The objective of this project is to demonstrate the applicability and the economic and practical advantages of protein-free medium using the new effective protein-free SMIF media line and a corresponding cell adaptation protocol which shall be applied to current industrial processes with mammalian cell cultures producing pharmaproteins and vaccines. There is an increasing demand from clinicians and patients for human therapeutics manufactured by processes fee of any component of human or animal origin. In addition, the worldwide competition induces manufacturers to currently improve their process strategies and to adapt them to the latest standard. Especially, the step to the use of protein-free media is one of the expectations that have been frequently pointed out and that contains essential economical benefits. The improvement of biopharmaceuticals as proposed for this demonstration project is of highest public interest with respect to medical standards. Due to the broad spectrum of methods and production processes used by the different European pharmaceutical companies, demonstration of the application of protein-free media needs the concerted effort and cooperation of highly competitive manufacturers and research institutes involved in the production of biopharmaceuticals. The four groups that have joined together will unite their specific knowledge and expertise into a multi-disciplinary approach that will cover the major application aspects in mammalian cell cultivation and production. By focussing activities of several competitive European industrial companies and the corresponding biotechnological research, the advantageous and reliable application of a new protein-free culture media line combined with a necessary adaptation strategy for conserving process specific cell properties under these conditions will be comparably demonstrated by means of 4 partner-specific and 3 commercially relevant manufacturing processes based on different production cell lines and different production systems see table 1).
Nr Cell Product Bioreactor Pre-Cul-Demonstra- Aeration Process Lineture Scale tion Scale Strategy
1 BHK rh growth airlift 20L 1000
2 CHO rh antibody fluidised 100
100 Lextern continuous bed perfused
3 MDCK virus stirred2 L 100 Lmembrane batch vaccine tank
4 CHO rh blood stirred2 L 50 L membrane/ continuous factor tank sparging perfused system
Table 1: Process configuration used by the partners (1: TU-BS, 2: Polymun, 3: Chiron Behring, 4: Pharmacia) All products used by the companies in this demonstration project are of highest clinical importance and should be released to the pharmaceutical market in the foreseeable future.
To prove the validity of this improved technology (combination of protein-free medium for all phases of different cultivation processes and a directed cell adaptation procedure to this medium), growth and productivity of producer cell lines growing under protein-free medium conditions as well as expression stability and product integrity of the respective recombinant products and viral vaccine will be analysed and compared to the corresponding conventional and present used procedures. Comparison of costs for production and purification will show economical advantages. Feasibility studies for selected production processes under current development will be performed in pilot and/or production scale which will represent operational reality. Even in one case the product manufactured will be used for further clinical trials and has to be subjected to the complete quality control required.
The project comprises the following work package to achieve the aims: 1. Adaptation of cells to the protein-free media line and establishment of working cell banks providing cell material for cultivation processes. 2. Demonstration of the applicability and advantages of SMIF protein-free media line for cell culture production/cultivation processes in pilot and production scale.
3. Demonstration of the applicability and advantages of protein-free SMIF medium for product extraction and purification.
4. Verification of product quality and integrity.
Funding SchemeCSC - Cost-sharing contracts
112 87 Stockholm