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Advanced cell-based products generated via automated and manual manufacturing platforms under the quality by design principle: Are they equivalent or different?

ABSTRACT: Mesenchymal stem/stromal cells (MSCs) are multipotent stem cells that can be isolated from bone marrow, adipose tissue, the umbilical cord, dental pulp, etc. These cells have unique properties that give them excellent therapeutic potential, including immunoregulation, immunomodulation, and tissue regeneration functions. MSC-based products are considered advanced therapy medicinal products (ATMPs) under European regulations (1394/2007); thus, they must be manufactured under good manufacturing practices and via effective manufacturing methods. The former can be achieved via a proper laboratory design and compliance with manufacturing protocols, whereas the latter requires an approach that ensures that the quality of the products is consistent regardless of the manufacturing procedure. To meet these daunting requirements, this study proposes an exchangeable approach that combines optimized and equivalent manufacturing processes under the Quality by Design (QbD) principle, allowing investigators to convert from small laboratory-scale to large-scale manufacturing of MSC-based products for clinical applications without altering the quality and quantity of the cell-based products.

SUBMITTER: Hoang DM

PROVIDER: S-EPMC10205494 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Advanced cell-based products generated via automated and manual manufacturing platforms under the quality by design principle: Are they equivalent or different?

Hoang Duc M DM Nguyen Quyen T QT Phan Trang T K TTK Ngo Anh T L ATL Pham Phuong T PT Bach Trung Q TQ Le Phuong T T PTT Bui Hoa T P HTP Thanh Liem Nguyen LN

Heliyon 20230503 5

Mesenchymal stem/stromal cells (MSCs) are multipotent stem cells that can be isolated from bone marrow, adipose tissue, the umbilical cord, dental pulp, etc. These cells have unique properties that give them excellent therapeutic potential, including immunoregulation, immunomodulation, and tissue regeneration functions. MSC-based products are considered advanced therapy medicinal products (ATMPs) under European regulations (1394/2007); thus, they must be manufactured under good manufacturing pra ...[more]

PMID: 37229156

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Project description:IntroductionCurrent production facilities for Cell-Based Health care Products (CBHPs), also referred as Advanced-Therapy Medicinal Products or Regenerative Medicine Products, are still dependent on manual work performed by skilled workers. A more robust, safer and efficient manufacturing system will be necessary to meet the expected expansion of this industrial field in the future. Thus, the 'flexible Modular Platform (fMP)' was newly designed to be a true "factory" utilizing the state-of-the-art technology to replace conventional "laboratory-like" manufacturing methods. Then, we built the Tissue Factory as the first actual entity of the fMP.MethodsThe Tissue Factory was designed based on the fMP in which several automated modules are combined to perform various culture processes. Each module has a biologically sealed chamber that can be decontaminated by hydrogen peroxide. The asepticity of the processing environment was tested according to a pharmaceutical sterility method. Then, three procedures, production of multi-layered skeletal myoblast sheets, expansion of human articular chondrocytes and passage culture of human induced pluripotent stem cells, were conducted by the system to confirm its ability to manufacture CHBPs.ResultsFalling or adhered microorganisms were not detected either just after decontamination or during the cell culture processes. In cell culture tests, multi-layered skeletal myoblast sheets were successfully manufactured using the method optimized for automatic processing. In addition, human articular chondrocytes and human induced-pluripotent stem cells could be propagated through three passages by the system at a yield comparable to manual operations.ConclusionsThe Tissue Factory, based on the fMP, successfully reproduced three tentative manufacturing processes of CBHPs without any microbial contamination. The platform will improve the manufacturability in terms of lower production cost, improved quality variance and reduced contamination risks. Moreover, its flexibility has the potential to adapt to the modern challenges in the business environment including employment issues, low operational rates, and relocation of facilities. The fMP is expected to become the standard design basis of future manufacturing facilities for CBHPs.

Project description:Albumin, widely recognized as a highly sensitive and specific marker of hepatocellular carcinoma (HCC), is currently unavailable in the diagnostic laboratory because of the lack of a robust platform. In a prior study we detected albumin mRNA in the majority of intrahepatic cholangiocarcinomas using a novel branched chain RNA in situ hybridization (ISH) platform. We now explore the utility of albumin ISH as a marker of hepatocellular differentiation in HCCs, and compare its sensitivity with Hep Par 1 and Arginase-1. We evaluated 93 HCCs and its mimics including neuroendocrine tumors of the gastrointestinal tract (n=31), neuroendocrine tumors of the pancreas (n=163), melanoma (n=15), and gallbladder carcinoma (n=34). We performed ISH for albumin and immunohistochemistry for Hep Par 1 and Arginase-1. Five previously uncharacterized hepatic neoplasms from our files were also evaluated. Immunohistochemistry for Arginase-1 was performed on 59 intrahepatic cholangiocarcinomas. In addition, 43 HCCs evaluated on the manual platform were also examined on the automated instrument. Fifty-five percent of HCCs were moderately differentiated and 39% poorly differentiated. The sensitivity of ISH for albumin was 99%, with 92 of 93 HCCs staining positive for albumin. In contrast to ISH, the sensitivity of immunohistochemistry for Hep Par 1 and Arginase-1 was 84% and 83%, respectively. The sensitivity of albumin for poorly differentiated HCCs was 99%, whereas that for Arginase-1 and Hep Par 1 was 71% and 64%, respectively. Ninety-seven percent of the HCCs showed albumin positivity in >50% of tumor cells using the ISH platform, as compared with 76% and 70% for Hep Par 1 and Arginase-1 immunohistochemistry, respectively. Three of the 5 previously uncharacterized neoplasms were positive for albumin ISH. Automated albumin ISH platform performed equivalently to the manual format, with albumin reactivity in >50% of tumor cells in all 43 cases that were tested on both platforms. All non-HCCs were negative for albumin. All 59 intrahepatic cholangiocarcinomas were negative for Arginase-1. In conclusion, branched chain ISH performed on manual and automated mode is a robust assay for detecting albumin with sensitivity for poorly differentiated HCCs superior to Arginase-1 and Hep Par 1. When interpreted in conjunction with Arginase-1, albumin ISH offers a high level of sensitivity and specificity.

Dataset Information

Advanced cell-based products generated via automated and manual manufacturing platforms under the quality by design principle: Are they equivalent or different?

Publications

Advanced cell-based products generated via automated and manual manufacturing platforms under the quality by design principle: Are they equivalent or different?

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