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Microbial Technologies & pDNA
Wacker Biotech offers innovative technologies for the efficient and cost-effective production of biologics, including live microbial products, vaccines and plasmid DNA. Via collaboration with XL protein, Wacker Biotech can offer unique solutions for plasma half-life extension, if desired. According to the properties of the target protein, we recommend the most suitable production strategy using ESETEC®, FOLDTEC®, LIBATEC® and PLASMITEC® technologies.
Plasmid DNA (pDNA) is nowadays much in demand for nucleic acid-based gene therapies, for novel vaccines or as a starting point for innovative therapeutic agents, including messenger RNA (mRNA) and viral vectors. Wacker Biotech offers capacities for pDNA GMP manufacturing ranging up to 650 L stainless steel fermenters, including continuous lysis. Fermentation, downstream purification including continuous lysis, and pDNA quality control are part of our proprietary PLASMITEC® platform. A highly experienced, specialized team provides products and services that meet the highest quality and compliance standards.
The production site in San Diego is equipped with 43 L single-use bioreactors and 650 L stainless steel fermentation vessels, including continuous cell lysis. Corresponding primary recovery and downstream capabilities are available to suit various customer needs along the manufacturing path. Our team is highly experienced and has been manufacturing GMP-compliant pDNA since 2003 (more than 100 GMP batches released).
Controlled secretion is a key feature of our improved ESETEC® technology for the production of difficult-to-express pharma proteins. Wacker Biotech’s unique E. coli secretion system allows the controlled release of correctly folded proteins in high yields into the culture broth. It comprises engineered E. coli K12-based host strains, a set of proprietary plasmids and a genetic toolbox of co-expressed helper molecules to increase and control secretion. The technology has been successfully used for the production of a wide variety of recombinant proteins for clinical use, even those that are difficult to produce, including therapeutic Fabs, scaffolds and single-domain antibodies with yields of up to 14 g/L.
With strain development and up to three times lower cost of goods sold (COGS), ESETEC® is a better alternative to mammalian systems for non-glycosylated proteins.
Similar to mammalian cells, the ESETEC® secretion strains can transfer proteins in their biologically active form across the outer cell membrane into the culture medium. ESETEC® is routinely used in biopharmaceutical manufacturing and has been scaled up to 4,500 L fermentation batches. Secreted product titers can reach up to 14 g/L depending on the protein of interest. For more complex molecules, we created a new controlled product release technology based on decoupling the production phase from the release phase. In controlling the exposure time to overexpressed chaperones and isomerases in the periplasm, Wacker Biotech has succeeded in optimizing the folding step and maximizing the level of secretion, leading to the best possible results for each target protein. ESETEC® allows the fully functional molecule to be recovered from the culture broth, simplifies downstream purification and reduces manufacturing costs.
ESETEC® perfectly combines the benefits of secretion with the fast growth of microbial systems, enabling more cost- and time-efficient production of any non-glycosylated therapeutic protein. Based on process simulations, ESETEC® reduced the cost of goods by a factor of 3 compared to mammalian cells (assuming identical titers and process yields) due to the faster growth of E. coli. The annual output of a dedicated 1,500 L CHO system was 30 kg, compared to 111 kg using ESETEC® on the same scale. This significant advantage in productivity and costs is mainly driven by the shorter fermentation times and the fact that no viral depletion steps are needed.More about ESETEC®
FOLDTEC ® provides unique solutions for the sophisticated manufacturing of biopharmaceuticals by refolding, in synergy with Wacker Biotech’s high-cell-density fermentation systems. The FOLDTEC® technology is based on proprietary E. coli strains optimized for high-quality inclusion bodies and superior yields (up to 12 g/L) and our comprehensive refolding expertise.
While Wacker Biotech’s own ESETEC® technology has proven highly efficient in producing soluble proteins via secretion, poorly soluble biologics form aggregated inclusion bodies within the cell. Here protein refolding is a key production stage for achieving the desired active properties. FOLDTEC® – our proprietary E. coli strains, complemented by our years of experience in refolding and a tailored screening approach – offers better efficacies, smaller folding volumes and fully scalable manufacturing processes, without the need for antibiotics or undesired phage components.
Folding optimization with FOLDTEC® can increase yields by 20-fold compared to state-of-the-art processes, as shown for production process of recombinant Thrombin.More about FOLDTEC®
With its LIBATEC® platform, Wacker Biotech offers its customers vast experience in process development and optimization, as well as in the manufacturing of live microbial products (LMPs). EMA/FDA-approved production lines are available for this, with volumes from 250 L (single-use reactor) to 1,500 L (stainless steel fermenter).
The LIBATEC® platform is suitable for a wide range of LMPs and fermentation regimes, allowing aerobic as well as specific anaerobic bacteria to be used. Wacker Biotech can set up and run closed production systems (monoseptic processing), ensuring maximum culture purity and allowing specific routes of application, such as parenteral administration.
Our proven track record and experience in the LMP field allows us to meet the requirements of any project at every development phase. Our expertise extends to:
- Replacing animal-component-containing media
- Maintaining cell viability throughout the production process by developing new freeze-drying cycles if necessary
- Process characterization, process validation, clinical and commercial GMP manufacturing experience with LMPs
Following upstream and downstream processing, the bulk drug substance or drug product can be filled into vials or freeze-drying trays. Integrated drug product production, including lyophilization, provides a seamless manufacturing process, which may be critical in cases where there are limited hold times between cell harvesting, filling and storage. Wacker Biotech performs aseptic filling within the GMP fill & finish facility, which includes both formulation / preparation and the main filling area, supporting batch sizes up to 20,000 units (DIN 2R to 20R) and bulk lyophilization runs up to 65 L.More about LIBATEC®
Microbial and m-RNA-Based Vaccines
Wacker Biotech has more than 20 years of experience as a CDMO for vaccines using microbial hosts. Our expertise extends to the process development and manufacturing of a variety of vaccine products, ranging from live attenuated, inactivated and (conjugated) polysaccharide vaccines, to protein- and mRNA-based vaccines. EMA/FDA-approved production lines are available for this, with volumes of 250 L (single-use reactor) up to 1,500 L (stainless steel fermenter).
Our production sites are home to state-of-the-art biosafety levels 1 (Halle, Jena) and 2 (Amsterdam) facilities, as well as an explosion-proof room (Amsterdam) for manufacturing vaccine products under ICH and GMP quality guidelines. Our stainless-steel fermenter has a capacity of 1,500 L, and our single-use reactors can accommodate volumes of up to 250 L. Furthermore, at our site in Amsterdam, we operate a modern GMP fill-and-finish facility for aseptic filling operations of up to 20,000 vials (DIN 2R to 20R) per batch as well as bulk lyophilization up to 65 L. Wacker Biotech has produced and released more than 650 GMP vaccine batches for clinical (phase I to III) and commercial applications. We provide efficient solutions for customer-specific process development and process transfer, complemented by tailored analytics for quality control.
A major limitation of most biopharmaceutical proteins and peptides is their fast clearance from circulation via kidney filtration, which strongly hampers their efficacy in human therapy. In collaboration with the German company XL-protein GmbH, Wacker Biotech offers the production of PASylated biopharmaceuticals using
ESETEC® . The great synergy results in high yields of PASylated biologics, with titers of several g/L. For example, PASylated Fabs can be produced with yields > 4 g/L.
Visit www.xl-protein.com to learn more about PASylation® .
Wacker Biotech has extensive expertise in the development and performance of the PEGylation step of biologics and synthetic peptides in our GMP facilities.