Choosing a Cell Culture Media Development Strategy for Biopharmaceutical Production

In 2012, the three best selling drugs were biologics. While biologics continue to move into the top spots in drug sales, they are also more complex to manufacture than their small molecule counterparts. The manufacturing of biologics is an intricate process and a large part of that process is focused on product yield. Product yield drives manufacturing capacity, drug availability and drug cost. As a result biopharmaceutical companies are regularly searching for ways to improve yield. Factors that drive yield include, among others, unique characteristics of the cell line or product itself, cell culture media, product quality requirements, manufacturing equipment and downstream purification techniques.

This blog focuses on cell culture media and considerations for choosing a media development strategy for biopharmaceutical production. The primary focus is on CHO cell lines, since they are the predominant cell line used for manufacturing biologics. However, most of these options would also apply to other cell lines used in manufacturing, including stem cell lines.

Cell Culture Media Development Considerations

When weighing all of the factors that go into media development it can be a rather daunting task. To begin, there are several key areas that need careful consideration prior to selecting a development strategy.

Stage of Product Development

When thinking about media development, the stage of product development must be considered. Early stage product development is often focused on quickly producing product for animal or proof of concept studies and early clinical trials (prior to Phase III). At this stage in development, it may not be necessary to devote considerable time and resources to developing a highly optimized media. The primary reason for this is that it is still unknown whether the product will be successful in the clinic. If the product is unsuccessful then valuable optimization time and resources have been wasted. In this early stage, some biopharmaceutical companies look to an off the shelf media to meet their needs, this is particularly true for small to medium size companies that have not developed an in-house platform media. Companies with a platform media frequently utilize their platform media, but add little or no additional optimization.

In late stage development, where high product yield is critical to efficient manufacturing and minimizing cost of production, optimization for each cell line becomes more important. It is also at this stage that a cell line is usually scaled up to large scale manufacturing equipment, and this typically requires an adjustment of the media strategy. At this point companies can choose from a number of development options, which will be described later, however most will opt for a more robust media optimization project at this point. This makes sense as the product has proven itself in the clinic and is worth the investment of resources to optimize for commercialization.


A company’s media development timeline frequently correlates with stage of development. As mentioned above, early stage development requires a quick turnaround. Still, tight timelines are also frequently a part of late stage development. Companies must weigh how much time they have to dedicate to media optimization and choose a media development strategy that best fits this need.


Cost also correlates with product development in that, as mentioned, no one wants to risk a large financial investment in an unproven product. Cost is also a very important part of the decision making process in late stage development. Companies must determine how much capital and human resources they want to devote to media optimization versus other key goals. It is important to select a media development strategy that supports the current project, but not at the expense of other key objectives.


Biopharmaceutical companies must take stock of their existing experience in media development and decide if this is a competency that the company has already developed, or if it will require additional expertise. The next question is whether obtaining this expertise is something that the company wants to pursue or is it preferable to partner with a media company that is already skilled in media development.

Media Formulation Complexity

It is important to remember that formulating a medium is a complex process that requires a depth of knowledge in cell biology, cell culture and cell culture ingredients, just to name a few. It also requires extensive knowledge of key chemicals and ingredients and the ability to manage these ingredients to avoid chemical reactions and prevent precipitation, insolubility or removal of nutrients. To aid development, companies frequently utilize high throughput screening and scale down systems to select and optimize media formulations. In addition, the use of statistical design of experiments is often used to maximize development time.

Cell lines are unique and as such need a specially suited environment for them to thrive. There are several different factors that influence this ability to thrive and achieve optimal productivity. One area is cell nutrient demands; different cell lines utilize nutrients differently. Another challenge is component toxicity, this can occur when a media component works well in most CHO cell lines, but creates toxicity in a more finicky line. Both of these issues can sometimes be resolved by evaluating component concentration. Lastly, waste accumulates differently, as some cell lines produce more waste, which can create toxicity if it isn’t properly managed. By looking at a cell line’s metabolism, these issues can be addressed, nutrient supply can be maintained at optimal levels, and waste accumulation can be managed effectively.

The required product quality of a target protein can also impact media development. Culture conditions, low cell viability at harvest, certain media components and impurities are just some of the factors that can have a deleterious effect on quality. Product quality must be evaluated during media development and the medium must be adjusted to address any negative impacts.

Cell Culture Media Development Strategy Options

After weighing specific goals for media development and their distinct situation, companies often select one of the following strategies that meets their needs best:

Off the Shelf Media

Some companies may opt to use a pre-made “off the shelf” media and feeds particularly in early phases of development where they need a quick turnaround with little time or resource investment. Smaller companies that do not have media development capabilities already in-house and do not wish to invest heavily in a media development group or the necessary equipment may also find this option is a good fit.

There are several advantages to going with an off the shelf media, including no development cost and a very short timeline. With so many commercial media options available, relatively quick, easy media screening of a cell line is likely to find a good match that provides a good balance of growth and productivity. In addition, when buying off the shelf media, companies do not have the added burden of sourcing raw materials and verifying the quality. Of course, companies may want to conduct a quality audit of the media company, but this is a much easier process than auditing several raw material suppliers.

As a company enters late stage development, off the shelf media may not provide all the optimization that they require. However, if a cell line is doing well in an off the shelf media, it is worthwhile to contact the media manufacturer to see if they can optimize the formulation for a particular cell line. This would be less costly and time consuming than a full media development project and may yield improved results with significantly less development. Another option is to test several off the shelf media feeds to find the best synergy with the existing media. This can be done in conjunction with an off the shelf media or can be used to boost an in-house media formulation.

Partner to Develop a Custom Media Formulation

Companies can employ a media development company to formulate a custom media for their cell line. In this strategy, companies work closely with their media partners to provide them with the cell line, any special characteristics, process requirements, desired product quality, manufacturing equipment information and any other pertinent information. The media development company then utilizes their team of experts and equipment to test many different media combinations.

Since media development companies have all these competencies and this is their primary focus, they are able to fulfill timelines for media development much quicker than in-house development. Full base media and feeds can be formulated in 6-12 months, depending on complexity. Media companies utilize different tools for testing media formulations, initially 96 well plates and/or shake flasks are used to screen for promising candidates. Promising candidates are then selected for further testing in scale down systems to predict performance at larger scale. Some companies that have integrated equipment competencies will test in larger scale scenarios including bench top scale and pilot scale, up to 2,000 liters. Adjustments can them be made to more closely match manufacturing scale.

Once the formulation is developed, companies have a choice as to whether they want to pay an additional cost for the recipe so that they can source raw materials and mix the media themselves or if available, they can arrange to purchase the pre-mixed powder media or in some cases even liquid media. Again, an advantage of purchasing the pre-mixed media is that companies do not have to manage the entire supply chain of raw materials.

Partnering is an attractive option for companies that want to have expertise and experience without developing those competencies in-house. It is more costly than optimizing an off the shelf media, but results should be better and it is still less expensive than developing the media in-house. Media companies also usually offer regulatory support and can provide a drug master file (DMF) and other regulatory documents for customers to provide to FDA.

Develop Media In-house

Some companies decide to develop their production media in-house. Most develop a platform media designed to support several different cell lines expressing different proteins. The platform media can support early stage production with little or no optimization and later be optimized on an as needed basis to address specific cell lines. While it is generally recognized that cell culture media development is best when it is cell line specific, it is too time consuming for companies to develop a novel media for each cell line. The platform approach allows for late stage optimization of the media and feeds to optimize productivity.

Once developed, an in-house media may provide more flexibility when purchasing raw materials or adjusting various components of the formulation. It also allows companies to know all the components of their media for regulatory purposes. However this is probably not critical with regulatory support from media companies. Companies that have a large number of products moving through their pipeline may find it is more cost effective to have a team who can do this work in-house. It may also provide the opportunity for improved workflow assuming there is good communication with cell line development and downstream purification.

One disadvantage is that the timeline is quite a bit longer to develop in-house, my sources say 18-24 months on average to develop an effective platform media in-house. Costs are also higher due to staffing requirements.

Hybrid – Develop Media In-house, but Employ a Media Partner to Optimize for Specific Cell Lines

Companies can also choose to elect a combination strategy. For companies that have an existing platform media that is not performing as expected, this could be a really valuable option. A media company may be able to provide a different approach or may spot another opportunity for improvement. This option is also valuable, if timelines are tight and company resources are being utilized in other areas.

Optimizing media could include improving media ingredient solubility, finding the best concentration of certain nutrient or other factors, and adding additional nutrients, growth factors or other supplements. The timeline for optimization projects is also very short; it can be as little as 8-12 weeks for optimized base media and feeds.


Deciding which strategy to follow for media development is complex and also very important. Cell culture media is an important factor in determining product yield, product quality, and cost of manufacturing. Careful analysis of company goals, timelines, budgets, and competencies are necessary in selecting the right strategy.

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