The ability to rapidly deploy manufacturing capacity will be a strategic asset of the pharmaceutical industry in the future. NNE Pharmaplan has developed the “Bio on demand” concept for flexible facilities. According to the international pharma engineering company with an annual turnover of about  250 million, the concept allows drug manufacturers to bring products to market faster. Since 2011 NNE Pharmaplan has designed many Bio on demand facility projects for global pharmaceutical companies. Dr. Michael Reubold asked Dr. Frank Nygaard, senior technology partner, biopharmaceuticals at NNE Pharmaplan, about the current and future pharma production trends and the elements and benefits of the Bio on demand concept for next generation bioprocessing.

CHEManager International: The design of most pharma production facilities is still dominated by traditional stainless steel reactors with fixed piping and tank layout. Will this manufacturing technology vanish in the near future?

F. Nygaard: The global capacity for commercial biopharmaceutical manufacturing is dominated by traditional stainless steel facilities with fixed piping and tank layout. These aging facilities were initially designed for single products, but are now widely undergoing upgrades to enable multiproduct manufacturing allowing more efficient facility utilization. Prior investment in existing capacity and/or a need for large-scale capacity might still favor manufacturing from traditional stainless steel facilities in the future. However, a clear trend for utilizing single-use systems for flexible manufacturing is seen as it is estimated that more than 80% of the new products being tested in early clinical trials are manufactured using single-use systems.

This widespread use of single-use technology for new product developments together with recent years of significant improvement in biopharmaceutical processes make single-use technology an attractive alternative to stainless steel. Some of the key risks associated with the introduction of new products are mitigated by significantly lower upfront investment costs, and a more seamless technology transfer from clinical to commercial manufacturing is expected. Therefore, we believe that the trend we see with increased use of single-use systems in clinical manufacturing will translate into commercial manufacturing as well.

What are the driving forces behind the growing need for flexible, multipurpose and more cost-effective pharma manufacturing facilities?

F. Nygaard: On the surface, the main objective for pharmaceutical manufacturing today remains to deliver on output targets. In spite of this, conditions for reaching these targets have changed significantly in recent years. With output targets more or less defined, the previous main task was to keep the facility running in a stable and efficient manner. Growing uncertainty and an overall faster pace have added a whole new dimension to achieve success within the pharmaceutical industry today. Growing concerns about, e.g., health-care expenditure and cost pressure, increased regulatory pressure, patent expiry and generic competition as well as pharma M&A all add to an increased level of uncertainty and change in the pharmaceutical industry.

Pharma M&A deals are chasing each other and are accelerating the market consolidation. On the other hand, personalized therapies will further drive the fractionation of the biopharmaceuticals market. How do these opposed trends influence manufacturing strategies?

F. Nygaard: Both trends — M&A and personalized therapies — are pushing for the need for flexible, multipurpose and more cost-effective manufacturing. The pharmaceutical industry has seen growing revenues for years, and the investors will continue expecting growth rates that intensify the search for pharma companies to achieve this growth. The first half of 2015 saw more than $200 billion worth of pharmaceutical deals completed, which is three times the amount of the first half of 2014. A recent analysis of pharma’s top 50 growth drivers in 2013 revealed that one-third of the products ended up in the possession of the company marketing them via M&A activity. Some of these products sourced through M&A already have high volume demand while others may be more niche products that only require smaller batches in campaign-based production schemes similar to personalized therapies.

By 2016, five of the top 10 biopharmaceuticals are expected to be monoclonal antibodies, and biosimilar versions of these blockbusters will most likely become available in the coming years. Will this kick-start the demand for smaller batch sizes and campaign-based production schemes?

F. Nygaard: The competition from biosimilar versions of current blockbuster products will likely change the landscape for biomanufacturing over time, although at different pace depending on the geographical region. Short term, I think we will continue to see large-scale blockbuster originator products being manufactured for global supply from a limited number of sites. However, this large-scale global supply from few sites will gradually be challenged as the alternatives mature. There is an increasing demand for local manufacturing of biopharmaceutical products in many emerging markets. This will likely change market supply to these growing regions as biosimilar products become available for local manufacturing. Another factor is the increasing awareness on public health-care expenditure in both EU and US, which may also influence the penetration rate for new biosimilar products.

The Bio on demand idea combines standardization with customization and flexibility. What design characteristics and equipment are typical for a Bio on demand facility?

F. Nygaard: The core of the Bio on demand concept is built around single-use bioreactors — short: SUBs. Single-use technology decouples the process from the building, which gives a lot of flexibility. The implementation of single-use technology is generally maximized to the extent feasible from both a practical as well as a financial perspective. A Bio on demand facility design is therefore characterized by the absence — or only limited — complex distribution matrices for fluids as connections are flexible. A feature of the Bio on demand facility design is the ease of capacity expansion. The footprint of a 2,000 L SUB is not drastically larger than a 500 L SUB and by reserving space for fitting out the cell culture area with extra SUBs, you may achieve a capacity expansion from, e.g., two times 500 L for early clinical material to six times 2000 L for commercial production. The progress of the single-use technology has expanded well beyond bioreactors, mixing systems and hold systems. Single-use transfer sets for chromatography and filtration are well-established and disposable chromatographic columns and single-use flexible fill & finish modules are also frequently implemented into Bio on demand designs.

How do you customize a Bio on demand facility to meet the technical, operational and regulatory requirements of each specific customer?

F. Nygaard: The Bio on demand facility is based on a configured-to-order idea. Although being based on a high degree of standardization, it is adaptable to customer needs, national and local requirements, site-specific conditions as well as international regulations. The standard facility is designed for an open process architecture, where process equipment from a full range of suppliers can be used to build the optimal process train. This flexibility is reflected in ample space for processing operations, reserved workflow routes and readiness for room classification changes. This will enable to install and switch process equipment as needed and work with equipment and consumables from all suppliers.

How does the flexible approach of Bio on demand open the way for optimizing processes and operations in a biopharmaceutical facility?

F. Nygaard: The less predictable product pipelines and increasing pressure for delivering products faster to the market call for a new generation of manufacturing facilities that focus on agility. Having access to smarter ways of planning and foreseeing future needs, smarter solutions for maintaining flexibility and methods to reduce complexity and risk of fast-track engineering projects will be key competitive parameters in future biopharmaceutical manufacturing facilities. The Bio on demand standard facility concept is designed for easy configuration to company requirements and local conditions. That means that you can create your own company-specific standard facility, which can be deployed to a number of locations with only minor reconfigurations for local conditions. This standardization reduces risk and speeds up the facility project by applying proven project management methods for project realization.

Does the Bio on demand concept work for a revamp of existing facilities as well or is it predestinated for greenfield plants that are designed from scratch?

F. Nygaard: On-site construction offers the highest degree of flexibility and ability to shape your facility. This method offers few limitations in, e.g., ceiling height, floor loads and number of floor levels. However, converting an existing building space is also possible and could potentially be the fastest and most cost-effective route to biomanufacturing capacity. Time-critical activities such as various permissions may already be in place, and timelines for project execution can potentially be compressed by initiating parallel work in multiple sections of the facility independent of weather and seasons if roof and climate shell is established.

In terms of geographies, where do you see the highest demand for your manufacturing concept?

F. Nygaard: We see a global interest for our flexible Bio on demand facility design concept as it addresses some of the changing expectations of success within pharmaceutical manufacturing. Main features include flexible production with the ability to quickly accommodate changes in production demands as well as an open architecture concept allowing seamless implementation of new technologies and practices.

We currently see a huge demand for flexible facility design concepts like Bio on demand in the emerging markets, especially in the BRIC countries. Macroeconomic factors and a strong incentive for establishing local manufacturing of complex biological products have led to an urgent need for manufacturing facilities in these countries. Incentives for local manufacturing include, e.g., Productive Development Partnership initiatives providing a unique platform to facilitate local production and increase access to appropriate and affordable medicines in these countries.

Which different types of facilities have you designed and built so far?

F. Nygaard: Being an engineering and consulting company focused on pharma engineering, the diversity of facilities designed and built by NNE Pharmaplan covers practically all kinds of facilities from the small and simple ones to the gigantic and highly complex stainless steel facilities with fully automated systems. The Bio on demand concept addresses the small to mid-size facilities designed with flexibility in mind as described above.

Have you spotted any similarities?

F. Nygaard: An analysis of the Bio on demand facility designs reveals a number of common trends. Two-thirds of the facility designs were for locations within the BRIC countries. All designs were made for manufacturing complex proteins including mAbs. All facilities were designed for clinical production initially, of which half of them were also designed for commercial manufacturing and one-fourth with manufacturing up to product launch. One-third of the commercial scale design also included an option to scale-out the batch size to up to 6,000 L. Although modular construction was evaluated in 10%-20% of the concepts, we see that the construction designs for all Bio on demand facilities are stick built.

In general, we also see that facility designs for pilot scale and launch are using single-use technology for process and support — media and buffers — whereas the majority of the commercial designs are hybrid solutions with stainless steel systems for media and buffer preparation and the recovery using a centrifugation step. All Bio on demand facility designs are considering capacity expansion as part of the business strategy starting small and subsequently increase the capacity by, e.g., swapping equipment with larger systems, fitting out the manufacturing areas with additional systems and/or adding new manufacturing “blocks” to the existing manufacturing by preparing for this expansion in the early facility design. Nearly half of the designs also considered implementing continuous manufacturing into the manufacturing strategy.

We also see that half of the designs included a flexible fill and finish allowing end-to-end manufacturing. These flexible solutions we see in the Bio on demand designs are based on customer requests and the “configured-to-order” idea using a high degree of standardization and an open-process architecture as described above.