter the market. As a result, two thirds of forecasts are incorrect, with high rates of significant over or underestimation.
On the other hand, when a company underestimates capacity and fails to meet demand, the resulting stock-out can mean loss of sales, product risk, internal and external backlash, patient disappointment and significant damage to company and brand reputation. Companies often overestimate demand when there is greater market volatility or they were simply overly optimistic, resulting in misappropriation of capital. Companies that forecast capacity on the high side will run very inefficient processes.
Based on their demand forecast, companies must evaluate the benefits of producing their product in-house, outsourcing all production, or a combination. For companies highly uncertain about demand, outsourcing is a more risk-averse option than incurring the high cost of building and maintaining suites or facilities that could remain idle. In fact, more than three quarters of biomanufacturing companies reported that the less certainty they have about demand, the more likely they are to outsource1. The decision to outsource is made at a high level to mitigate risks from incorrect demand forecasts. Other companies outsource because they simply lack capacity.
For example, if you need two to six 1,000-liter bioreactors, should you build six and perhaps run at 33% utilization, which will raise the cost of goods? Or acquire two or three bioreactors for in-house production and leverage contract manufacturing for any additional manufacturing needed, building insurance into the forecasting? Or contract all production to your CMO or CDMO? Outsourcing is a more flexible option, as CMOs generally have more capacity, capabilities, and new technologies and can more easily accommodate the demand.
Outsourcing provides greater flexibility and ability to achieve forecasts. Many companies use a mix of in-house and outsourced production to maximize their options. Often, companies outsource for products that would have too many associated costs to begin production or they simply lack capacity in-house.
Accurate forecasting involves cost-saving decisions on taxes, intellectual property strategy and insurance of capacity. Moving manufacturing outside the U.S. typically results in tax breaks, tax credits and avoidance of high corporate taxes. Certain countries — such as Switzerland, Ireland, the Netherlands, Denmark and Luxembourg will negotiate tax rates and offer tax incentives. In some regions, regulatory agencies offer tax advantages for producing smaller volumes in certain geographic areas rather than running larger batches at a single site.
Regarding intellectual property, the U.S. has considerably longer patent durations than Europe. If you make and sell a product in Europe and it reaches the patent cliff, you pay no royalty. Coupled with tax breaks, you can realize tremendous cost advantages.
Since market demand is highly unpredictable several years in advance, biopharma companies need flexible, scalable capacity that can accommodate uncertainty. Companies can reduce the risk in demand forecasting by outsourcing part or all of their product production to a CDMO with a variety of adaptable manufacturing arrangements that can accommodate uncertainty, and flexible, scalable solutions that can help mitigate risk.
Contract biomanufacturing organizations adapt to specialized market needs
As biologics surpass small molecule drugs in the pipeline, the demand for specialized biomanufacturing services, technologies and expertise from CMOs and CDMOs has never been greater. More biologics targeting narrower therapeutic classes, such as orphan indications and specialized medicines, are competing to be first to market, driving a heightened need for improved efficiency, productivity and capacity, as well as advanced, integrated expertise and versatile services.
According to a Nice Insight survey, the year 2015 saw a big jump in expenditure for outsourcing services. The majority of pharmaceutical and biotech companies (43%) spent $51 million to $100 million on outsourcing and 28% spent more than $100 million. Three quarters said this expenditure is likely to increase in the next five years. In the previous year, most companies spent only $10 million to $50 million.7
To compete in this challenging marketplace, companies are increasingly relying on external service providers to streamline biomanufacturing, avoiding the high capital expenditure and long lead times needed to construct, equip and validate manufacturing facilities. The costs to build and maintain manufacturing facilities are significantly higher and riskier than working with an outsourcing facility. More commonly, companies outsource because they do not have sufficient available capacity in their own sites to include a new product.
While the demand for outsourcing services continues to increase, comparing various partner options for the manufacture of sensitive biologics and choosing a service provider can be difficult. Strategic outsourcing to a highly experienced CDMO with expertise in biomanufacturing, a global network and integrated services improves flexibility, and is a faster, more economical approach to producing biologics. By minimizing supply chain complexity, end-to-end, fully integrated services can reduce development timelines and costs, accelerating time to market.
Service providers that have a global network with redundant capabilities enable creative manufacturing, immediate access to leading-edge technologies, and back-up supply, eliminating capacity constraints and the risk of supply shortages. Global facilities also offer tax and other financial benefits when certain processes are conducted outside the U.S.
Other important qualifications when vetting a CMO/CDMO are versatile capabilities, advanced technologies, and flexible manufacturing solutions that offer speed, cost savings and reliability. A service partner capable of multiplexing, for example, allows for adaptable biomanufacturing that can adjust to fluxes in demand and saves labor costs.
Service providers offering continuous bioprocessing with perfusion technology and the ability to scale, as well as flexible, modular and disposable technologies also facilitate time to market and lower capital investments and operating costs. Access to alternative downstream process techniques, such as both single-use and flexible stainless-steel technologies, can improve yields while lowering costs and run times. Expertly designed cGMP facilities with custom manufacturing suites that can match the needs of your molecule from development through commercial scale provide additional flexibility.
As the demand for CDMO services for biomanufacturing continues to increase, companies are becoming more selective when choosing a service provider. They are increasingly seeking fully integrated strategic partners who can demonstrate reliability, flexibility, expertise and the capacity to react to their biomanufacturing needs and new market trends.
References
1. Langer, E.S., “4 Key Trends in Biomanufacturing in 2016”, based on a report from BioPlan Associates Bioprocess Online, March 16, 2016. www.bioprocessonline.com/doc/ key-trends-in-biopharmaceutical-manufacturing-in-0001.
2. Walker, N., “Will Biosimilars Make a Difference for the CMO/ CDMO Market?” Pharmaceutical Outsourcing. November 30, 2015. www.pharmoutsourcing.com/Featured-Articles/180627- Will-Biosimilars-Make-a-Difference-for-the-CMO-CDMO-Market.
3. Miseta, E. “New Biologics Create Need for Patient-friendly Injectors.” Clinical Leader, March 8, 2016. www.clinicalleader. com/doc/new-biologics-create-need-for-patient-friendlyinjectors- 0001.
4. Novel Drugs 2015 Summary, FDA Center for Drug Evaluation and Research. January 2016.
5. Negron, F., “Patheon Continues to Build API Capabilities.” Contract Pharma, October 2015; 38-40.
6. “Impact of Incorrect Forecasts on New Product Launches”. An independent executive research study by ORC International.
7. 2016 Nice Insight survey of 1,173 representatives from pharma and biotech companies.
Published 3/18 PATH0728