An analysis using the Cortellis Competitive Intelligence database showed a yearly increase in contracts between companies for outsourcing mAbs production to CDMOs (Fig. 2). Especially in 2020, the number of contracts increased rapidly with the addition of the number of outsourced contracts for the rapid manufacturing of COVID-19 therapeutic mAbs. The results of the survey confirmed that 22 of mAbs subject to contract manufacturing agreements had reached the market as of 2020. This represents approximately 20% of the total number of mAbs launched in 2020, suggesting that CDMOs have played an important role in the development process of mAbs.

Trends in Contract Manufacturing Deals Related to mAbs. The Annual and Cumulative Number of Contract Manufacturing Deals from 2000 to 2020 Related to mAbs was Illustrated. The Bars and the Line Represent the Numbers of Annual and Cumulative Deals, Respectively.

Next, to identify the evolution of the roles/functions required of CDMOs, a survey and analysis of how the content of commissioning contracts has changed was conducted. Figure 3 presents the results of this analysis. First, the nature of contract manufacturing agreements changed after 2010. Prior to 2010, most requests were made by companies with revenues of USD 100 million or less and were predominantly Phase 1 or Phase 2 agreements. This is interpreted as the reason that in the early years of mAbs development, DBFs with annual revenues of less than USD 100 million were the main players, and the mAbs they created were the main focus. These DBFs had drug discovery technology, but owning manufacturing facilities was a risk, and it is thought that they outsourced their manufacturing, including the production of investigational medicines, to CDMOs.

Distribution of Contract Manufacturing Deals Related to mAbs by Development Stage. Each Bubble Represents a Contract Manufacturing Deal with a Relative Size of Revenue of a Licensee. The Vertical and Horizontal Axes Indicate Development Stages of Drugs and Years of Transactions, Respectively.

Notably, since 2010, there has been a sharp increase in requests by companies with revenues of more than USD 5 billion. Existing pharmaceutical companies, including mega pharma companies, have ample funds and are therefore able to own their own manufacturing facilities. One of their objectives in outsourcing manufacturing to CDMOs would be to expand their manufacturing capacity. In addition, the fact that they often outsource manufacturing after the pre-registration phase makes it highly likely that they are outsourcing to accommodate adjustments in manufacturing volumes after launch.

Another important point is that, from 2010 onwards, some of the contracts for the clinical development phase can be identified as being outsourced by existing mega pharma companies. This is presumably because CDMOs have developed and internalised key technologies for the manufacture and development of antibody medicines, forming a comprehensive technology platform, which enables them to provide value to existing pharmaceutical companies beyond the expansion of their manufacturing capacity.

In order to investigate why existing pharmaceutical companies are increasingly seeking to outsource to CDMOs, the capability of CDMOs and the changes they are undergoing were investigated and analysed. As representative CDMOs, Lonza Group AG, Samsung BioLogics Co, Ltd, Boehringer Ingelheim GmbH, FUJIFILM Diosynth Biotechnologies, Wuxi AppTec, Inc, AGC Biologics were investigated. The survey and analysis of the contract arrangements and their changes. Figure 4 revealed that until 2010, the contract arrangements were for contract manufacturing of antibody drugs. However, from 2011 onwards, contracts related to patent rights, technology-supply and development support have increased, accounting for about half of the total. This confirms the trend described in the previous section and indicates that the role of CDMOs in mAbs industry has changed since around 2010.

Changes in the Nature of Transactions Related to mAbs by Representative CDMOs. Types of Contracts Related to mAbs Undertaken by the Selected CDMOs (Lonza Group AG, Samsung BioLogics Co., Ltd., Boehringer Ingelheim GmbH., FUJIFILM Diosynth Biotechnologies, Wuxi AppTec, Inc. and AGC Biologics) were Illustrated, Divided into Four Periods as Shown. The Transaction Categories Encompass Manufacturing of mAbs (Black), Early Research/development (Red), Development/commercialization License (Blue), Development Services (Green), Non-exclusive Patent Rights (Yellow), and Other Proprietary Technologies (White).

Figure 5 shows the number and type of international patents applied by the major CDMOs to mAbs. As shown in Fig. 3, before 2010, CDMO had mainly outsourced manufacturing from DBFs that possessed drug discovery technology but did not have their manufacturing facilities, so the capability in terms of manufacturing technology was sufficient. This shows the strategy of the CDMO industry as a whole, which was to develop the business by accumulating manufacturing experience, while at the same time gaining capability in upstream drug discovery research and development. The formation of a technology platform based on these efforts contributed to the expansion of partnerships with existing pharmaceutical companies in the early stages of development, and is considered to have earned the company an important position in the value chain for the development and manufacture of mAbs today.

Trends in Patent Applications Related to mAbs by Representative CDMOs. Trends in PCT Patent Applications By the Selected CDMOs (Lonza Group AG, Samsung BioLogics Co., Ltd., Boehringer Ingelheim GmbH., FUJIFILM Diosynth Biotechnologies, Wuxi AppTec, Inc. and AGC Biologics) were Illustrated from 2002 to 2020. The Patent Categories Encompass Manufacturing of mAbs (White), New mAbs (Yellow), Formulation (Blue), Optimisation of the mAb Structure (Green), and the Discovery Of mAbs (Black). The Vertical and Horizontal Axes Represent the Number of Applications and Application Years, Respectively.

Based on these series of results, the present study identifies the role of CDMOs in the development process of mAbs and the evolution of their function in the industry bird’s eye view. Three triggers that prompted the functional change of CDMOs are considered to have been responsible for the change in the function of CDMOs.

The first trigger was the FDA Modernisation Act, which came into force in 1997 [23]. This Act consolidated biopharmaceutical product and manufacturing applications into one document, the BLA; before 1997, switching or expanding manufacturing facilities after an application required a new application. Furthermore, the FDA regarded CDMOs as part owners of the product, so for pharmaceutical companies to use CDMOs, sensitive data had to be shared and the name of the CDMO also had to appear on the product packaging, which greatly discouraged the willingness to use CDMOs [24].

The second trigger was M&A of DBFs by established pharmaceutical companies: between 2004 and 2009, a wave of acquisitions of DBFs with important antibody drug discovery technologies and developments by established pharmaceutical companies occurred [11]. During this period, many established pharmaceutical companies were facing patent expirations, pipeline phenomena, and cost pressures, and were looking for ways to improve their profit margins. They were also being squeezed by generic competition and needed strategies to improve research productivity and reduce costs. One of the strategies they took was the acquisition of DBFs for a comprehensive inclusion of their biopharmaceutical pipeline [25]. There are many reasons why pharmaceutical companies steered their acquisitions of DBFs. One of the most important reasons is that mAbs were more difficult for generic manufacturers to copy than chemically derived active pharmaceutical ingredients. Because their molecular mechanism of action depends on multiple domains, regulatory approval of mAbs biosimilars is subject to specific science-based guidelines and high development costs [26]. This may have accelerated the acquisition of DBFs by existing pharmaceutical companies. This made it important for CDMOs to take on contract manufacturing from existing pharmaceutical companies in addition to DBFs.

The last trigger is a functional change by the CDMO itself. While the first and second triggers are external factors, the last trigger is an internal factor that the CDMOs themselves have pulled in order to increase their value in the antibody drug industry. The evolution of the CDMO’s function and role in the antibody drug industry as a result of each trigger is shown in Fig. 6: Step-1 was as a development partner as a complement to the manufacturing capacity of the DBFs, Step-2 as a pure manufacturing capacity complement to existing pharmaceutical companies and Step-3 as a complement to existing pharmaceutical companies. Step 3 is a development partner of an existing pharmaceutical company. The findings reinforce the mechanism of the mAbs development process, as previous studies have described the important role played by DBFs, but with limited reference to CDMOs.

The Historical Evolution of CDMOs. Historical Stages (Steps 1 to 3) of CDMOs and triggers of their Transitions (Triggers 1 to 3) were Schematically Illustrated. The Services are Targeted at Clinical Development and Subsequent Processes, while the Beneficiaries of the Services are Organized into DBFs and Large Scale-Pharmaceutical Firms (Mega Pharma Companies).