Towards robust cell culture processes — Unraveling the impact of media preparation by spectroscopic online monitoring

Brunner, Matthias; Brosig, Philipp; Losing, Monika; Kunzelmann, Marco; Calvet, Amandine; Stiefel, Fabian; Bechmann, Jan; Unsoeld, Andreas; Schaub, Jochen

doi:10.1002/elsc.201900050

Cited by 8 publications

(4 citation statements)

References 56 publications

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“…Cryopreserved products can be stored in appropriate conditions and be delivered to the patient as needed, for on-site thawing and true "off-the-shelf" administration Lamers-Kok et al Journal [24]), CellGro Stem cell growth medium, SCGM from CellGenix (e.g., Additional file 1: Table S1, rows 14-15; Additional file 3: Table S3, row 29 [69]), NK MACS ® from Miltenyi [70], α-MEM (Additional file 3: Table S3, rows 16, 17, 21 [25]) and X-VIVO ™ 10 (e.g., NK-92 cell products in Additional file 2: Table S2, rows 38-50; Additional file 4: Table S4, rows 10, 12-34 [71]). According to GMP requirements for raw materials, the cell culture medium formulation used in the manufacturing of cell therapeutics must be defined, approved, and regularly verified [72]. As the formulation of commercially available media is often not (completely) disclosed, fulfillment of such requirements might be at risk.…”

Section: Nk Cell Expansion and Activation Methodsmentioning

confidence: 99%

Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

Lamers-Kok¹,

Panella²,

Georgoudaki³

et al. 2022

J Hematol Oncol

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Natural killer (NK) cells are unique immune effectors able to kill cancer cells by direct recognition of surface ligands, without prior sensitization. Allogeneic NK transfer is a highly valuable treatment option for cancer and has recently emerged with hundreds of clinical trials paving the way to finally achieve market authorization. Advantages of NK cell therapies include the use of allogenic cell sources, off-the-shelf availability, and no risk of graft-versus-host disease (GvHD). Allogeneic NK cell therapies have reached the clinical stage as ex vivo expanded and differentiated non-engineered cells, as chimeric antigen receptor (CAR)-engineered or CD16-engineered products, or as combination therapies with antibodies, priming agents, and other drugs. This review summarizes the recent clinical status of allogeneic NK cell-based therapies for the treatment of hematological and solid tumors, discussing the main characteristics of the different cell sources used for NK product development, their use in cell manufacturing processes, the engineering methods and strategies adopted for genetically modified products, and the chosen approaches for combination therapies. A comparative analysis between NK-based non-engineered, engineered, and combination therapies is presented, examining the choices made by product developers regarding the NK cell source and the targeted tumor indications, for both solid and hematological cancers. Clinical trial outcomes are discussed and, when available, assessed in comparison with preclinical data. Regulatory challenges for product approval are reviewed, highlighting the lack of specificity of requirements and standardization between products. Additionally, the competitive landscape and business field is presented. This review offers a comprehensive overview of the effort driven by biotech and pharmaceutical companies and by academic centers to bring NK cell therapies to pivotal clinical trial stages and to market authorization.

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Section: Nk Cell Expansion and Activation Methodsmentioning

confidence: 99%

Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

Lamers-Kok¹,

Panella²,

Georgoudaki³

et al. 2022

J Hematol Oncol

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“…The integration of PAT is not necessarily limited to the fermentation/cell culture process itself. For example, the suitable uses of PAT as an on-line monitoring tool during cell culture media preparation was shown by Brunner and co-workers (Brunner et al, 2019). By 2D fluorescence spectroscopy, media variability and its corresponding root cause were detected.…”

Section: Upstreammentioning

confidence: 99%

Systematic assessment of process analytical technologies for biologics

Gillespie

Wasalathanthri

Ritz

et al. 2021

Biotech & Bioengineering

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The application of process analytical technology (PAT) for biotherapeutic development and manufacturing has been employed owing to technological, economic, and regulatory advantages across the industry. Typically, chromatographic, spectroscopic, and/or mass spectrometric sensors are integrated into upstream and downstream unit operations in in-line, on-line, or at-line fashion to enable real-time monitoring and control of the process. Despite the widespread utility of PAT technologies at various unit operations of the bioprocess, a holistic business value assessment of PAT has not been well addressed in biologics. Thus, in this study, we evaluated PAT technologies based on predefined criteria for their technological attributes such as enablement of better process understanding, control, and highthroughput capabilities; as well as for business attributes such as simplicity of implementation, lead time, and cost reduction. The study involved an industry-wide survey, where input from subject matter industry experts on various PAT tools were collected, assessed, and ranked. The survey results demonstrated on-line liquid Chromatography (LC), in-line Raman, and gas analysis techniques are of high business value especially at the production bioreactor unit operation of upstream processing. In-line variable path-length UV/VIS measurements (VPE), on-line LC, multiangle light scattering (MALS), and automated sampling are of high business value in Protein A purification and polishing steps of the downstream process. We also provide insights, based on our experience in clinical and commercial manufacturing of biologics, into the development and implementation of some of the PAT tools. The results presented in this study are intended to be helpful for the current practitioners of PAT as well as those new to the field to gauge, prioritize and steer their projects for success.

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“…A long shelf life could significantly improve the flexibility of the manufacturing schedule. However, there are limited publications on how nutrient levels change during storage, and more importantly, on how preparation conditions impact long‐term medium stability 15 …”

Section: Introductionmentioning

confidence: 99%

“…However, there are limited publications on how nutrient levels change during storage, and more importantly, on how preparation conditions impact long-term medium stability. 15 Here, we investigated the impact of highly concentrated cell culture media final preparation pH, preparation temperature, and storage temperature conditions on media quality by examining AA profiles. A panel of 16 amino acids, including glutamic acid (GLU), aspartic acid (ASP), histidine (HIS), lysine (LYS), methionine (MET), tyrosine (TYR), serine (SER), arginine (ARG), leucine (LEU), phenylalanine (PHE), proline (PRO), threonine (THR), valine (VAL), asparagine (ASN), isoleucine (ILE), and tryptophan (TRP), was tested by ultra-performance liquid chromatography to provide an insight into complex feed medium quality.…”

Section: Introductionmentioning

confidence: 99%

Impact of preparation pH and temperature on amino acid stability of highly concentrated cell culture feed media

Cui

et al. 2022

J of Chemical Tech & Biotech

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BACKGROUND The stability of amino acids (AAs) in a highly concentrated cell culture medium is affected by medium preparation and storage conditions. Variability in the concentration of medium components (including AAs) can influence cell culture performance and product quality attributes. RESULTS In this report, the impact of preparation pH, preparation temperature, and storage temperature was evaluated on the stability of 16 AAs in a highly concentrated cell culture feed medium. Optimizing the medium pH enabled an increase in the initial feed medium concentration by 30% plus 3.9 g L−1 tyrosine with no observed precipitation after 28 days. Up to 6.0 g L−1 tyrosine can be supplemented in the medium at ~pH 10 without precipitation. Moreover, preparing the medium at 40–50 °C prevented precipitation during storage at 4–8 °C. A slight negative impact on AA stability during this high‐temperature preparation was observed, but this impact was negligible relative to the AA degradation observed during extended storage of media prepared at 37 °C. The optimal preparation pH and temperature allowed the concentrated medium to be stored at 4–8 °C with minimal AA degradation and without precipitation. These discoveries were further supported by principal component analysis of AA profile similarity before and after storage at different pH and temperature conditions. CONCLUSION This study describes the medium preparation parameters to improve AA stability and mitigate precipitation issues. The optimization strategy will facilitate the development of robust cell culture production processes. © 2022 Society of Chemical Industry (SCI).

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Towards robust cell culture processes — Unraveling the impact of media preparation by spectroscopic online monitoring

Cited by 8 publications

References 56 publications

Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

Systematic assessment of process analytical technologies for biologics

Impact of preparation pH and temperature on amino acid stability of highly concentrated cell culture feed media

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