Research & Clinical Trials : Cellular Manufacturing Program

Cellular Manufacturing Program

Cellular Manufacturing Program

Interdisciplinary Stem Cell Institute, Clinical Research Cell Manufacturing Program (ISCI-CRCMP)

Facility Description

The Clinical Research Cell Manufacturing Program (CRCMP) exists to facilitate the translational development of cellular therapies from basic research projects to clinical practice. The goal of the CRCMP is to provide the rapid and safe transition of basic research ideas. This includes the qualification and testing of reagents, scale-up of methods, development of Standard Operating Procedures (SOPs), ongoing process validation, and the provision of a controlled good tissue practice (GTP) and good manufacturing practice (GMP) infrastructure and support for compiling Investigational New Drug (IND) applications.

The CRCMP consists of three components: a) the Cell Production Facility (CPF), b) the Development Laboratory (DL), and c) the Pre-clinical Laboratory (PL). Processing of clinical products requiring long term culture is conducted in the CPF, while pre-clinical development and scale up procedures are undertaken in the DL. Production of cellular products for animal studies is performed in the PL and includes mouse, rat, and pig products for in vitro and in vivo studies and human cell products for studies in NOD/SCID mice.

The CPF occupies approximately 2,500 square feet on the 9th floor of the Biomedical Research Building, including 6 clean room labs, several other laboratories along with various laboratory support areas and office space. The designated Development Laboratory occupies 640 square feet and is conveniently located next to the CPF and the PL. The PL occupies 1344 square feet of laboratory space for production of animal cell products and isolation of cell lines for research studies. The translation of such therapies requires significant development and scale up to meet the stringent clinical standards required for patient infusion. The CRCMP provides the resources to do this in an effort to facilitate and expedite clinical trials in patients.

Facility Structure
• 1 Clean Rooms with 6 tissue culture rooms and general clean room area
• DL consists of 2 tissue culture rooms and general lab work area
• 1 GLP research lab with 4 tissue culture rooms and general work area

The Clinical Research Cell Manufacturing Program (CRCMP)

Dr. Joshua Hare, MD, Professor of Medicine and Director, ISCI, oversees the CRCMP operations and provides the leadership on strategic planning for facility services. Reporting directly to Dr. Hare is Aisha Khan, Executive Director of Laboratory Operations of the ISCI Cell Processing Facility. Ms. Khan manages all projects of the cell processing facility. Under the direction of Aisha Khan, ISCI’s CRCMP has experienced substantial overall growth in clinical grade stem cell products. Our facility currently provides cell products for more than 20 clinical trials across the UM’s campus and collaborators from other intuitions. This growth is expected to continue throughout FY 2016 as we embark on developing new cell types, specifically umbilical cord blood derived stem cells. Additionally, we will increase cell production of our bone marrow derived stem cells to accommodate an NIH contract for the Cardiovascular Cell Therapy Research Network (CCTRN) – a nationwide network of seven centers conducting clinical trials of stem cell therapy for cardiovascular diseases. This new trial is internationally acclaimed for its use of a novel cell combination approach developed at ISCI.
Clinical research and pre-clinical research studies and cell productions are conducted under the supervision of Dr. Malik and Ms. Valasaki, both possess extensive experience in cellular manufacturing and research & development of novel products. CRCMP has a well-established and well maintained Quality Program under the direction of Ms. Longsomboon who has over 17 experiences in regulatory and quality assurance in the field. Dr. Bacallao supervises a team of scientists in conducting and developing techniques such as cells analysis, characterization and stability studies, etc.

Current Status and Services Available

The CRCMP is actively operating and providing UM and other investigators with processed tissue and cell products for use in clinical and basic translational research. The facility is licensed and accredited as required for processing and use of cellular products. The laboratories are fully equipped to routinely process tissues, cells and vaccines, separation and purification of selected cell types, including dendritic cells, stem cells, bone marrow stromal and mesenchymal cells, and osteoblasts.

List of Services:
• Hematopoietic Stem Cell Selection
• Selection of CD34+ cells
• Bone Marrow Mononuclear Cell Isolation by Density Gradient & Cryopreservation
• Culture and Expansion of Human Marrow-Derived Mesenchymal Stem Cells & Cryopreservation
• Product Characterization assays
• Cord Blood Processing, Culture, Expansion & Cryopreservation
• Schwann Cell Culture, Expansion & Cryopreservation
• Dendritic Cell Vaccine Production
• T- Regulatory Cell Selection & Cryopreservation
• Cytokines Testings
FACS Analysis
• Immunostaining Assays
• Endotoxin Testing
• Protein Composition Assessment
• Thawing of Mesenchymal Stem Cell Products
• Thawing of Stem Cells (CD34+)
• Thawing of Human T-Reglutory Cells
• Thawing of Human Bone Marrow Cells
• Complete Count
• Viability Assessment Using Trypan Blue
• Development of Analytical Assays
CFU Assay
PCR Assay
• Elisa Assay
• Gram Stain Testing
• Process Development
• Process Validation
SOP Development
• Validation Guidance for Equipment, Processing, & Quality Control Assays
• Writing SOPs for Quality Systems
• Writing SOPs for analytical methods
• Stability and storage studies
IND CMC writing

Clinical Product Types:
• Human (Allo/Auto) Bone Marrow Derived MSCs
• Human (Allo) Cord Tissue Derived MSCs
• Human (Allo/Auto) Fat Derived MSCs
• Human Cord Blood Derived MSCs
• Human Cord Blood Cells
• Human c-Kit+ Cardiac Stem Cells Human c-Kit+ Kidney Stem Cells
• Human Bone Marrow Mononuclear Cells (MNC) Human Dendritic Cells
• Human Tumor Lysate
• Human Schwann Cells
• Human T-Regulatory Cells
• Human Endometrial MSCs
HEK 293 Cell
• AVV2

Pre-Clinical Product Types:
• Rat MNCs
• Porcine MNCs
• Canine MNCs
• Porcine c-Kit+ Cardiac Stem Cells Rat
• Bone Marrow Derived MSCs Mice
• Bone Marrow Derived MSCs Porcine
• Bone Marrow Derived MSCs Canine
• Bone Marrow Derived MSCs Rat Fat
• Derived MSCs
• Mice Fat Derived MSCs
• Porcine Fat Derived MSCs
• Canine Fat Derived MSCs
• Porcine c-kit+ Kidney Stem cells

Cell Production Facility (CPF)

The CPF is a restricted access (card key controlled) laboratory, in which all essential equipment is continuously monitored and alarmed. Quality Management Program is well established and maintained. This system includes monitoring of production process, approval of supply qualification, Standard Operating Procedures (SOP), equipment qualifications and quality control, product outcome and analysis. The facility consists of six separate production suites which contain a BSC, incubators, bench top centrifuge, and microscopes. The laboratory is HEPA filtered, under appropriate air handling (positive pressure) and meets class 10,000 specifications in the manufacturing suites (1-4) and class 100,000 in the general laboratory, LN2 freezer room, storage room and gown in/out areas. Laboratory equipment is cleaned and maintained according to the established quality control (QC) schedule. Open manipulations are performed in class 100 Bio Safety Cabinets (BSCs). The comprehensive quality system includes, but is not limited to, both internal and external audits, assuring compliance with the current federal (FDA) requirements (21 CFR Part 1271 & 21 CFR Part 210 & 211) and other applicable standards AABB, FACT, and JCAHO (CLIA). The quality system is organized to monitor CMP day-to-day operational and manufacturing activities, to prevent, detect and correct deficiencies that could affect donor and patient safety and the safety, purity, potency, or efficacy of manufactured products.

Facility holds 13 ongoing clinical trials with variety of conditions, ranging from cardiovascular disease, idiopathic pulmonary fibrosis (IPF), frailty, burns, brain tumor, and Schwann cells for spinal cord injury patients.

Our CPF has been actively generating human mesenchymal stem cells for several years. We follow best practices and have established processes that address the entire lifecycle of project operations starting from establishment of a contract with the Principal Investigator to project completion and close-out. Our facility has extensive experience in contract research. The Interdisciplinary Stem Cell Institute was selected as a Cell Manufacturing Facility in 2014, for the Cardiovascular Cell Therapy Research Network (CCTRN). For this grant, more than a dozen reputable cell processing facilities competed. The grant is funded by the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI). The CCTRN network conducts research to evaluate the use of cell-based treatment strategies for people with cardiovascular disease – an area in which the Interdisciplinary Stem Cell Institute (ISCI) has been a leader in the nation since 2008. For the CCTRN grant, our CPF will manufacture MSCs from autologous bone marrow and c-kit+ cardiac stem cells (CSCs) from endomyocardial biopsies. The selection of our CPF for the CCTRN grant to produce regenerative cells is a testimony of the experience, expertise, and superior quality of work products delivered by our facility.

Our facility was recently awarded the prestigious PACT: Production Assistance for Cellular Therapies from National Heart Lung and Blood Program (NHLBI) as a facility assisting investigators nationwide in developing the pre-clinical products that will eventually translate into products to be used in clinical trials. We have built an organization that delivers excellence every day.

We are FACT accredited and are in the process of pursuing AABB accreditation. We have developed several new products in a short period of time and are actively collaborating with other leaders in the field such as University of Maryland, Cornell University, University of Indiana, Ocata Therapeutics Inc, and RxMP Therapeutics, LLC.; our team processes Schwann cells for transplant after spinal cord injury, in collaboration with the Miami Project for Cure Paralysis and, we process Dendritic cells for Sarcoma and Giloblastoma trials for the Sylvester Cancer Center. In addition, we are on target to increase cell production of our bone marrow derived stem cells to fulfill our NIH contract needs for the CCTRN Network (a nationwide network of seven centers conducting clinical trials of stem cell therapy for cardiovascular diseases).

Cell Sorting Room (CSR)

A cell sorting room is part of the CPF and meets Class 100,000 requirements. In the Flow room we have a MoFlo XDP high speed cell sorter, this instrument has the capacity to sort at speeds up to 70,000 cells per second with multi parameter sorting capabilities. The MoFlo is contained within a biosafety cabinet, so all cell manipulation and sorting is performed at class 100 level.