Leveraging Experience To Support Biologics Manufacturing from Gene to Product

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In recent years, customer requirements for contract development and manufacturing organization (CDMO) services have changed. CDMOs have developed into partners, consultants, and providers of specific services, all preferably coming from a single source.

Richter-Helm is one driver of a transparent, flexible, guided, and solution-oriented way of partnership, offering its clients a full-service approach along the entire journey from gene to finished product. The company has a strong heritage and is known for providing best-in-class CDMO solutions including a unique knowledge base in process and analytical validation, process performance qualification (PPQ) procedures, and commercial production of therapeutic proteins and peptides, antibody-like scaffolds (e.g., variable-domain heavy-chain, VHH), bacterial vaccines, and plasmid DNA (pDNA) products. The global pharmaceutical industry expects and requests high-quality standards. Our services are verified regularly by national and international regulatory bodies, including the European Medicines Agency (EMA), US Food and Drug Administration (FDA), Japan’s Pharmaceuticals and Medical Devices Agency (PMDA), Brazil’s ANVISA health regulatory agency, and South Korea’s Ministry of Food and Drug Safety (MFDS).

Challenges and Possibilities
Some major challenges faced by CDMO businesses include tight timelines, unpredictable supply chains, and the need to develop and implement state-of-the-art processes to serve continuing new developments of drugs and therapies. Such trends have emerged especially during and after the COVID-19 pandemic.

To eliminate both the increased risk and the added time and costs associated with multiple technology transfers among several providers, it is important for drug developers to work with one-stop–shop CDMOs. Thus, the trend to outsource projects to partner CDMOs is increasing. Doing so offers promising new opportunities for CDMO companies with respect to growth of business, implementation of new technologies, establishment of expertise in certain areas, and building of strong and long-term business partnerships.

Another challenge in the CDMO business is recruitment of qualified personnel and experts for ongoing project success. Qualified scientists, operators, and laboratory staff — as well as project and business managers — are in high demand especially for the pharmaceutical and CDMO sectors. Richter-Helm overcomes this challenge through a continuing good reputation within the market and by offering the opportunity for talented staff to grow within an expanding and healthy environment.

The pDNA Market
Emerging cutting-edge technologies include messenger RNA (mRNA) vaccines, plasmid DNA (pDNA) vaccines, cell and gene therapy (CGT) approaches, and cell-free production of active pharmaceutical ingredients (APIs). Such new modalities and processes can be found increasingly in pharmaceutical company pipelines.

Because of ongoing developments in advanced therapeutics, the pDNA market has experienced significant growth. Plasmids are produced as critical raw materials for manufacturing of, e.g., mRNA and RNA interference (RNAi) products. Plasmids also provide DNA templates for CGT approaches and are essential starting materials for production of viruses such as lentiviruses and adenoassociated viruses (AAV) as well as for use in cell-free expression systems. In addition, pDNA can be used directly in some vaccines and biotherapeutics, for which it serves as a drug substance itself.

Richter-Helm offers an established, ready-to-use platform approach to providing pDNA products at high yields at full current good manufacturing practice (CGMP) grade or quality as requested by clients. The high-performance, proprietary RHB-pART pDNA process includes generic and validated quality testing for plasmids in different matrices and at different plasmid sizes, with high purification success demonstrated by the high ratio and maintenance of supercoiled pDNA (≥95%). The process is fully scalable from 10-L to 1,000-L fermentation volumes. With over 25 years of experience and expertise in pDNA production, Richter-Helm is a partner of choice for pDNA production and supply at different grades and in different quantities for multiple applications.

Protein-Based APIs
Strong advancements in drug-design tools also have led to development of new therapeutic molecules in the protein-API market. Such molecules are promising as potent medicines for treatment of many diseases, including oncological disorders. In the near future, the market for protein therapeutics will develop and grow further.

Many recombinant proteins are manufactured using Escherichia coli and Pichia pastoris as microbial cell factories. Antibody-like scaffolds are gaining increased attention for their flexibility, small size, and potential applications within the oncology field. Production of recombinant proteins is a core competency of Richter-Helm that includes molecules such as nanobodies/VHH and fragment antigen-binding (Fab) antibody fragments. Richter-Helm is a well-known expert in the microbial manufacture of protein-based APIs.

A new and exciting field in protein manufacturing is cell-free synthesis of proteins — especially cytotoxic proteins — from pDNA templates. A key advantage of this approach is the ability to make proteins with modified, nonnaturally occurring amino acids. Overall, 60% of the projects performed at Richter-Helm involve production of recombinant proteins in microbial and cell-free systems.

Capacity Expansion
Richter-Helm is reacting rapidly to emerging new opportunities in the fast-moving pharmaceutical and bioprocessing environment. Expanding both production and development capacities provides a reliable way to speed time-critical products to clinic and market at small and especially large and commercial scales.

Richter-Helm’s new multipurpose facility is designed for maximum flexibility (see photo, previous page). It will add a total area of about 10,000 square meters and handle projects at 300-L and 1,500-L fermentation volumes for microbial production as well as related mid- and downstream operations. Increased product yield for proteins and pDNA will come from 100% oxygen-aeration technology for high-density fermentation of E. coli and yeast cells.

The new site includes further space for analytical laboratories, warehousing, and technical areas. The expansion of Richter-Helm’s business is based fundamentally on supporting future organic growth. With a strong track record and over 30 years in business, the company has advanced from a small biotechnology organization to a trusted and valued partner for clients worldwide — from smaller biopharmaceutical companies to multinational “big pharma” groups. We can deliver technically advanced services at different scales, especially large clinical scales up to commercial scale. To further increase biomanufacturing efficiency, we are applying and implementing digital technologies into the whole manufacturing process: e.g., digitalization of process design and targeted process characterization to facilitate process development.

New projects can start at Richter-Helm either from scratch for full development or as existing process technologies transferred for large-scale production or market supply — or for support with materials for clinical studies and development of new products.

Achievements and Goals
Contributing to the health of people is a major goal of Richter-Helm. Driven by that idea, the company continually invests in the future of its business to be a key player and valued CDMO partner for the global pharmaceutical industry. With a flexible, transparent, forward-looking, and customer-oriented way of working, Richter-Helm delivers tailor-made solutions efficiently and with high quality standards. One-stop–shop offerings from development to release of finished product — including project management and regulatory support positions — make the company a partner of choice for production of late-clinical and commercial products.

Our profession is quality. As a GMP manufacturer with a 30-year track record of success, Richter-Helm is highly experienced with regulatory provisions of major regulatory bodies including the EMA and FDA. The company plans to continue growing its capacity over the long term to offer more reliable and highly specialized CDMO services for protein- and pDNA-based projects to support the global pharmaceutical and biotechnological industries.

Dr. Thilo Kamphausen is director of business development (49-4331-1230-451, [email protected]), and Dr. Kai Pohlmeyer is managing director (49-40-55290-430, [email protected]) at Richter-Helm BioLogics GmbH & Co. KG, Suhrenkamp 59, 22335 Hamburg, Germany; 49-40/55-290-801; https://www.linkedin.com/company/richter-helm-biologics.