The market for biopharmaceutical contract manufacturing organisations (CMOs) has changed rapidly. While many began as a result of product companies renting out excess capacity, pure-play companies focused solely on providing contract services have emerged. There has also been a change in the type of service offered; instead of providing manufacturing contracts only for shortterm projects, many are now engaged in more strategic relationships with sponsors.

CMOs have become CDMOs that offer not just manufacturing capabilities, but also a range of early development services, making them one-stop shops that provide support from the initial cell-line development to commercial manufacturing. Many differentiate by offering vertically integrated services that include, for example, specialised capacity to produce antibody drug conjugates, or they add product characterisation technology to support early and late-stage development.

This specialist offering has helped drive market growth in small, sometimes virtual, biotechnology companies that create new product concepts before using a CDMO to carry out the development. Large pharma companies, which lack in-house development and manufacturing capability for biologics, however, are using CDMOs for product development, and so the market continues to grow. A report by Mordor Intelligence projected that the global pharmaceutical contract manufacturing market would grow from $65.1 billion in 2016 to $94.38 billion by 2022.

Special access

While sponsors originally used providers as a way to reduce costs, the 2017 Nice Insight CDMO Outsourcing survey found that CDMOs were increasingly regarded as a means of providing access to specialised technology. Although pharmaceutical companies are increasingly using CDMOs rather than a larger number of service providers, they are working on nurturing more in-depth relationships with a smaller number of preferred suppliers. The latter need to be agile – sponsors have to predict the volume of product they will need at launch several years in advance, and CDMOs must be able to cope with rapidly rising and falling demand.

Boehringer Ingelheim (BI) is a research-driven pharmaceutical company that is well established in the biopharmaceuticals and contract manufacturing spheres. It registered its first biologic in 1983, and acquired its first contract manufacturing client in 1995. It now has a large biopharmaceuticals business unit offering manufacturing services for industrial customers and has produced more than 25 biopharmaceuticals for global markets. Its US arm, BI Fremont, currently employs more than 500 people and is growing rapidly.

At a time when economic pressures – including competition from generics and biosimilars, and pressure from governments and insurance companies for cheaper drugs – it’s essential for sponsors to remain as competitive as possible. To do this, they need partners who can innovate.

Innovation in this context is a multifaceted term that can include new processes and new technologies, but also new ways of using existing technologies.

“Improvements with regard to quality and reliability in supply continuity should be considered as innovation, especially in the field of biopharmaceutical manufacturing,” says BI’s corporate senior vice-president Dr Uwe Bücheler. “The capability to reliably deliver products of high quality to patients suffering from serious diseases such as cancer or autoimmune disorders is of utmost importance for sponsors and CMOs.”

What, though, motivates innovation, and how might sponsors ensure that new developments are in line with their particular goals? “Working with a CMO in any development stage of the product means strong collaboration on both sides, and in many cases over a long period of time during the life cycle of a product – ten years or longer,” says Bücheler. “The product company has to be aware when it starts outsourcing, especially in late stage and commercial manufacturing for biopharmaceuticals, that this in general requires a long-term partnership.”

Working with a CMO in any development stage of the customer product means strong collaboration on both sides, in many cases over a long period of time.

Working relationships

As well as a technological fit, a good cultural and value fit between sponsor and CDMO is something that should always be considered, and achieving a close working relationship with the sponsor is key. “As a CMO, BI has established a governance structure together with its customers, which assures alignment on different levels regarding the development plan of customer products as well as future product demands,” says Bücheler.

Biologics are highly complex to manufacture and require a good deal of technical expertise, as well as raw manufacturing capability. BI offers development and manufacturing services that, Bücheler says, span “the entire production technology chain from DNA to fill and finish”.

The technology it offers encompasses the production of antibodies, recombinant proteins, non-antibody scaffolds and antigen-binding fragments, as well as pDNA from either mammalian cell culture or microbial fermentation systems.

As a result of the considerable progress in treating cancer and autoimmune diseases with “innovative monoclonal antibodies”, BI has seen increasing demand from customers for manufacturing biologics. In response, it has greatly increased its development and production capabilities for mammalian cell cultures – currently, most manufacturing capacities offered by CDMOs are focused on mammalian cell culture rather than, for example, gene or cell therapy.

Last year, it opened a production site for biopharmaceuticals in Shanghai, which will provide development and clinical services to Chinese and multinational customers. It also announced its intention to open a new biopharmaceutical production facility in Vienna, which will manufacture therapeutically active recombinant proteins and pDNA from microorganisms and yeast, as well as investing $217 million in the upgrade and expansion of its Fremont manufacturing facility.

Recently, moving away from blockbuster drugs that are manufactured at scale, towards specialist, lower-volume drugs that have to be made more quickly has become a trend. In the future, an expected increase in personalised medicine will require even smaller drug quantities, but Bücheler’s colleague, Jens Vogel, president and CEO of BI Fremont, has said that he expects to see a return to blockbuster drugs, particularly immunotherapies, such as checkpoint inhibitors, where one drug works with a wide range of cancer indications. The two trends, taken together, will require small-scale, flexible production and high-capacity manufacturers capable of producing drugs at scale. While BI has centres in Biberach, Germany, and Fremont, US, that manufacture large volume products, it is also able to work at a smaller scale.

“For the biopharmaceutical production of clinical trial supplies or biologics for the treatment of rare diseases, smaller reactors are required,” says Bücheler. “Within BI’s production network, there is also the possibility of producing on a smaller scale using, for example, disposable bioreactors. These are single-use reactor inlays of smaller volume – up to 2,000L – which enable smooth transfer between our sites in Biberach, Shanghai and Fremont.”

BI, says Bücheler, is committed to innovation. Between 2016 and 2020, it will invest €11 billion in innovation, including €5 billion for preclinical research and development, “of which around one third is designated for collaborations with external partners”. BI’s focus on innovating can be seen in its introduction of project-in-development teams, which have dedicated budgets enabling them to come up with ideas about the design and engineering of new equipment. One innovation the teams created was iSkid – integrated continuous single-use process and equipment.

One for all

Continuous manufacturing, a relatively new development, is very different from traditional approaches. The idea is that all processing operations are combined in a single machine, into which excipients and API are fed continuously. The material then flows through every step in the process to produce a finished product. Its numerous benefits include hugely reduced time-to-market; scalability; less energy and water use, resulting in lower operating costs; and higher quality.

“Continuous downstream processing is very attractive for all manufacturers to overcome bottlenecks for high-titre processes in cell culture,” says Bücheler. “At its site in Fremont, BI is actively working in the field of continuous processing and considers this site its excellence centre for this technology. Continuous processing is attractive for molecules that are expressed at only very low titres, or for very complex molecules from mammalian cell cultures.”

Bücheler agrees that small incremental innovations can lead to big outcomes. As an example, he cites a trend towards an “incremental increase in production titres, especially in mammalian cell lines”. He adds, “Many years ago, titres of 1–2g/L have been the average – today, state-of-the-art processes result in at least 4g/L titres, especially in Chinese hamster ovary. Based on this, BI, as a CMO, can optimise the output of its facilities and therefore handle the growing product demands of its customers.”

Continuous downstream processing is very attractive for all manufacturers to overcome bottlenecks for high-titre processes in cell culture.

BI’s long history, combined with a depth of expertise, puts it in a good position to respond to its customers’ needs. The key to fruitful partnerships between sponsors and providers is flexibility. “BI believes that securing supply throughout the entire product life cycle, transferring customer projects at any stage and delivering to almost any scale can make it easy for customers to outsource products,” concludes Bücheler.