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Gene Therapy / Cell Therapy / Stem Cells – Regulations for the "New Biologics" William R. Tolbert, Ph.D. AOAC-SC...
Applications of FDA Authority Through Product-Centric Centers
Review of Cell-Based Products
Products Regulated in OCTGT <ul><li>Somatic cell therapies </li></ul><ul><li>Tumor Vaccines </li></ul><ul><li>Gene therapi...
Somatic   cell therapies Gene therapies <ul><li>Cell therapies are products composed of human or animal cells, or from phy...
Gene Therapy
Vectors for delivery
Autologous   cells   transduced   with   vector
Somatic Cell Therapy
Xenotransplantation <ul><li>Xenotransplantation is any procedure that involves the transplantation, implantation, or infus...
Xenotransplantation – Not Feasible
The Pre-2005 Regulatory Environment for Manufacturing <ul><li>21 CFR PART 11—ELECTRONIC RECORDS; ELECTRONIC SIGNATURES  [ ...
How are Cell-Based Products Different? <ul><li>Potential for adventitious agents in starting material - possible lack of a...
FDA Driving Forces & Challenges for Cell Products <ul><li>Previous approach (pre 1997) fragmented inadequate inadequate </...
Cell and Tissue Characteristics <ul><li>Autologous vs. Allogeneic </li></ul><ul><li>Viable vs. Nonviable </li></ul><ul><li...
FDA Regulation of Cellular and Tissue-based Products <ul><li>Human cells, tissues, or cellular or tissue-based products ba...
New FDA Regulation <ul><li>21 CFR 1271:  PART 1271— HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS   </li></...
21 CFR Part 1271
Regulatory Requirements for HCT/P’s
“ 361” HCT/Ps (Human cells, tissue and cellular and tissue based products) <ul><li>Regulated solely under section 361 of t...
21 CFR 1271.10 (“Below the line”) <ul><li>HCT/P regulated solely under section 361 of PHS Act and regulations in part 1271...
21 CFR 1271.10 (“Below the line”) <ul><ul><li>(3) Manufacture of HCT/P does not involve the combination of the cell or tis...
21 CFR 1271.10 (“Below the line”) <ul><li>(4) Either: </li></ul><ul><ul><li>(i) HCT/P does not have a systemic effect and ...
Minimal   Manipulation <ul><li>(1) For structural tissue, processing that does  not alter  the  original relevant characte...
Homologous   Use <ul><li>The repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues wit...
“ 351” HCT/Ps (Human cells, tissue and cellular and tissue based products)   <ul><li>Regulated under sections  361 and 351...
21 CFR Part 1271 Establishment Registration and Listing <ul><li>Requires establishments to register with FDA and list HCT/...
21 CFR Part 1271 Donor Eligibility <ul><li>Screening and testing of most cell and tissue donors for relevant communicable ...
21 CFR Part 1271 Good Tissue Practices (cGTPs) <ul><li>Procedures and controls to prevent introduction, transmission and s...
cGTP Basics <ul><li>Methods, facilities, and controls for manufacturing to prevent infectious disease contamination </li><...
21 CFR Part 1271  Inspection and Enforcement   <ul><li>Applicability </li></ul><ul><ul><li>Above the line (351 HCT/Ps) – S...
CBER’s Bioresearch Monitoring Branch <ul><li>Conduct pre-approval data audit inspections </li></ul><ul><li>Investigate com...
CBER is assigning more inspections of  ongoing studies under IND/IDE <ul><li>Cell therapies </li></ul><ul><li>Gene transfe...
FY 2006 HCT/P Inspections  354 Total  44.1 234 All other HCT/Ps 42.8 36 Cord blood stem cells Peripheral blood stem cells ...
Human Stem Cells <ul><li>Stem Cell-Based Therapies  –  Stem cells, directed to differentiate into specific cell types, off...
Bone marrow stroma/Mesenchymal stem cells Facilitate hematopoietic reconstitution
 
 
Human Embryonic Stem Cell Lines <ul><li>Issues Receiving Attention: </li></ul><ul><ul><li>Media used for culturing hES cel...
 
Human Embryonic Stem Cell Lines <ul><li>Human ES Cell Lines Established on Non-Human Feeder Cell Layers </li></ul><ul><ul>...
Cell Therapy Product Characterization   <ul><li>Morphologic evaluation  </li></ul><ul><li>Unique biochemical markers  </li...
Product Safety and Efficacy  <ul><li>Safety Issues:  </li></ul><ul><ul><li>Sterility (bacterial, fungal, mycoplasma)  </li...
Cell Therapy Preclinical Assessment: Activity and Safety   <ul><li>Cell Fate Post Transplant  </li></ul><ul><li>Post trans...
Cell Therapy Preclinical Assessment: Animal Models <ul><li>Animal Models </li></ul><ul><ul><li>Use of existing models (i.e...
Cell Therapies: Characterization   <ul><li>Issue: Key questions for safety and effectiveness </li></ul><ul><li>What are th...
Manufacturing Facilities <ul><li>Capacity Issues </li></ul><ul><ul><li>Patient-Specific vs. Allogeneic </li></ul></ul><ul>...
Open vs. Closed Manufacturing Systems <ul><li>FDA Cleared or Approved Sterile Tube Connecting Device (STCD) – Tubing Welde...
<ul><li>Example Facility </li></ul><ul><li>Standard Cell Therapy Unit </li></ul><ul><ul><li>150 ft 2 ,   2 Operators </li>...
WRT&A
WRT&A
WRT&A
WRT&A
Paradigm for Delivery of Patient-Specific Products <ul><li>Massive Single Plant </li></ul><ul><ul><li>Problems with In-com...
WR Tolbert & Associates Consultants to the Biopharmaceutical Industry 11483 Cypress Woods Drive San Diego, CA 92131-3535 8...
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Gene Therapy / Cell Therapy / Stem Cells – Regulations for the &quot;New Biologics&quot;

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Gene Therapy / Cell Therapy / Stem Cells – Regulations for the &quot;New Biologics&quot;

  1. 1. Gene Therapy / Cell Therapy / Stem Cells – Regulations for the &quot;New Biologics&quot; William R. Tolbert, Ph.D. AOAC-SCS Regulatory & Compliance Conference Friday March 30, 2007 – 10:50 AM
  2. 2. Applications of FDA Authority Through Product-Centric Centers
  3. 3. Review of Cell-Based Products
  4. 4. Products Regulated in OCTGT <ul><li>Somatic cell therapies </li></ul><ul><li>Tumor Vaccines </li></ul><ul><li>Gene therapies </li></ul><ul><li>Xenotransplantation </li></ul><ul><li>Combination products </li></ul><ul><li>Devices used for cell/tissues </li></ul><ul><li>Unique assisted reproduction (ooplasmtransfer) </li></ul><ul><li>Anti-idiotype antibodies </li></ul><ul><li>Tissue and tissue based products </li></ul>
  5. 5. Somatic cell therapies Gene therapies <ul><li>Cell therapies are products composed of human or animal cells, or from physical parts of those cells. </li></ul><ul><li>Gene therapies introduce genetic material into the body to replace a defective or missing gene, or to treat or cure a disease medical condition. </li></ul>
  6. 6. Gene Therapy
  7. 7. Vectors for delivery
  8. 8. Autologous cells transduced with vector
  9. 9. Somatic Cell Therapy
  10. 10. Xenotransplantation <ul><li>Xenotransplantation is any procedure that involves the transplantation, implantation, or infusion into a human recipient of either (a) live cells, tissues, or organs from a nonhuman animal source, or (b) human body fluids, cells, tissues or organs that have had ex vivo contact with live nonhuman animal cells, tissues or organs. </li></ul>
  11. 11. Xenotransplantation – Not Feasible
  12. 12. The Pre-2005 Regulatory Environment for Manufacturing <ul><li>21 CFR PART 11—ELECTRONIC RECORDS; ELECTRONIC SIGNATURES [ Computer Use ] </li></ul><ul><li>21 CFR PART 58—GOOD LABORATORY PRACTICE FOR NONCLINICAL LABORATORY STUDIES [ GLPs ] </li></ul><ul><li>21 CFR PARTs 210-211—CURRENT GOOD MANUFACTURING PRACTICE [ cGMPs ] </li></ul><ul><li>21 CFR PARTs 600-680—BIOLOGICAL PRODUCTS </li></ul><ul><li>21 CFR PART 820—QUALITY SYSTEM REGULATION [ Medical Device GMPs ] </li></ul>
  13. 13. How are Cell-Based Products Different? <ul><li>Potential for adventitious agents in starting material - possible lack of adequate methods for testing or removal. </li></ul><ul><li>Requirement for “aseptic </li></ul><ul><li>processing” </li></ul><ul><li>Inability to effectively “sterilize” the product and often implantation must occur before testing is complete. </li></ul>
  14. 14. FDA Driving Forces & Challenges for Cell Products <ul><li>Previous approach (pre 1997) fragmented inadequate inadequate </li></ul><ul><li>New products (e.g. stem cells, tissue-engineered, etc.) </li></ul><ul><li>New manufacturing technologies, degree of manipulation </li></ul><ul><li>Increasing public health concern </li></ul><ul><li>Increasing demand for cells and tissues </li></ul><ul><li>Public confidence in products - expectation for expectation for safe & effective product </li></ul><ul><li>Industry standards not always followed, not enforceable </li></ul>
  15. 15. Cell and Tissue Characteristics <ul><li>Autologous vs. Allogeneic </li></ul><ul><li>Viable vs. Nonviable </li></ul><ul><li>Banked vs. Unbanked </li></ul><ul><li>Homologous vs. Non-homologous function </li></ul><ul><li>Minimal vs. More than minimal manipulation </li></ul><ul><li>Structural vs. Systemic function </li></ul><ul><li>Combination product– device, biologic or drug </li></ul>
  16. 16. FDA Regulation of Cellular and Tissue-based Products <ul><li>Human cells, tissues, or cellular or tissue-based products based products [ HCT/P’s ] </li></ul><ul><ul><li>Articles containing human cells or tissues that are intended for transplantation, infusion or transfer into a human recipient </li></ul></ul><ul><ul><li>Not including vascularized organs, allogeneic bone marrow transplantation, transfusable blood/blood components, xenotransplantation </li></ul></ul><ul><li>Provides a unified, comprehensive regulatory framework </li></ul><ul><li>Provides a tiered regulatory approach </li></ul><ul><ul><li>level of regulation proportional to the degree of risk </li></ul></ul>
  17. 17. New FDA Regulation <ul><li>21 CFR 1271:  PART 1271— HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS </li></ul><ul><ul><li>Subpart A—General Provisions </li></ul></ul><ul><ul><li>Subpart B—Procedures for Registration and Listing </li></ul></ul><ul><ul><li>Subpart C—Donor Suitability </li></ul></ul><ul><ul><li>Subpart D—Current Good Tissue Practice ( cGTPs ) </li></ul></ul><ul><ul><li>Subpart E—Additional Requirements for Establishments Described in § 1271.10 (PHS 361 Products) </li></ul></ul><ul><ul><li>Subpart F—Inspection and Enforcement of Establishments Described in § 1271.10 (PHS 361 Products) </li></ul></ul><ul><li>Final Rule is effective May 25, 2005. </li></ul>
  18. 18. 21 CFR Part 1271
  19. 19. Regulatory Requirements for HCT/P’s
  20. 20. “ 361” HCT/Ps (Human cells, tissue and cellular and tissue based products) <ul><li>Regulated solely under section 361 of the Public Health Service Act and 21 CFR Part 1271 (or 1270) </li></ul><ul><ul><li>(“Below the line products”) </li></ul></ul><ul><ul><li>Traditional: bone, tendons, corneas, </li></ul></ul><ul><ul><li>Newly regulated: reproductive, autologous cord blood </li></ul></ul><ul><ul><li>Part 1271 fully effective May 25, 2005, for all HCT/Ps recovered after that date </li></ul></ul><ul><ul><li>Cell based products that meet the Part 1271 limits </li></ul></ul><ul><ul><li>Human heart valves and dura mater now regulated solely under 361/1271 if not more than minimally manipulated </li></ul></ul><ul><ul><li>No market notification or approval required. </li></ul></ul>
  21. 21. 21 CFR 1271.10 (“Below the line”) <ul><li>HCT/P regulated solely under section 361 of PHS Act and regulations in part 1271 if it meets all of the following criteria: </li></ul><ul><ul><li>(1) HCT/P is minimally manipulated </li></ul></ul><ul><ul><li>(2) HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent </li></ul></ul>
  22. 22. 21 CFR 1271.10 (“Below the line”) <ul><ul><li>(3) Manufacture of HCT/P does not involve the combination of the cell or tissue with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P </li></ul></ul>
  23. 23. 21 CFR 1271.10 (“Below the line”) <ul><li>(4) Either: </li></ul><ul><ul><li>(i) HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or </li></ul></ul><ul><ul><li>(ii) HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and is for: </li></ul></ul><ul><ul><ul><li>(a) Autologous use </li></ul></ul></ul><ul><ul><ul><li>(b) allogeneic use in a first-degree or second-degree blood relative, or </li></ul></ul></ul><ul><ul><ul><li>(c ) reproductive use </li></ul></ul></ul>
  24. 24. Minimal Manipulation <ul><li>(1) For structural tissue, processing that does not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement; and </li></ul><ul><li>(2) For cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of the cells or tissues </li></ul><ul><li>Guidance for Industry and FDA Staff: Minimal Manipulation for Structural Tissue Jurisdiction Update </li></ul><ul><li>(www.fda.gov/cber/gdlns/minimaljur.htm) </li></ul>
  25. 25. Homologous Use <ul><li>The repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor . </li></ul>
  26. 26. “ 351” HCT/Ps (Human cells, tissue and cellular and tissue based products) <ul><li>Regulated under sections 361 and 351 of the PHS Act and under the FDC Act </li></ul><ul><ul><li>“ Above the line” – do not meet all Part 1271 definition limits for “361” products </li></ul></ul><ul><ul><li>Traditional: Cell based products requiring compliance with Parts 210, 211 and Parts 600 </li></ul></ul><ul><ul><li>Subject to routine FDA inspections </li></ul></ul><ul><ul><li>Requires market approval licensing (IND/BLA) </li></ul></ul>
  27. 27. 21 CFR Part 1271 Establishment Registration and Listing <ul><li>Requires establishments to register with FDA and list HCT/P’s </li></ul><ul><ul><li>Exclusions for some (e.g., storage, carriers, contractors engaging only in recovery and transport) </li></ul></ul><ul><li>Lists criteria to determine if HCT/P’s regulated solely under 361 PHS Act </li></ul>
  28. 28. 21 CFR Part 1271 Donor Eligibility <ul><li>Screening and testing of most cell and tissue donors for relevant communicable diseases </li></ul><ul><ul><li>Exception for autologous donor/ sexually intimate partner </li></ul></ul><ul><li>Donor must be eligible prior to HCT/P administration </li></ul><ul><ul><li>Free of risk factors & clinical evidence of communicable disease </li></ul></ul><ul><ul><li>Acceptable test results </li></ul></ul><ul><ul><li>Limited exception to use when eligibility determination not completed </li></ul></ul><ul><ul><ul><li>urgent medical need, w/o other comparable HCTP available </li></ul></ul></ul><ul><ul><li>Limited use of HCT/P from an ineligible donor </li></ul></ul>
  29. 29. 21 CFR Part 1271 Good Tissue Practices (cGTPs) <ul><li>Procedures and controls to prevent introduction, transmission and spread of communicable disease by HCT/P’s </li></ul><ul><ul><li>communicable disease agents – prior to and during manufacturing </li></ul></ul><ul><li>Organized around core requirements, with supporting requirements </li></ul><ul><ul><li>Follow all GTP requirements applicable to function performed </li></ul></ul><ul><ul><li>Requirement for a Quality Program </li></ul></ul><ul><li>Flexibility to determine how to meet requirements </li></ul>
  30. 30. cGTP Basics <ul><li>Methods, facilities, and controls for manufacturing to prevent infectious disease contamination </li></ul><ul><li>Broad goals applicable to the wide range of HCT/Ps </li></ul><ul><li>Establishments have the flexibility to determine how to meet goals through their own procedures </li></ul><ul><li>Requires a quality program to prevent, detect, and correct deficiencies that could increase communicable disease risk </li></ul>
  31. 31. 21 CFR Part 1271 Inspection and Enforcement <ul><li>Applicability </li></ul><ul><ul><li>Above the line (351 HCT/Ps) – Same as for other Biologics and Devices (Clinical, Pre Approval, Post Approval) </li></ul></ul><ul><ul><li>Below the line (361 HCT/Ps) – New requirements specified (Any time after registration) </li></ul></ul><ul><li>Inspections </li></ul><ul><ul><li>May include your establishment, facilities, equipment, finished and unfinished materials, containers, processes, HCT/Ps, procedures, labeling, records, files, papers, and controls required to be maintained under Part 1271. </li></ul></ul><ul><ul><li>May question the personnel of the establishment as necessary to determine compliance </li></ul></ul><ul><ul><li>May take samples, may review and copy any records required to be kept under this part, and may use other appropriate means to record evidence of objectionable observations </li></ul></ul><ul><ul><li>The inspection may be made with or without prior notification </li></ul></ul><ul><ul><li>The frequency of inspection will be at the agency’s discretion </li></ul></ul>
  32. 32. CBER’s Bioresearch Monitoring Branch <ul><li>Conduct pre-approval data audit inspections </li></ul><ul><li>Investigate complaints </li></ul><ul><li>Answer questions about Good Clinical Practices </li></ul><ul><li>Help evaluate concerns about data integrity </li></ul><ul><ul><li>Clinical investigators </li></ul></ul><ul><ul><li>Sponsor/Monitor/CROs </li></ul></ul><ul><ul><li>IRBs </li></ul></ul><ul><ul><li>GLP/Nonclinical Labs </li></ul></ul>
  33. 33. CBER is assigning more inspections of ongoing studies under IND/IDE <ul><li>Cell therapies </li></ul><ul><li>Gene transfer </li></ul><ul><li>Vaccines </li></ul><ul><li>Blood products </li></ul><ul><li>Devices </li></ul><ul><li>For FY 2005, CBER inspected 50 sites enrolling pediatric subjects </li></ul>
  34. 34. FY 2006 HCT/P Inspections 354 Total 44.1 234 All other HCT/Ps 42.8 36 Cord blood stem cells Peripheral blood stem cells 45.7 87 Reproductive tissues Hours/ Inspection Number of Inspections Type of HCT/P establishment
  35. 35. Human Stem Cells <ul><li>Stem Cell-Based Therapies – Stem cells, directed to differentiate into specific cell types, offer the possibility of a renewable source of replacement cells and tissues to treat diseases including, spinal cord injury, burns, heart disease </li></ul><ul><ul><li>“Adult” Stem Cells – Less pluipotent, immune rejection issues </li></ul></ul><ul><ul><li>“Embryonic” Stem Cells – More pluipotent, ethical / political issues </li></ul></ul>
  36. 36. Bone marrow stroma/Mesenchymal stem cells Facilitate hematopoietic reconstitution
  37. 39. Human Embryonic Stem Cell Lines <ul><li>Issues Receiving Attention: </li></ul><ul><ul><li>Media used for culturing hES cells is routinely supplemented with bovine serum (concern over BSE/TSE, vCJD) as well as other animal-derived ancillary products. </li></ul></ul><ul><ul><li>Characterization of therapies derived from hES cells as xenotransplantation products: use of irradiated murine embryonic fibroblast feeder layers. </li></ul></ul><ul><ul><li>Published technical report in Nature Medicine: Human embryonic stem cells express a nonhuman immunogenic sialic acid (Neu5Gc). </li></ul></ul><ul><ul><li>Karyotypic / genetic stability of long-term hES cell cultures </li></ul></ul>
  38. 41. Human Embryonic Stem Cell Lines <ul><li>Human ES Cell Lines Established on Non-Human Feeder Cell Layers </li></ul><ul><ul><li>Fit the definition of xenotransplantation as defined in CBER Guidance for Industry issued April 2003. </li></ul></ul><ul><ul><li>FDA DOES NOT intend xenotransplantation requirements to preclude use of hES cell lines in human clinical trials. </li></ul></ul><ul><ul><li>For stem cell products derived from hES cell lines raised on non-human feeder layers it may be necessary to demonstrate that the hES cell line is free from infectious agents that may pose a risk for transmission to recipients. (Adventitious agent testing is equally important when feeder layers are comprised of human cells) </li></ul></ul>
  39. 42. Cell Therapy Product Characterization <ul><li>Morphologic evaluation </li></ul><ul><li>Unique biochemical markers </li></ul><ul><li>Gene and protein expression analysis </li></ul><ul><li>Cellular impurities profile </li></ul><ul><li>Biologic activity/Potency </li></ul><ul><li>Identity: HLA, other unique marker </li></ul>
  40. 43. Product Safety and Efficacy <ul><li>Safety Issues: </li></ul><ul><ul><li>Sterility (bacterial, fungal, mycoplasma) </li></ul></ul><ul><ul><li>Purity </li></ul></ul><ul><ul><li>Identity </li></ul></ul><ul><ul><li>Segregation and tracking </li></ul></ul><ul><li>Efficacy Issues: </li></ul><ul><ul><li>Potency </li></ul></ul><ul><ul><li>Stability </li></ul></ul>
  41. 44. Cell Therapy Preclinical Assessment: Activity and Safety <ul><li>Cell Fate Post Transplant </li></ul><ul><li>Post transplant survival </li></ul><ul><li>Cell migration </li></ul><ul><li>Cell differentiation </li></ul><ul><li>Cell phenotype expression </li></ul><ul><li>Anatomic/functional integration into host physiology </li></ul><ul><li>Tumorigenic / proliferative potential </li></ul>
  42. 45. Cell Therapy Preclinical Assessment: Animal Models <ul><li>Animal Models </li></ul><ul><ul><li>Use of existing models (i.e., EAE model) to “predict predict” activity & safety </li></ul></ul><ul><ul><li>Incorporate activity & toxicity endpoints in an animal model of disease </li></ul></ul><ul><ul><ul><li>Comparative anatomy & pathophysiology to humans </li></ul></ul></ul><ul><ul><ul><li>Consider the route of administration/delivery system </li></ul></ul></ul><ul><ul><ul><li>Immune tolerance to human cells….or </li></ul></ul></ul><ul><ul><ul><li>use of analogous cells from animals </li></ul></ul></ul><ul><ul><li>Understand abilities & limitations of model(s) used </li></ul></ul>
  43. 46. Cell Therapies: Characterization <ul><li>Issue: Key questions for safety and effectiveness </li></ul><ul><li>What are the critical characteristics to measure: </li></ul><ul><ul><li>Genes (30,000 30,000-40,000/cell) </li></ul></ul><ul><ul><li>Proteins? (40,000/cell) </li></ul></ul><ul><ul><li>Secreted molecules? (5,000/cell) </li></ul></ul><ul><ul><li>Microenvironment? </li></ul></ul><ul><li>Can Can’t measure everything! </li></ul><ul><li>How to identify what matters? </li></ul>
  44. 47. Manufacturing Facilities <ul><li>Capacity Issues </li></ul><ul><ul><li>Patient-Specific vs. Allogeneic </li></ul></ul><ul><ul><li>Processing Time </li></ul></ul><ul><ul><li>Quarantine Issues </li></ul></ul><ul><li>Aseptic Processing for All Steps </li></ul><ul><li>Labor Intensive </li></ul><ul><li>High Level of Support Requirements </li></ul><ul><li>Scheduling Issues </li></ul>
  45. 48. Open vs. Closed Manufacturing Systems <ul><li>FDA Cleared or Approved Sterile Tube Connecting Device (STCD) – Tubing Welders Developed for the Blood industry. </li></ul><ul><li>STCDs may be used for interconnecting sterile bag systems for cell and gene therapy applications. </li></ul>
  46. 49. <ul><li>Example Facility </li></ul><ul><li>Standard Cell Therapy Unit </li></ul><ul><ul><li>150 ft 2 , 2 Operators </li></ul></ul><ul><ul><li>Capacity 25 to 100 Products / Year </li></ul></ul><ul><li>Clinical Facility </li></ul><ul><ul><li>6 Units – 5,000 ft 2 (18%) </li></ul></ul><ul><ul><li>Capacity 150 – 600 Products / Year </li></ul></ul><ul><li>Commercial Facility </li></ul><ul><ul><li>24 Units – 25,000 ft 2 (15%) </li></ul></ul><ul><ul><li>Capacity 600 – 2,400 Products/Year </li></ul></ul>
  47. 50. WRT&A
  48. 51. WRT&A
  49. 52. WRT&A
  50. 53. WRT&A
  51. 54. Paradigm for Delivery of Patient-Specific Products <ul><li>Massive Single Plant </li></ul><ul><ul><li>Problems with In-coming Patient Cells/Tissue </li></ul></ul><ul><ul><li>Problems with Product Distribution </li></ul></ul><ul><ul><li>No Real Economy of Scale </li></ul></ul><ul><li>Production Units in Major Hospitals </li></ul><ul><ul><li>Optimum for Patient-Specific Transportation Issues </li></ul></ul><ul><ul><li>Problems with Quality Oversight and Technical Expertise; Facility Issues </li></ul></ul><ul><li>Multiple Regionally Located Plants </li></ul><ul><ul><li>Concentrate Expertise and Quality Oversight </li></ul></ul><ul><ul><li>Feasible Receiving and Shipping of Cells/Products </li></ul></ul>
  52. 55. WR Tolbert & Associates Consultants to the Biopharmaceutical Industry 11483 Cypress Woods Drive San Diego, CA 92131-3535 858-693-8163 wrt@wrtolbert.com / www.wrtolbert.com

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