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Medium and Feed Development

Xell offers targeted, rapid and efficient services for the development of custom cell culture media.

As a leading company for custom cell culture media and feed development, Xell is your ideal partner to find solutions that meet your cell line‘s individual needs and empower them to deliver highest product yields. Depending on the application, and in close collaboration with you, we carefully choose individual target values for process performance. Following a streamlined workflow, we combine powerful spent media analysis with intelligent DoE and process simulations in order to reach your objectives in the most efficient way.

We have previously developed custom cell culture media and feeds for cell lines like CHO, BHK, hybridoma, HEK and other human cell lines for customers throughout the biotech industry. Individual and highly efficient, these customized solutions represent the essence of Xell’s expertise. All of our media and feed products are chemically defined, animal component-free and available as liquid or powder formulations.

Custom medium development can be planned and managed according to your needs and timeline. With our long-standing experience we can support your processes for applications such as:

  • Production of diagnostic and therapeutic proteins
  • Vaccine production
  • AAV production
  • Lentivirus production
  • Gene/Cell therapy applications
  • Production of biomass for novel food

Let’s talk about your process challenges and take advantage of a free feasibility study to evaluate the potential of custom development now – click here.

Our development process

Our collaborative team of experts leverages powerful tools, models and platforms to ensure that Xell effectively and efficiently meets the diverse needs of its customers.

Custom cell culture media development process
Fig. 1

Fig. 1: Development of a platform medium for a protein-producing CHO cell line. Viable cell density (vcd) and viability of batch and fed-batch cultivations in shaking flask and in bioreactor scale are compared using a commercially available reference medium, a developed interstage medium and the developed platform medium. The latter provides an excellent basis for further fast and efficient development steps.

Fig. 2

Fig. 2: Maximum product titer for the cultures shown in figure 1. Titer in platform medium was 1.4–fold for batch cultivations and 2.6–fold for a bioreactor process with a simple feed, compared to reference cultivation.

One of Xell’s partners, BIBITEC GmbH, is a successful GMP-certified CMO. The company is specialized in process development as well as flexible and rapid production of recombinant proteins and monoclonal antibodies from bench to 200 L scale with mammalian cells for clinical trials up to phase III. One well-known achievement of BIBITEC is the development of an EMA approved erythropoietin biosimilar (Silapo®).

BIBITEC applied Xell’s customized medium and feed solutions in the GMP-production of material for pre-clinical and phase I clinical trials. The therapeutic recombinant fusion protein was produced in fed-batch processes with a CHO cell clone. Process development was performed in 2 L scale whereas the production process for clinical material was accomplished in a 100 L stainless steel stirred tank bioreactor.

Cultivations were performed under standard conditions. A temperature shift was initialized when cells entered the stationary phase. Upscaling was successful and reproducible growth performance could be demonstrated for a cultivation of 15 days (see FIG. 1). The peak viable cell density of significantly more than 1.3E+07 cells/mL at day 6 decreased slightly within the stationary phase due to volume increase by feeding. Consequently, very high viabilities were maintained throughout cultivation, dropping marginally below 90 % at day 15. Product formation of the fusion protein was monitored by RPHPLC. In both scales, comparable yields were detected (see FIG. 2). This case study is one example for the successful application of Xell’s customized medium and feed solutions in a GMP-production of therapeutic material. For further information, please contact us: info@xell.ag.

Fig. 1

Fig. 1: Viable cell density and cell viability in the 100 L production process run are comparable to runs from process development in 2 L scale, demonstrating the successful upscaling of the process. The shaded area illustrates the results of three independent 2 L runs.

Fig. 2

Fig. 2: Relative product concentration for the 100 L scale production process run and runs from process development in 2 L scale (shaded area, n=3).

Process Services

Our intensive work in the field of mammalian cell culture processes makes us an excellent partner for solving your process challenges.

With our flexible and customer focused approach we provide efficient concepts and supply capacities to realize your research projects. To optimize and streamline your process, we apply our broad technology and knowledge platform. Please contact us for any project challenges you wish to discuss.

With our broad range of analytical methods (cell growth, product quantification and qualification, flow cytometry applications), we offer detailed characterization of your cell lines. Cell line stability and selection pressure are possible issues to be addressed. Depending on the culture medium, the concentration of selection reagents may need to be adapted to guarantee stable production while maintaining high process performance. Furthermore, we recommend the evaluation of long-term stability, which can be critical when extended seed-train periods are necessary.

Fig. 1

Fig. 1: Comparison of process values for a monoclonal antibody (mAb)-producing CHO cell line at three time points of a high passage experiment. Peak viable cell density was measured in bioreactor batch cultivations. mAb titer was determined by HPLC and relative gene levels were measured by quantitative real-time PCR. Loss of productivity was detected in long-term culture and was attributed to product gene loss.

Fig. 1

Fig. 2: Flow cytometric analysis of a CHO cell line cultivated in a high passage experiment. Heavy and light antibody chains were measured after intracellular staining with fluorescently labeled antibodies. A subpopulation with no HC expression was already detected in the mid-term culture. The long-term culture exhibited no HC expression and reduced LC expression. These results are reflected by the HPLC measurements of mAb titers (see FIG. 1).

With our key competences in medium development and manufacture, we know that raw materials (production, origin, quality) and production technology are crucial factors influencing the quality of the final medium product. As a result, the same medium formulation can lead to deviating process performances (see FIG3 and 4). We therefore offer to test raw material sources and to compare different suppliers. Furthermore, we recommend respective biological testing of potential raw materials and evaluation of products from different suppliers with regard to process performance and production. Powder and liquid media characterization as well as solubility studies of your products are also part of our portfolio.

Fig. 1

Fig. 3: Comparison of growth performance of a HEK cell line in pre-culture passaging and batch cultivation with one medium formulation containing different variants (1-5) of one raw material for each culture.

Fig. 1

Fig. 4: Peak viable cell densities achieved in batch shaker cultivations with the same medium formulation produced by two different suppliers for three CHO cell lines.

Lot-to-lot variation is a well-known effect in media production and can occur even in chemically defined media. It can be caused e.g. by change of raw materials, minor changes in the powder production process or the solubilization procedure. Furthermore, lot-to-lot variation can occur due to impurities in raw materials. Components such as amino acids in USP/pharma grade with ≥ 98-99% purity may still contain foreign amino acids and trace metals. To evaluate variation in your media lots, we highly recommend biological performance tests and respective analytics. For that, we can establish and perform routine lot testing (see FIG5).

Fig. 1

Fig. 5: In-house testing of different medium lots of a chemically defined medium formulation developed by Xell. The test was performed with a CHO cell line to define thresholds for biological performance testing of the powder lots.

Process development such as feed strategy optimization can take up a lot of time and resources. With our long-standing experience in cell culture technologies and medium development we can provide process development services including:

  • Development/optimization of a feeding strategy
  • Metabolic optimization of feeding
  • Optimization of seed trains and handling procedures
  • Parameter profiles, e.g. pH, temperature, DO
  • Development/optimization of perfusion processes
Fig. 1

Fig. 6: Optimization of a perfusion process from initial to final process.

Cell culture medium and feed selection typically involves screening and benchmarking of alternative off-the-shelf culture media from several suppliers. With our long-standing experience in cell culture technologies and medium development we can provide expertise and resources for these routine studies. We will include any chemically defined media of your choice and are not limited to media produced by Xell.

Whether you are just starting to set up a cell culture lab, experiencing process limitations, seeing batch-to-batch variations of your current medium/process or having troubles in your scale-up – we are your trusted partner for scientific consulting. With years of experience in cell culture technologies, medium development and medium production in liquid and powder form we deliver rapid and targeted support to your challenges.