Merck

Media Development

Media Process Development

SELECTING THE RIGHT MEDIA AND FEED STRATEGY

To maximize performance of cell lines, biopharma manufacturers must find the right media, relevant to their production mode. For instance, perfused seed trains and production bioreactors require new media formulations for optimal performance.

Feed strategies must be based on empirical data from media screening and optimization, as well as nutrient testing. Feed volumes and timing of feed administration should be determined for each specific process and cell line via high throughput (HTP) and design of experiment (DOE) approaches. These can be conducted internally or by partnering with experts to expedite simultaneous screenings.


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SAFE HANDLING AND EFFICIENT MIXING OF DRY POWDER CELL CULTURE MEDIA

Dry powder cell culture media formulations provide many advantages for shipping and storage. To leverage these benefits, dry powder media formulations need to be highly soluble and homogeneous. These properties can be achieved by the combination of optimized milling procedures and suitable formulation technologies. Additionally, media should arrive in a format that is convenient to handle, such as pre-weighed dry powder bags that connect directly to hydration tanks. This minimizes product contamination risks, safeguarding employees and facilities. When mixing, especially at high volume, good dispersion and dissolution of particles can be managed with specially designed single-use mixing systems.

Intensifying the Seed Train using HCDC and Specially Designed Expansion Media

From thawing a single vial of cells, to expanding cells for a GMP manufacturing batch run is time-consuming, labor intensive, and requires open cell culture operations. Use of a High Cell Density Cryopreservation (HCDC) method, which feeds into the first seed train bioreactor, can streamline the overall process. As the frozen volume is relatively high, single-use bags are more appropriate than vials. This allows HCDC to be used in closed processing, thus reducing contamination risks.

Perfusing the seed train is a solution for achieving higher cell densities, and it is recommended to use specially designed expansion media for an optimal result. It enables high seed inoculation of your production bioreactor through higher cell biomass or reduces your upstream footprint by decreasing the number of bioreactors in the seed train. In addition, it saves time by eliminating adaptation during transfers from the vial thaw to expansion and production.

REDUCING VIRAL CONTAMINATON RISKS WITH NON-ANIMAL ORIGIN RAW AND CHEMICALLY DEFINED RAW MATERIALS

Contamination often originates from raw materials and animal-derived components such as bovine serum or trypsin. Wherever possible, raw materials and animal-derived components at high risk of virus contamination should be replaced with low(er)-risk alternatives, such as chemically defined cell culture media and non-animal origin recombinant supplements. They also simplify regulatory processes.

OVERCOMING INSOLUBLE OR UNSTABLE AMINO ACIDS

The essential amino acids tyrosine and cysteine present a challenge when used in upstream processing, due to low solubility (tyrosine) and low stability (cysteine) at neutral pH. To simplify fed-batch processes and enable high available concentrations of both amino acids, chemically modified tyrosine and cysteine enable a single feed strategy at neutral pH. Other benefits of this approach include reduction of feed volume and increased volumetric productivity.

ENSURING LOT-TO-LOT CONSISTENCY OF RAW MATERIALS

Lack of consistency in raw materials can create significant variation in upstream processes, causing unexpected loss of cell density and viability – and ultimately, reduced yield. A better understanding of raw materials increases ability to control process variabilities. This can be achieved by tracing the supply chain back to raw materials and characterizing them.

EXPEDITING RAW MATERIAL QUALIFICATION

Current regulatory and industry guidelines do not define clear standards for chemicals used in upstream bioprocessing. In the absence of standards, drug manufacturers rely heavily on their suppliers for efficient sourcing and qualification of raw materials; however, typical timelines to collect raw material information via questionnaires and separate statements can be unacceptably long, often taking several weeks. Consequently, manufacturers are seeking supply partners who can provide raw materials that are stringently qualified to industry-leading standards and are supported by comprehensive documentation packages that meet pharmaceutical manufacturers’ information needs when qualifying raw materials, completing a risk assessment or optimizing a manufacturing process.


Workflow

Upstream Strategy

Upstream Strategy

Successfully advancing molecules from the laboratory to the clinic quickly without sacrificing product quality, process efficiency, or patient safety

Cell Line Development

Development begins by selecting single-cell clones that can produce the biologic of interest, then screening for clones that are stable, productive, and scalable

Bioreactor Production

Choosing an upstream platform must take many considerations into account, including scalability and quality control of the bioreactors and mixers

Monoclonal Antibody Manufacturing

Monoclonal antibody manufacturing is a highly templated approach used to produce mAb-based immunotherapies. Robust, scalable process solutions are required at every step to ensure high therapeutic concentration and process safety, while meeting speed-to-market and cost containment concerns.