Together with Phacilitate we developed a survey with over 30 cell and gene therapy professionals to find out what the prominent challenges are with regards to raw materials and how the industry is approaching automation of raw material processes. This article presents the results as well as some perspectives from Bluebird Bio, Cellex Cell Professionals and others.
Read the article & view the infographic
The manufacture of cell and gene therapies (CGT) is particularly sensitive and requires a comprehensive understanding of the materials used in the manufacturing process to ensure a safe, efficacious, and high-quality product. Successful CGT manufacturing is therefore dependent on the use of high-quality raw materials (ancillary materials according to the USP). The manufacturing of raw materials for CGT manufacturing is however not well regulated and is not supervised by any health authority. Despite arising guidance in this area existing guidelines are, essentially, recommendations rather than guidelines. Geographical discrepancies make regulatory considerations even more complex. Each region has its own regulatory agencies that view CGT manufacturing in a different way. Getting a clear understanding of regulatory requirements around the quality of raw materials can therefore be challenging.
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Consequently, we advise to choose raw materials that comply to all global regulatory guidelines. Current existing guidelines are:
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:
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.
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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Speed up your serum-free culture with CellGenix® TCM
CellGenix’ superior T Cell Medium shows several benefits for your T cell culture:
– No need to add serum at any time
– High cell yield already early on
– T cell products with an early-memory phenotype
– High proportion of polyfunctional cells
We invite you to watch the video for more details.
Freiburg, Germany, October 8, 2020 – CellGenix GmbH, a pioneer for GMP grade reagents and a leading global supplier of high quality raw and ancillary materials for cell and gene therapies, announces the completion of the second phase of their facility expansion. CellGenix has reconstructed and expanded their production facility for cytokines and implemented a state-of-the art automated filling and freeze-drying line.
By implementing an automated filling and freeze-drying line and increasing bulkware production footprint, finished product capacity for cytokines is substantially increased. This continues to enable CellGenix to meet the fast-growing demand for critical raw and ancillary materials as more customers reach late-stage clinical development and commercialization of their cell and gene therapies. Scaling up from phase I or II clinical trials to large-scale commercial manufacturing, the demand for GMP cytokines often rises by several magnitudes. Consequently, a secure supply chain is imperative. A delay in delivery or change in product quality could lead to delays in production, not only increasing costs but also putting precious patient samples in jeopardy.
The newly designed and expanded facility enables CellGenix to streamline their production processes. The automated filling process also provides increased accuracy and reduced risks, which further increases the safety of their preclinical and GMP cytokines. The automated filling, stoppering and capping system (operates under an Open Restricted Area Barrier System (ORABS) and) is compliant with EU GMP Annex 1 for the manufacture of sterile medicinal products, also taking into account the new version which is currently under revision.
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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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At Phacilitate Leaders World 2020 in Miami, CellGenix led a breakfast briefing to discuss the challenges the advanced therapies industry is facing when it comes to raw materials. Chaired by Frank Hecht, the hour-long briefing brought us a stellar panel line-up of:
This video is linked to Youtube
Our Head of R&D Cell Culture Systems, Ulla Schultz, recently joined a panel discussion focusing on the challenges faced by cell therapy manufacturers in the development of allogeneic CAR-T.
What will you learn?
The experts in this roundtable are:
You can watch the panel discussion here.
Press Release, May 13, 2020
With the Cell and Gene Therapy space evolving, the demand for automated and closed-system solutions to simplify and secure manufacturing processes increases. To bring the industry forwards, CellGenix is building partnerships with companies developing next generation automated cell and gene therapy manufacturing platforms like Ori Biotech.
Utilising innovations from both Ori Biotech and CellGenix, users of the Ori Biotech 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. 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.
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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:
|
CellGenix Am Flughafen 16 |
Ori Biotech Jason C. Foster
|
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In this application note, we show how enhanced T cell expansion along with the generation of an early differentiated phenotype can be achieved using the G-Rex® system with CellGenix® serum-free reagents, such as CellGenix® T cell Medium (CellGenix® TCM) supplemented with CellGenix® IL-7 and IL-15.
Using serum-free reagents in your manufacturing process removes potential risk and variability introduced when using human serum, yielding a product with a low proportion of PD-1+ cells. The G-Rex® system reduces handling steps for more efficient production, eliminating the need to change media and refeed cytokines over an 11-day culture. The system is scalable, closed system versions are available, and it is widely used in clinical settings.
You can download the application note here.
How do you secure your raw material supply in the ongoing COVID-19 pandemic? Our experts give tips in this expert roundtable about overcoming raw material challenges in cell & gene therapy manufacturing.
Other topics that are discussed are sterile connectivity between GMP raw materials and closed automated cell processing systems, raw material variability and stability, customization vs standardization, regulatory guidelines and how to establish a collaborative business model with your raw material supplier.
The experts in this roundtable are:
You can watch the roundtable here or read the transcript.
CellGenix proudly announces the launch of its T cell medium CellGenix® TCM GMP-Prototype for serum-free expansion and differentiation of T cells. This new T cell medium promotes an early onset of T cell expansion, making it optimal for short protocols and a faster cell therapy manufacturing process.
Features
The medium is initially offered as GMP-Prototype (GMP will be available soon). The performance is identical to the future CellGenix® GMP TCM, allowing for a seamless transition to GMP.
Application
Learn more about CellGenix® T Cell Medium GMP-Prototype
