Efficient Integration of Single-Use Equipment During Capacity Expansion Projects

By Nick Hutchinson

More than ever before, biopharmaceutical companies are able to establish their own in-house biomanufacturing capabilities. The adoption of single-use technology has reduced the need for expensive utilities systems and large manufacturing footprints. The inherent flexibility of this technology is allowing firms to connect steps in the production process with relative ease and without the need for fixed stainless steel pipework. Upfront capital costs have diminished and although operating costs remain, they are incurred only when the success of a drug candidate or licensed product warrants further production. Thus, single-use technologies provide a means to mitigate the risk of wasting large capital expenditures in the event a molecule is unsuccessful in the clinic or on the market.

Good engineering practices are key

Single-use technology is available for nearly every step in a biopharmaceutical manufacturing process below a certain scale of production. Biologics such as monoclonal antibodies and viral vaccines can be produced using processes in which the entire product, media and buffer flow-paths are disposable. However, companies attempting to install or expand new biomanufacturing capacity should be mindful that they should follow good engineering practices to maximize the probability of success. Despite the ease with which firms can install single-use capacity, relative to traditional stainless steel projects, this can nevertheless lead to an insufficient consideration of how firms should integrate single-use equipment with other steps in the process chain. The overlooking of proper integration can lead to incorrect equipment sizing, poor equipment design or an incomplete solution being developed. This can result in process failures, delays and the need to perform costly engineering rework.

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Supplier Capabilities Underscore Their Value Creation Potential

By Dr. Nick Hutchinson

The introduction of single-use technologies into biomanufacturing process increasingly requires the industry to operate as a cohesive network of organizations that function across all levels of the supply chain to ensure the safe and efficient production of biopharmaceuticals.

Biomanufacturers engage in a variety of activities that require them to work with suppliers ranging from the replacement of existing production equipment in established processes through to the development, manufacture and introduction of innovative, new-to-world biologics products. The nature of these projects influences the type of relationship that biomanufacturers will seek from their suppliers

KE Kristian Möller and Pekka Törrönen, working at the Helsinki School of Economic and Business Administration, published an article describing a spectrum on which a business’ projects may sit (Möller & Pekka, 2003). At one end of the spectrum lie projects in which firms are attempting to gain maximum efficiency from existing resources and technology and require a low level of relational complexity with their suppliers. At the opposite end of the spectrum are those future-orientated partnerships in which actors in the network co-create value and can lead to radical innovations that open up new business opportunities.

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Intensifying Biopharmaceutical Production

Transitioning to next-generation biomanufacturing is a strategic objective for large Biopharma

The demand for biopharmaceuticals continues to grow. Populations are aging in the mature markets such as North America and Europe. They need medicines to maintain their health and manage chronic conditions. With unprecedented amounts of information via digital technology, patients in growth markets are more aware of, and demanding access to, the latest medical technologies. There are many opportunities for biopharmaceutical companies to increase revenues but the path to success is not straightforward. The demand from patients is leading to escalating healthcare costs that many analysts fear are unsustainable. Policy makers in mature markets are grappling with the challenge of making patient care affordable and are increasingly asking pharmaceutical companies to demonstrate the value of their products. Rapidly growing markets across the globe have diverse medical needs and differing policies that determine how companies receive payment for their biopharmaceutical products.

Larger biopharmaceutical companies are experiencing increased competitive pressures. Biosimilars are likely to erode the margins of products that were once ‘cash cows’. Expensive drug development programs have not always delivered the blockbuster innovator drugs that would offset the revenues lost to generics. Large pharmaceutical companies have spun-out biotech business units to increase their market focus. Small start-ups with specific expertise and focus on new therapeutic approaches such as cell therapies have the chance to disrupt the industry.

There is plenty for biopharmaceutical executives to reflect upon. Investors have called for greater discipline in product portfolio management, measures to cut bloated cost structures and even further break-ups. Optimizing a firm’s global biomanufacturing network will be one piece of the jigsaw through which they can achieve competitive advantage.

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Optimizing Biomanufacturing Capacity and Flexibility

By: Nick Hutchinson

Applying the “Lean Lens”

Jessica Morse (Amgen) spoke on ‘Optimizing capacity and flexibility in the Amgen, Rhode Island manufacturing plant’ at the BioProcess International Conference & Exhibition, 2016. The Rhode Island facility has been operational since 1986 and was originally a single-product facility for the production of Embrel. Now the facility produces multiple products for both commercial and clinic supply. Amgen’s projection for their future product requirements requires that the plant will need to increase its output. Previous projects have optimized bioreactor titers but now the company is seeking ways of using their time in the facility more effectively to increase productivity.

Reducing facility downtime

In the past, Amgen would shut down the Rhode Island facility for 30 days each year in order to perform maintenance operations. Now the company uses shorter facility shutdowns that it is able to fit into their normal production plan. This is reducing, even eliminating the need for the 30 days annual shutdown and allows Amgen to use a greater amount of facility time for producing batches of product. The company has analysed the risk of not performing non-value adding maintenance activities and are applying the philosophy that “if it is not broken, don’t fix it”. They have applied a science-based equipment maintenance program to ensure they are focusing on the right preventative maintenance activities.

Debottlenecking the facility

Amgen have adopted a methodical approach to understanding and responding to debottlenecking opportunities within the plant. They are adopting a phased implementation approach to debottlenecking activities to increase plant utilization over the upcoming years. The company is accelerating its run rate through activities such adding additional equipment and the strategic use of single-use technologies

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Optimizing Biomanufacturing Using Three Different Methods

A recap from the morning sessions during day 1 of BPI in Boston, MA.

Biomanufacturers are using increasingly sophisticated methods to optimize their processes to maximize the efficiency of their production assets and reduce their cost of goods in order to gain competitive advantage.

  1. Design of Experiments

Martin Kane, a Data Scientist from Exponent described how engineers can apply Design of Experiments (DoE) methods as a powerful set of tools for understanding and optimizing bioprocess systems. DoE allows companies to understand the average “Design Space” for their processes and describe them with simple mathematical models. In this way, Kane (who was speaking at the Manufacturing Optimization and Process Intensification: Predictive Models and Product Lifecycle Management session at the BioProcess International Conference & Exhibition, 2016) allows manufacturers to reduce their development time and increase throughout said.

Kane recommended that companies use a three-step approach in which DoE screens are performed to identify factors that could influence the process, secondly the design space is characterized and then, finally, the models are verified using a small number of process runs. This verification stage allows companies to demonstrate that the defined operating ranges are robust yet unfortunately, engineers often miss this stage.

  1. Computational Fluid Dynamics

Suresh Nulu, a Senior Engineer from Biogen Inc presented at the same conference session. He described a case study on the use of predictive models to optimize drug product mixing processes, “Faster, Cheaper, Better”. He explained that ‘at-scale’ mixing studies with drug product are very expensive to perform. Furthermore, the costs associated with a failed mixing step are extremely high. Biogen wanted to develop a comprehensive data package that leveraged both experiments and Computational Fluid Dynamics (CFD) for different single-use mixers under a range of conditions. By having this data package the company hoped to avoid ‘at-scale’ studies but the new approach required a culture shift as staff learned to trust the data generated by predictive modelling.

CFD modelling data proved its utility and helped to identify dead-zones that engineers may not have otherwise identified due to the location of probes. Biogen verified the models using experimental data to ensure that they were “fit for purpose” predictive models. The experimental and CFD data aligned very closely with one another.

The mixing data packages created define mixing times at different impeller speeds and at three different mixing volumes. The company identified upper and lower boundaries that avoid dead-zone at low impeller speeds and both vortexing and foaming at high impeller speeds. Control limits for mixing steps were subsequently defined within the design space.

By combining the use of experiments with CFD modelling, Biogen was able to proactively explore the design space and;

  • Eliminate ‘at-scale’ surrogate studies during process transfers.
  • Make data-driven equipment-sizing decisions during process transfers.
  • Eliminate ‘at-scale’ studies often used to understand the effects of equipment on Biogen’s drug product.
  • Set process controls and sampling strategies during process development.
  1. Continuous Process Verification

Concluding the session, Tom Mistretta, Principal Engineer at Amgen described the company’s approach to maximizing the value of commercial-scale data. Mistretta explained that the driver for this work were the needs of their increasing complex product pipeline with multiple modalities, expanding geographical footprint and the availability of systems that effectively aggregate data.

The company uses continuous process verification as part of their lifecycle management approach. Mistretta pointed out that a typical commercial batch will generate over 500 QC entries, 2000 batch record entries and 500 million continuous data point entries. Biotech companies can use this data to identify and control sources of bioprocess variation leading to further process performance optimization.

Mistretta gave an example of a case study in which Amgen analyzed data from commercial-scale lots to identify a process performance parameter that was under sub-optimal control. The company was able to improve the control of the parameter using process analytical technology, which resulted in higher process yields without having a detrimental impact on the product’s critical quality attributes. The insights gained from continuous process verification are being fed back into the process design activities of pipeline processes. This is allowing Amgen to increase their staffing and facility flexibility. Furthermore, the process improvements are reducing the number of manufacturing lots the company needs to run, it is reducing the environmental impact Amgen is having and improving sustainability.

 

About the author: Nick Hutchinson is a Technical Content Marketing Manager at Sartorius Stedim Biotech.

[Whitepaper] Strategies for Creating Flexibility in New and Legacy Biomanufacturing Facilities

Whitepaper Summary:

While innovation and market demand have had a phenomenal impact on drug development, the manufacturing side has been somewhat slower in evolving to newer, more flexible and cost-effective technologies. However, there is a definite trend in transitioning legacy facilities and new facilities away from the traditional one product-one facility biomanufacturing model in order to capture market demand and produce multiple products in the same facility. So transformative technologies are being incorporated into new facilities as well as aging/legacy facilities with the goal of maximizing capacity and efficiency and also driving down costs.

In 2015, customers who had used single-use technologies for 10 years had significant cost benefits: 20-30% reduction in operating costs, 40-50% reduction in capital costs, and 30% reduction in time-to-build as compared to traditional stainless steel technology. [1] The cost benefits come from significantly reduced setup and switchover times providing flexibility for manufacturers to quickly change their product lines. Disposables require less maintenance, sterilization, clean steam, chemicals, and energy. [2]

Another highly cost effective transition that is gradually being implemented for portions of the manufacturing process is the switch from batch to continuous manufacturing. Continuous manufacturing saves money, time and space, with impressive advantages over batch processing. [3] Footprints are estimated to be 40-90 percent smaller, resulting in 20-76 percent lower capital expenditures as compared to batch systems. Other advantages include increased capacity for production, less maintenance and lower energy use. Also, there is less time required for scale-up from clinical to commercial scale production. [2]

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9 Predictions for the Future of the Biomanufacturing Industry

The current technological and economic climate surrounding the biomanufacturing industry is the perfect environment for rapid development. As the industry moves forwards, many doors have now been firmly opened by technological advancement and innovation, and many things that were not possible even a year ago, are now commonplace.

Over the past six months we’ve spoken to dozens of industry leaders and asked for their predictions for the future of the industry. We’ve gathered 9 of the most common answers below…

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