K. Fritchman (DON FARRALL/GETTY IMAGES)
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In the biopharmaceutical industry, the drive to obtain higher therapeutic protein yields from a production process continues
to be a key objective for controlling expenses and resource requirements. Although many factors contribute to protein yield,
a key element is media optimization. A thorough understanding of a cell's nutritional requirements in a given process is essential
to developing a high performance medium and feed strategy. Large biopharmaceutical companies often develop and optimize their
own in-house media formulations, the manufacture of which are then outsourced to a media supplier. A media optimization project,
however, can be time consuming and labor intensive if the proper tools and resources are not available. Outsourcing media
optimization to an experienced supplier, skilled in biopharmaceutical applications, can significantly decrease development
time and costs.
COLLABORATE WITH THE OUTSOURCING PARTNER
To select the right partner for media design and optimization, several key factors must be considered, with the most important
being the collaborative nature of the supplier. It is essential that the biopharmaceutical company and supplier work together
in a partnership, with full transparency to all data. This helps ensure that proper decisions are made to increase the likelihood
of success when the manufacturing process is implemented. Another key consideration is the supplier's understanding of biopharmaceutical
production process requirements and the media optimization strategy it uses. A methodical optimization strategy, specifically
created for production cell lines and including Design of Experiments (DOE) is essential for an optimized formulation. The
designed experiments must be coupled with a strong analysis of spent media to ensure a thorough understanding of the entire
process.
In addition, significant consideration should be given to the facilities that will be used for the optimization of the media
formulation and subsequent media manufacturing. The facility should not only be able to supply the resources needed to perform
the media optimization and to scale up production of the cell culture media, but also must satisfy rigorous quality and regulatory
requirements that meet and even exceed the high standards required by the biopharmaceutical industry.
PRE-AUDIT THE FACILITY
When outsourcing cell culture media manufacturing, one must consider the facility itself as a critical component of the overall
process. To ensure product consistency and performance, the facility must be pre-audited before manufacturing begins. There
are several key attributes of a cGMP cell culture media manufacturing facility that one should assess. A high level of control
of the raw materials, such as animal-origin information and strategic sourcing for reliable supply, along with a highly segregated
process and personnel flow, are paramount. These should include a stringent animal-free raw material policy and complete segregation
of all manufacturing areas, including personnel flow throughout the facility, as well as individual equipment suites with
zoned HVAC systems to eliminate cross-contamination risk. The facility must include modular cleanroom systems with hardened
PVC-coated walls and ceilings with cove transitions for ease of cleaning and full-viewing corridors that allow complete access
to the facility without compromising room integrity. Automated clean-in-place (CIP) and steam-in-place (SIP) processes must
be available as well as robust business continuity systems, including emergency utility back-up systems. The facility must
have fully integrated cell culture media and supplement manufacturing capabilities with the ability to produce complete formulations
for the full range of expression systems, including mammalian cell culture, microbial fermentation, and cell therapy.
The facility must be highly versatile with a fully scalable lot size capability including flexible packaging suites, that
offer a wide range of filling capabilities and custom-packaging solutions. State-of-the-art milling technologies, such as
pin mills, are preferable to ensure excellent particle size consistency, minimal heat generation, and easy cleaning using
a CIP system with ultra pure water. Powder production must be highly versatile and fully scalable, offering a wide range of
filling capabilities and custom-packaging solutions. In addition, the water used for liquids should be water for injection
and USP-purified water to reduce bioburden and control endotoxin levels.
