Consequently, we advise to choose raw materials that comply to all global regulatory guidelines. Current existing guidelines are:

• USA: USP Chapter <1043> [1], USP Chapter <92> [2]
• Europe: Ph. Eur. General Chapter 5.2.12 [3]
• Global: ISO Technical Standard-20399 [4]

An additional challenge arises from the fact that all current regulations and guidance documents are not aimed at the manufacturers of the raw materials. Instead, they assign ultimate responsibility for quality and suitability of the raw materials to the user, the CGT manufacturer. Raw material suppliers and the quality of their products is not certified by regulatory bodies, the user himself is responsible to verify compliance to quality standards. As one result, most CGT manufacturers decide to perform identity and purity testing as raw material control tests. Potency testing for raw materials is however difficult, especially since there is a large variability and poor comparability of available biological assays.

Standardization of quality requirements of raw materials would bring much needed regulatory harmonization. Until such quality standards are set, CGT manufacturers need to work in close cooperation with their supplier to get the necessary support. Raw material suppliers should offer full transparency to mitigate the risk to an acceptable level. They can do this by providing:

1) Detailed batch specific test results on the Certificate of Analysis (CoA)

Detailed batch specific test results make it easier for both the CGT manufacturer and the regulatory agencies to assess the raw material product quality as well as regulatory compliance. It in addition makes it easier to compare raw materials from different batches or suppliers. Batch specific test results including their validated test methods should cover identity, quantity, purity and impurities, and safety.

2) The possibility to audit the manufacturing site

Audits allow CGT manufacturers to ensure that the raw material supplier has a clearly defined system for quality monitoring in place. This will help to determine if they are compliant with local and global quality requirements.

3) Comprehensive product-specific documentation (e.g. Drug Master Files (DMF), Regulatory Support Files, TSE certificates, & customized documentation for regional authorities)

Being able to provide product-specific documentation for critical raw materials to authorities speeds up the regulatory approval process. Since regional authorities can ask for varying documentation, we recommend choosing a raw material supplier that is able to offer customized documentation on request.

4) Documentation on product stability & consistency studies performed by Quality Control

Extensive stability studies should be conducted by the raw material supplier to determine the maximum shelf life for all raw materials and recommended storage conditions. These studies ensure that the raw materials remain consistent throughout the recommended storage times under appropriate storage conditions. To ensure the quality and consistency of raw materials, consistency studies should in addition be performed by the raw material supplier. The importance of batch-to-batch consistency of critical raw materials is also emphasized in Ph. Eur. General Chapter 5.2.12 [3] and ISO Technical Standard-20399 [4].

5) Well defined animal-derived component-free (ADCF) policy

Materials of biological origin, particularly of human or animal origin, can present risks, including transmission of adventitious agents or introduction of biological impurities. This does not necessarily limit the use of animal-derived components for manufacturing raw materials. The main purpose of defining ADCF is to provide necessary information for a user’s risk assessment of raw materials. ISO Technical Standard-20399 [4] defines two ADCF levels:

• Level 1 (product level): the raw material does not contain any materials from animal or human source as its ingredients.
• Level 2 (production level): in addition to ADCF level 1, raw material is produced without the use of any materials from an animal or human source. This includes excipients, equipment or containers that come into contact with the raw material during production.

6) Change notifications prior to relevant product changes

Changes related to product specifications, labels, formulation, packaging, expiry dates or the production process should be communicated well in advance. This ensures that the CGT manufacturer can put the necessary preparations in place without causing delays in their production process.

To help improve existing regulatory guidance we are actively involved in many regulatory initiatives and discussions. Together with the USP we have written the first version of USP chapter <92> [2]. We were also actively involved in the discussions for the setup of Ph. Eur. General Chapter 5.2.12 [3] and contributed to the ISO Technical Committee TC276. This committee issued the first global guidance for raw materials suppliers and users – ISO Technical Standard 20399 [4] – which is currently being processed into an ISO standard to improve global reach and acceptance. The guidance provides general requirements and guidance to ensure the quality and consistency of raw materials used in CGT manufacturing.

An initiative in which we are currently involved is one from the Alliance for Regenerative Medicine (ARM). They approached the European Directorate for the Quality of Medicines (EDQM) about the possibility of setting up a certification scheme for raw materials according to European Pharmacopoeia (Ph. Eur. General Chapter 5.2.12 [3]). This initiative is of critical importance because compliance to this general chapter is already demanded by regulators. Hence, a certification scheme would ease the regulatory burden for CGT manufacturers.

Another initiative that we are involved in is from the European Medicines Agency (EMA), who is evaluating the possibility of introducing a master file system in Europe. Drug Master Files (DMF) for raw materials are currently only available in the USA and Japan. A DMF is a regulatory instrument that provides confidential detailed information about the manufacturing conditions of a raw material (product’s chemistry, manufacture, raw materials used, stability, purity, impurity profile and packaging). It enables the raw material manufacturer to protect its intellectual property by allowing the FDA (or PMDA in Japan) to review the information in support of a third party’s submission. Using the detailed information provided in a DMF, the FDA can make a thorough assessment of the raw material’s quality and lot-to-lot consistency. Because of its great value to CGT manufacturers we have submitted eCTD DMFs to the FDA for our serum-free media and the large majority of our GMP cytokines. We currently offer the largest collection of eCTD DMFs for cytokines and growth factors.

Although these initiatives are promising, we propose that special workgroups should be set up that work on setting global quality standards for raw materials for CGT manufacturing. This would help reaching more global alignment between regulatory agencies.

References

1. USP General Chapter <1043> Ancillary materials for cell, gene, and tissue-engineered products  Crossref

2. USP General Chapter <92> Growth factors and cytokines used in cell therapy manufacturing  Crossref

3. Ph. Eur. General Chapter 5.2.12 Raw materials of biological origin for the production of cell-based and genet therapy medicinal products

4. ISO/TS 20399-1:2018 Biotechnology – Ancillary materials present during the production of cellular therapeutic products – Part 1: general requirements. ISO/TS 20399-2:2018 Biotechnology – Ancillary materials present during the production of cellular therapeutic products – Part 2: Best practice guidance for ancillary material suppliers. ISO/TS 20399-3:2018 Biotechnology – Ancillary materials present during the production of cellular therapeutic products – Part 3: Best practice guidance for ancillary material users  Crossref

BIO

Bernd Leistler

Bernd Leistler has a long track record as protein specialist. He joined CellGenix in 2003 and is currently responsible for all GMP and preclinical cytokine products for further manufacturing use, as well as process development for protein production which includes new packaging formats. Following his degree in chemistry he completed his dissertation on the structure, function, folding and assembly of oligomeric proteins. His professional career started at a leading manufacturer of diagnostic autoantibody immunoassays, where he managed the Biotechnology Department and developed it as a corporate service unit for recombinant and conventional human autoantigens and allergens.

Authorship & Conflict of Interest

Contributions: All named authors take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Acknowledgements: None.

Disclosure and potential conflicts of interest: Bernd Leistler is an employee of CellGenix GmbH. The author declares that they have no other conflicts of interest.

Funding declaration: The author received no financial support for the research, authorship and/or publication of this article.

Article & copyright information

Copyright: Published by Cell and Gene Therapy Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

Attribution: Copyright © 2020 CellGenix GmbH. Published by Cell and Gene Therapy Insights under Creative Commons License Deed CC BY NC ND 4.0.

Article source: Invited.

Revised manuscript received: Nov 19 2020; Publication date: Dec 1 2020.

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In a first expansion phase in 2018 CellGenix added additional space and personnel in its quality control, R&D, logistics and warehouse departments. By finishing both expansion phases, CellGenix has further strengthened their position as a leading supplier for large scale manufacturing in the cell and gene therapy space.

“The expansion of our facility is a result of the robust, sustainable, and profitable growth, generated by long standing and trustful customer relationships we achieved over many years. CellGenix is now well prepared for the future growth of the cell and gene therapy market. It supports our goal to further establish CellGenix as a key provider in the fight against disease, preferred supplier or raw and ancillary materials and trusted partner for large scale manufacturing of cell and gene therapies.” Felicia Rosenthal, Chief Executive Officer at CellGenix.

About CellGenix
CellGenix is a leading global supplier of high quality raw and ancillary materials for the expanding market of cell and gene therapy and regenerative medicine. CellGenix develops, manufactures and markets human cytokines, growth factors, and other recombinant cell culture components in preclinical and GMP quality as well as proprietary serum-free media for further manufacturing of ATMPs. As a former ATMP developer and manufacturer, in more than two decades CellGenix gained in-depth cell processing knowledge and superior regulatory expertise. With this unique background, CellGenix understands the high requirements their customers are facing during product development and the regulatory approval process. To meet the increasing demand of GMP quality raw materials for ATMP manufacturing CellGenix has recently expanded manufacturing capacity, built additional R&D and QC laboratories, and warehouse space. The upgrade also introduced state-of-the-art, automated, large-scale capacities for recombinant protein products in the existing GMP facilities. CellGenix is headquartered in Freiburg, Germany and operates a subsidiary near Boston in Portsmouth, USA.

For more information contact:

CellGenix GmbH
Am Flughafen 16
79108 Freiburg, Germany
Prof. Dr. Felicia M. Rosenthal
CEO
rosenthal@cellgenix.com

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Freiburg, Germany and London, UK, May 13, 2020 –  Ori Biotech Ltd, (Ori), an innovator in cell and gene therapy (CGT) manufacturing and CellGenix GmbH, a leading global supplier of high quality raw and ancillary materials for CGT and regenerative medicine, announced today a non-exclusive strategic partnership to achieve closed-system preparation, formulation and addition of CellGenix media and growth factors within CGT manufacturing for users of the Ori platform.

The Ori platform enables therapy developers and contract manufacturers to achieve more automated, more efficient CGT manufacturing in a closed system.  Utilising innovations from both Ori and CellGenix, users of the Ori manufacturing platform can eliminate process bottlenecks and open steps in media and growth factor formulation, preparation and transfers in order to enable higher throughput and reduced costs by eliminating manual handling steps.  Ori selected CellGenix’ raw material portfolio as a partner because of its high quality standards and over 25 years of experience.  CellGenix are experts in GMP manufacturing of raw materials which offer the highest quality and safety.

“Ori Biotech is continuing to build partnerships with best-in-class experts across the cell and gene therapy ecosystem to help enable our vision of integrated, closed system manufacturing,” said Farlan Veraitch, Co-Founder and CSO, Ori Biotech. “Innovation around the integration of high-quality materials from CellGenix into the Ori full-stack platform is another step toward enabling our customers to have a fully-closed manufacturing process from end-to-end, removing bottlenecks in formulation, preparation and process flow.”

“We are always interested in bringing the CGT industry forward by exploring innovative solutions that help simplify the production process as well as reduce the costs of goods”, said Felicia M. Rosenthal, CEO, CellGenix. “In addition to developing and producing our widely used raw materials and proprietary media solutions, we are building partnerships with companies developing next generation automated cell and gene therapy manufacturing platforms like Ori Biotech.” Till Puschmann, VP R&D and Business Development, CellGenix added “Through this collaboration our two companies will be able to offer our joint customers an innovative closed-system manufacturing platform including the necessary high-quality raw materials.”

“Through our ecosystem partnerships, we hope to provide our customers with integrated solutions that take some of the hassles out of their supply chain and manufacturing processes to allow them to focus on what they do best, delivering life-saving treatments to the patients who need them,” added Jason C. Foster, CEO, Ori Biotech.

About CellGenix

CellGenix is a leading global supplier of high quality raw and ancillary materials for the expanding market of cell and gene therapy and regenerative medicine.  CellGenix develops, manufactures and markets human cytokines, growth factors, and other recombinant cell culture components in preclinical and GMP quality as well as proprietary serum-free media for further manufacturing of ATMPs. As an ATMP developer and manufacturer, CellGenix gained in-depth cell culture knowledge and superior regulatory expertise. With this unique background, CellGenix understands the high requirements their customers face during product development and the regulatory approval process.  To meet the increasing demand for GMP quality raw materials for ATMP manufacturing CellGenix has recently expanded manufacturing capacity, built additional R&D and QC laboratories, and warehouse space. The upgrade also introduced state-of-the-art, automated, large-scale capacities for recombinant protein products in the existing GMP facilities. CellGenix is headquartered in Freiburg, Germany and operates a subsidiary near Boston in Portsmouth, USA. 
https://cellgenix.com/

 About Ori Biotech

Ori Biotech is a London- and Philadelphia-based CGT manufacturing technology company. Ori has developed a proprietary, flexible manufacturing platform that closes, automates and standardises manufacturing allowing therapeutics developers to further develop and bring their products from pre-clinical process development to commercial scale manufacturing.  The mission of the Ori platform is to fully automate CGT manufacturing to increase throughput, improve quality and decrease costs in order to enable patient access to this new generation of lifesaving treatments. Founded by Dr Farlan Veraitch and Prof Chris Mason in 2015, the Company has brought together a seasoned Board and executive management team with over 80 years of pharmaceutical, cell therapy and venture building experience including CEO Jason C. Foster (Indivior) and CBO Jason Jones (Miltenyi Biotec) alongside industry-leading expert advisors like Bruce Levine, Anthony Davies and Annalisa Jenkins.  www.oribiotech.com

 For more information contact:

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Cologne, Germany, December 19, 2019

CEVEC Pharmaceuticals GmbH (CEVEC), the expert in tailor-made recombinant glycoproteins and gene therapy vectors,  today announced that the Company’s cooperation partner CellGenix GmbH, a leading global supplier of GMP raw materials for cell and gene therapy and regenerative medicine, has launched CellGenix® GMP rh TGF-ß1 for cell and gene therapy applications based on CEVEC’s proprietary CAP®Go technology.

CellGenix® GMP rh TGF-ß1 is the third product resulting from an ongoing cooperation between CEVEC and CellGenix, which was established for the development and GMP production of selected cytokines using CEVEC’s proprietary expression technology CAP®Go. Other products include CellGenix® rh HGF and CellGenix® preclinical rh TGF-ß1. With the availability of TGF-ß1 in both, preclinical and GMP grade, CellGenix’ portfolio of growth factors now covers the entire value chain allowing a seamless transition from preclinical to clinical development and commercial manufacturing of cell therapy products.

“We are very happy to see our successful cooperation with CellGenix resulting in the next product derived from our CAP®Go expression platform,” said Dr. Nicole Faust, CEO & CSO of CEVEC. “With more and more advanced therapy medicinal products (ATMPs) in late stage clinical development, we are experiencing an increasing demand for GMP-grade raw materials. We are convinced that our CAP®Go expression platform based on thoroughly documented suspension CAP cell lines is the technology of choice for manufacturing these important reagents.”

“We are very pleased with the successful and supportive cooperation with CEVEC. CellGenix® GMP rh TGF-ß1 is the first GMP protein produced by CellGenix using CEVEC’s CAP®Go expression system,” commented Felicia Rosenthal, Chief Executive Officer of CellGenix. “CEVEC’s CAP®Go technology offers us an extensively characterized and animal-derived component-free expression platform that is safe and meets global regulatory standards. The collaboration with CEVEC allows us to further expand and strengthen CellGenix cytokines and growth factors product portfolio and thereby our position as raw material supplier for the cell and gene therapy space.”

TGF-ß1 – A highly potent advanced therapies medical product in cell-based treatments

Transforming growth factor-ß1 (TGF-ß1) is a cytokine that promotes the growth of induced pluripotent stem cells, embryonic stem cells as well as mesenchymal stem cells used in cell therapy applications. In addition, TGF-ß1 plays an important role in the differentiation of T cells into regulatory T cells (Tregs) and the expansion of these cells. Tregs are a specialized subpopulation of T cells that act to suppress immune responses, thereby maintaining homeostasis and self-tolerance. It has been shown that Tregs are able to inhibit T cell proliferation and cytokine production and therewith could play a critical role in the treatment of inflammatory diseases including autoimmune diseases.

CEVEC’s CAP®Go expression platform allows for the efficient recombinant GMP manufacturing of glycoproteins with authentic human post-translational modifications

The proper glycosylation of proteins such as TGF-ß1 is crucial for the functionality and efficacy of these molecules and can significantly improve physicochemical and pharmacological properties. Glycosylation capabilities are therefore a decisive factor when it comes to choosing the optimal cell lines for the production of these highly complex and difficult to express proteins. CEVEC’s CAP®Go expression platform comprises a comprehensive portfolio of glyco-optimized human suspension cell lines that differ in their glycosylation capabilities and allow for the scalable recombinant manufacturing of a variety of ATMPs used for cell-based treatments.

The development history of CAP®Go cell lines is fully known and thoroughly documented to provide full traceability. The CAP cells are grown in serum-free and animal component-free (ACF) medium which makes them a suitable cell substrate for GMP cell and gene therapy raw materials. CEVEC’s GMP-manufactured CAP® Master Cell Bank has been tested according to ICH Guidelines and WHO Recommendations for cell substrates. In addition, a Biologics Master File for CAP Technology (BB-MF) has been submitted to U.S. FDA and is referenceable for CAP® Technology Licensees, simplifying regulatory approval process for a CAP®-derived product.

About CellGenix:
CellGenix is a leading manufacturer and developer of premium-grade reagents for clinical cell culture needs. The company has more than two decades of in-house expertise in GMP manufacturing and development of products in the field of cell and gene therapy and regenerative medicine. The superior quality GMP raw materials are used by leading experts and are proven in clinical trials and commercial manufacturing throughout the world. CellGenix is headquartered in Freiburg, Germany and operates a subsidiary in Portsmouth, New Hampshire, USA, serving the North American market.

For more information, please visit www.cellgenix.com.
Follow CellGenix on LinkedIn.

About CEVEC:

CEVEC is a center of expertise for the production of biopharmaceuticals using a unique human cell-based expression system.

CAP®Go enables the production of high-end biologics. Complex, glycosylated proteins represent a significant portion of the human proteome and are notoriously difficult to express in conventional cell lines such as CHO. The CAP®Go expression platform comprises a portfolio of glyco-optimized human suspension cell lines for the highly efficient production of a broad range of difficult to express recombinant proteins with authentic human or designed post-translational modifications, including plasma proteins, blood coagulation factors and complex cytokines and growth factors.

CAP®GT is a fully scalable manufacturing platform for viral vector production. CEVEC has successfully developed CAP®GT suspension cell-derived viral packaging cell lines, including a stable, helper virus-free AAV production platform, which enable better scale-up and competitive production costs when compared to adherent cell culture systems. CAP®GT suspension cell lines grow to high cell densities and show excellent productivity for a broad range of viruses. Gene therapy vectors such as lentiviral, adenoviral, and adeno-associated viral (AAV) vectors can be produced at industrial scale.

For more information, please visit www.cevec.com
Follow CEVEC on LinkedIn and on Twitter

Contact:

CellGenix GmbH
Prof. Dr. Felicia M. Rosenthal
Chief Executive Officer
P.: +49 761 88889100
E.: publicrelations@cellgenix.com

CEVEC Pharmaceuticals GmbH
Dr. Nicole Faust
CEO & CSO
T.:+49 221 46020800
E.: info@cevec.com

MC Services AG
Dr. Solveigh Mähler
Public Relations
T.: +49 211 52925219
E.: solveigh.maehler@mc-services.eu

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