Well-defined project structure
Figure 2. A knowledgeable medium-development partner will help sponsors identify and set goals and priorities.
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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 3a. Life Technologies's media-manufacturing site in Grand Island, New York.
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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).
Medium supply terms
Figure 3b. Life Technologies's media-manufacturing site in Inchinnan, Scotland.
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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.
Intellectual property ownership
"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.
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