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The authors examine several issues that will help streamline negotiations between a service provider and a cell-culture medium consumer.
The rational design of cell-culture medium originated with Harry Eagle in 1955 when he began culturing cells in what would eventually become the progenitor of Eagles Medium (1). In subsequent decades, suppliers established a commercial market for the development and supply of cell-culture media. Over the next 45 years, these suppliers brought significant innovation to this field, including introducing the first serum-free medium, pioneering the creation of new media formats, and enabling many of the current high titer cell-culture processes. As the value of products derived from mammalian cells exponentially increased, so too has the demand for medium to culture cells. Today, cell-culture media for biological manufacturing represents a sizable market of more than $500 million, but more impressive is the cumulative value of therapeutic products enabled by these reagents, which totals more than $35 billion (2). Given the importance of these reagents, major suppliers, drug manufacturers, and other biotech companies continue to make significant investments to improve their cell-culture media platforms. Despite the tremendous value created by cell-culture media and the investment poured into research and development, this field remains a rather immature territory for efficient outsourcing models.
This article addresses some of the key issues that a company needs to think about when deciding to outsource development of a cell-culture medium. An outsourcing partner who understands these issues can provide guidance that will allow for informed choices about the sponsor's project goals.
The first place to start when considering outsourcing is the technical goals of the project. Project expectations can vary widely, even among members of the same team; therefore such expectations need to be fully vetted, and priorities need to be set during the preliminary outsourcing discussions. The specified goals will ultimately define the technical approach for the project. While multiple goals can be designed into a project, budget and time constraints likely will force both parties to set priorities.
For example, a project goal might be to improve process consistency by removing undefined components (e.g., hydrolysates) from the production medium (3). If this is the case, then targeting productivity improvements should also be considered as a separate development initiative because a developer would likely use a different technical strategy for eliminating hydrolysates than they would follow for improving cell productivity. In fact, these two particular goals can appear to be competing if a cell-culture medium is not properly balanced (4). Likewise, a development project aiming to optimize a medium for a specific clone will look significantly different from a project where the primary technical goal is to develop a platform medium that works across multiple products and multiple clones. In the latter case, a developer is often faced with selecting criteria that work best across multiple clones at the sacrifice of performance of any single clone.
Finally, within the technical scoping of the project it is important that the medium developed can ultimately be manufactured at a scale and in a format that will support commercial production (see Figure 1). Beyond production considerations, the developed medium will also become part of your chemistry, manufacturing, and controls (CMC) regulatory submission. It is therefore essential to have the requisite quality controls (i.e., process validation, release specifications, stability, and shipping robustness) to fulfill regulatory filing requirements. This final aspect of technical scoping is often overlooked by research scientists; however, a medium-development partner should frame these considerations to fit within the sponsor's overall technical strategy.
Figure 1. Commercial scale-up considerations should be part of any custom medium development. (All Figures are Courtesy of the Authors)
In defining the overall technical goals, it is important to understand the starting point for development, not only in terms of the medium one is starting with, but also in terms of the quality of the cell line and the expected yield. Regarding the medium, the goals one sets for optimizing an in-house medium that one has worked with for several years will likely be much more specific compared with a vendor's catalog product that has been minimally optimized. Likewise, the technical approach for a robust cell line with expected high yields will not be the same as a project designed to salvage a low-producing cell line where any improvement will be welcomed. The factors described above relating to the medium starting point and the quality of the cells (as well as the expected yield) will determine how substantial a development effort is needed (and therefore the time and cost of the program).
While scoping the technical aspects of a project to develop cell-culture medium, one needs to outline the project structure in parallel. Within the project structure, one needs to determine the amount of laboratory work that will be performed in-house versus outsourced, identify any critical performance steps that need end-user verification, and agree upon norms for joint team decisions. Also to be considered is whether the project has a time-critical element (such as the need for Phase II manufacturing in six months), as the technical strategy will be affected by how much experimental time can be dedicated to the project. For example, the sponsor may choose a sequential two-level study design followed by a central composite design of experiments (DOE) to pick the optimal medium formulation if the project can extend to 10–11 months; however if the sponsor has only three months, the project would more likely be designed following a single integrated basal medium or feed study to improve performance beyond current baseline (5). In each of these examples, having a knowledgeable media-development partner will allow the parties to set goals and priorities (see Figure 2).
Figure 2. A knowledgeable medium-development partner will help sponsors identify and set goals and priorities.
Beyond project specific decisions, performing the appropriate due diligence on a potential outsourcing partner's business processes is crucial. In particular, sponsors should inquire about success rates, functional roles within the project team, program management, and how the service provider manages crucial project decisions. Such "outsourcing best practices" are beyond the scope of this article, but are discussed in depth by several other authors (see, for example, the article by Douette et al. in this supplement). Most authors on this topic agree that a strong program-management infrastructure and proven track record are essential to minimizing the risks of outsourcing process development (6).
Figure 3a. Life Technologies's media-manufacturing site in Grand Island, New York.
Thinking about medium-supply terms at the outset of a medium-development project might seem premature, but addressing certain concepts at this phase will make the overall process smoother. A medium-development partner that has thought through supply issues, and preferably has an established plan for commercial medium supply, will have a long-term advantage as the project proceeds. One difficulty in addressing supply terms at the outset of a medium-development project is that since the final product does not yet exist (because the medium is still to be developed), any terms should be flexible enough to handle unexpected outcomes or changes in the overall project scope or design. In most cases, a supply agreement should include pricing tiers by volume based on annual forecasting and a common set of quality standards. In recent years, as the biopharmaceutical industry has become more focused on risk management, many companies have begun to seek additional safeguards against an extended interruption in culture media supply. Most suppliers will present redundancies within their manufacturing operations as an assurance of continuity of supply (see Figure 3a and 3b), and direct any additional safeguards to be outlined within a supply agreement. In general, it is a good strategy to ensure that the general supply concepts are covered and save the final details until the development program is complete.
Figure 3b. Life Technologies's media-manufacturing site in Inchinnan, Scotland.
"Lifting the veil of secrecy." "Breaking the code." Such phrases may sound like a plot for a 1920s movie, but in fact these expressions describe a challenge faced by every cell-culture scientist charged with improving bioreactor productivity while being blinded to the composition of the medium used to culture the cells. Historically, improvements in medium performance were primarily reimbursed to developers through profits on media sales, which led vendors to maintain successful innovations as trade secrets to recoup their R&D investment.
Despite this history, visibility to the composition of cell-culture media formulations is becoming a priority as the field becomes further specialized and therapeutic companies become more focused on product life-cycle management. As a result, the parties should discuss the level of knowledge-sharing about the composition of custom media in any outsourcing negotiation. Typically a project sponsor will desire disclosure of a medium formulation for regulatory and further internal development purposes, while the developer will be concerned about protecting intellectual property and freedom to operate. One standard approach is for the developer to maintain ownership of the medium formulation and contractually define end-user rights to the intellectual property. Often, such intellectual-property terms can be linked with supply-agreement terms that address everyone's business interests. Experienced outsource providers will have thoroughly thought through these issues and can offer helpful guidance on what is best practice as it relates to a specific project.
Although not a comprehensive listing, the areas discussed in this article are four of the most important issues that will help to streamline the negotiations between a service provider and a project sponsor interested in partnering on the development of a cell-culture medium. As the technology platforms continue to push new boundaries, we will need to continue to look for new ways to realize and share the value of those discoveries. The collective lesson for our industry has been that technical innovations in products and services must be matched with business innovation to continue to best serve patients.
It is clear that striking a balanced approach to the outsourcing discussion is crucial for achieving the project goals. An imbalance in any of the four areas discussed will set the outsourcing relationship on the course to disappointment; however, if done properly, a progressive philosophy on sharing risks and benefits will turn an arm's-length outsourcing relationship into a productive collaboration.
The authors wish to thank Cindy Goldstein and Laurie Donahue-Hjelle for their editorial contributions to this article.
TRENT CARRIER is General Manager of PD-Direct Services, STEVE GORFIEN is an R&D Director—Cell Culture Products and Services, and BRIAN GRIFFITH is Division Contracts Counsel, all at Life Technologies, Trent.Carrier@lifetech.com.
1. H. Eagle, Science, 122 (3168), 501–504 (1955).
2. Therapeutic Monoclonal Antibodies: World Market 2010–2015, ReportLinker.com 2010.
3. W.C. Paul et al., BioProcess Int. 7 (8), (2009).
4. D. Zhao et al., Biopharm Int. 21 (6) (2008).
5. T. Carrier et al., "High Throughput Technologies in Bioprocess Development," in Encyc. of Indust. Biotech., M. Flickinger, Ed. (Wiley, Hoboken, NJ, 2009).
6. S. Morris, BioProcess Int. 21 (12), 22-26, (2008).