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CABIMER’s Good Manufacturing Practices (GMP) Core facility

CABIMER’s Good Manufacturing Practices (GMP) Core facility is a Unit for ensuring that pharmaceutical products are consistently manufactured and controlled according to quality standards (QC). GMP is designed to minimize the Risk and ensure Safety. The GMP unit of CABIMER is a cell production core facility (UAPC-CABIMER) engaged in the scale-up of human cells considered as Advanced Therapy Medicinal Products (ATMPs) in accordance with article 17 of regulation (EC) nº 1394/2007. The production of ATMPs is carried out in accordance with GMP standards and handled with appropriate controls to ensure their safety, quality, and efficacy as a final medicinal product. UAPC-CABIMER was the first in Andalucía to obtain the Certification from the Spanish Agency of Medicines and Medical Devices (AEMPS, Agencia Española del Medicamento y Productos Sanitarios) to produce cellular medicaments (16 November 2009). On February 2012 and later on April 2015, UAPC-CABIMER passed the inspection of the GMP facilities by AEMPS and got the Accreditation for three more years. So far UAPC-CABIMER has produced approximately 100 doses of Cellular Medicaments under investigation (100 patients treated), contains two Production Units and, in collaboration with University Pablo de Olavide, trained more than 10 experts in Quality Control, Quality Assurance and Cellular Medicaments Production.

LINES OF ACTION

The UAPC-CABIMER facility is a fully equipped 57m² installation, is part of the Stem Cells Department and a Core facility of CABIMER. The UAPC-CABIMER has 2 production units for manufacturing ATMPs to use in Clinical Trials and Compassive Use and a fully independent Quality Control (QC) Unit. The UAPC-CABIMER follows the strict regulations established by Standard Operating Protocols (SOPs), which cover all issues of ATMPs manufacturing, including recordkeeping, personnel qualifications, sanitation, cleanliness, equipment verification, process validation, and complaint handling.

PERSONNEL

The full responsibility corresponds to the Scientific Coordinator and the Technical Manager (Technical Director) of the Unit; the key personnel of UAPC-CABIMER include the head of production, the head of quality units and the authorized persons.

The quality units comprise Quality Assurance (QA) and Quality Control (QC) functions and are combined in one department, the Head of Production and Quality Units are independent of each other. Full-time qualified personnel occupy key positions.

Quality Assurance: Quality Assurance covers all matters, which individually or collectively influence the quality of the ATMP product. The primary role of the QA is to assure that ATMPs are designed and developed in a way that meets the requirements of Good Manufacturing Practice (GMP). 

Quality Control: This unit deals with sampling, specifications and testing, together with the organisation, documentation and release procedures which ensure that the necessary and relevant tests are actually carried out and that ATMPs are not released for use until their quality has been judged to be satisfactory.

AIMS

General: The application of adult stem cells and stem cells derivatives as Regenerative Therapies for Cancer, Genetic, Metabolic, Autoimmune, Inflammatory and Degenerative Diseases and, more specifically, to develop cell-based therapies for type 1 and type 2 Diabetes Mellitus and its Complications.

Mandatory:

  • To ensure that patients are not exposed to any risk directly related to the Cellular Medicament under Investigation
  • To ensure that the results of Clinical Trials are not biased by defectively manufactured ATMP
  • To ensure that there is consistency between ATMP batches and that changes (if any) are adequately justified, recorded, filed and documented

Specific:

  • PRECLINICAL: To develop and improve

o   In-Vitro Cellular Models (Embryonic Stem Cell lines derived from monogenic diseases, “Disease in a Dish”, etc.)

o   Animal Models of type 1 DM and type 2 DM and other disease Model

  • CLINICAL:

o   To improve Cell Manufacturing under GMP conditionso   To Perform new Clinical Trials with restrictive end-points (optimal dose, single/multiple, best cell type, infusion/delivery of ATMPs…)

o   To promote Public-Private efforts to ameliorate new Cellular Therapies

o   To train experts and professionals in the Manufacturing and Use of Cellular Medicaments and other Advanced Therapies

EXPERTISE & REFERENCES

  1. More than 100 papers in the field of diabetes, including the Highly Cited paper that the preclinical work on the use of embryonic stem cells in the treatment of type 1 diabetes mellitus: Salguero-Aranda et al. (2016) Cell Transplant.; Soria et al. (2015) Expert Opin Biol Ther.; Pezzolla et al. (2015) PloS ONE; Kabelitz et al. (2008) Trends Immunol.; Vaca et al. (2006) Stem Cells and (2008) Exp Cell Res.; Roche et al. (2005) Transpl Immunol.; Leon-Quinto et al. (2004) Diabetologia; Soria et al. (2000) Diabetes, etc …
  2. Knowledge on the molecular and cellular basis of self-renewal, proliferation, differentiation and transplantation of stem cells in experimental models: Lorenzo et al. (2015) Sci Rep.; Escobero-Cousin et al. (2015) PloS ONE; Carrasco et al. (2014) Hepatology; Horrillo et al. (2013) Cell Death Dis.; Soria et al. (2013) Diabetes; Carrasco et al. (2012) J Clin Invest.; Calvanese et al. (2010) PNAS; Mora-Castilla et al. (2010) Cell Death Differ., etc …
  3. Know-how for the GMP production of Cellular Medicaments and its use in Clinical Trials: Cox et al. (2015) Eur J Immunol.; Escacena et al. (2015) Stem Cells Int.; Galvez-Martin et al. (2014) Stem Cells Dev.; Galvez-Martin et al. (2014) Eur J Pharm Biopharm.; Acosta et al. (2013) Diabetes; Gálvez et al. (2013) Br Med Bull.;  2013;105:85-105. Ruiz-Salmerón et al. (2011) Cell Transplant.; Hmadcha et al. (2009) J Cell Mol Med., etc …

 

INTELLECTUAL PROPERTY 

Patents:

-       Improved Culture Medium for human Progenitors Cells (hPC) (EP15382417.2)   Fundación Pública Progreso y Salud, University Pablo de Olavide, NewBiotechnic S.A. (2015)

-       Method for obtaining pancreatic beta cell surrogates by increasing pancreatic and duodenal homeobox 1 (PDX-1) expression (PCT/EP2015/070501) Fundación Pública Andaluza Progreso y Salud; University Pablo de Olavide; Instituto de Salud Carlos III; NewBiotechnic S.A. (2015)

-       Use of cord blood plasma to treat NK cell-mediated diseases and IFN-gamma mediated diseases (EP14382348.2) Fundación Pública Andaluza Progreso y Salud, Anthony Nolan Research Institute and Instituto de Salud Carlos III (2014)

-       Method for predicting treatment response and test for safe use of mesenchymal stem cells on inflammatory diseases (PCT/EP2014/066600) Fundación Pública Andaluza Progreso y Salud (2014)

-       Use of Mesothelial Cells in Tissue Bioengineering and Artificial Tissues (EP13382213.0) Fundación Pública Andaluza Progreso y Salud; Vissum Corporation;  Instituto de Salud Carlos III; NewBiotechnic S.A. (2013)

 

Clinical Trials:

1-    Advanced-terapy medicinal products (ATMPs) manufacturing:

- NCT01257776: Human Adipose Derived Mesenchymal Stem Cells for Critical Limb Ischemia (CLI) in Diabetic Patients

- NCT01745744: Application of Cell Regeneration Therapy With Mesenchymal Stem Cells From Adipose Tissue in Critical Chronic Ischemic Syndrome of Lower Limbs (CLI) in Nondiabetic Patients

- NCT02287974: Clinical Trial I/II Opened, Randomized and Controlled for the Study of the Use of Stem Cells Therapy in Insulinized Diabetic Patients Type 2 With Critical Ischemia in Lower Limbs (CLI): Study of the Needs of Insulin

- NCT-01056471: Autologous Mesenchymal Stem Cells From Adipose Tissue in Patients With Secondary Progressive Multiple Sclerosis

 

2-    Digital Substraction Angiography (DSA) quantification:

- NCT00872326: Autologous Bone Marrow Derived Mononuclear Cells in Treating Diabetic Patients With Critical Limb Ischemia

- NCT01257776: Human Adipose Derived Mesenchymal Stem Cells for Critical Limb Ischemia (CLI) in Diabetic Patients

- NCT01745744: Application of Cell Regeneration Therapy With Mesenchymal Stem Cells From Adipose Tissue in Critical Chronic Ischemic Syndrome of Lower Limbs (CLI) in Nondiabetic Patients

- NCT02287974: Clinical Trial I/II Opened, Randomized and Controlled for the Study of the Use of Stem Cells Therapy in Insulinized Diabetic Patients Type 2 With Critical Ischemia in Lower Limbs (CLI): Study of the Needs of Insulin

- NCT-00987363: Intraarterial Infusion of Autologous Bone Marrow in Diabetic Patients With Chronic Ischemia of Lower Limbs (CLI) no Revascularization

- NCT01408381: Intra-arterial Infusion of Autologous Bone Marrow Mononuclear Cells in Non-diabetic Patients With Critical Limb Ischemia (CLI)

Personnel

Scientific Coordinator: Dr. Bernat Soria

Technical Director: Dr. Karim Hmadcha

Quality Units:

Head of QC: Dr. Natalia Escacena (natalia.escacena@cabimer.es)

Head of QA: Maria Galvez (maria.galvez@cabimer.es)

Production Unit:

Head of Production: Victoria Jimenez (victoria.jimenez@cabimer.es)