Teaching Surgeons How to do
Cell Therapy
Tom Leemhuis, Ph.D.
Hoxworth Blood Center
University of Cincinnati Academic Health Center,
Cincinnati, Ohio.
OBJECTIVES
• Discuss strategy for how CT Lab might implement a
new cell therapy production process for a customer
other than BMT.
• Discuss lessons learned from incorporating
pancreatic islet isolation into an already busy CT
Lab.
BACKGROUND
• Department of Surgery requested opportunity to lease
cleanroom space to perform “their” pancreatic islet
isolation procedure.
• Surgeons and one technologist had performed and
published results of ≈ 50 autologous islet cell
transplants in previous 5 years for treatment of chronic
pancreatitis.
• Processing not in compliance with cGTP regulations
(part of same surgical procedure).
• Hoxworth agreed to help, but only if P.I. committed to
making autologous islet cell isolation conform to cGTP
regulations and CT Lab Quality Management Plan.
ASSUMPTIONS
• Customer (P.I.) is in same or collaborating academic
institution.
• P.I. wants to retain “ownership” of process.
• Pre-clinical safety (animal) studies are not required.
• IND application is not required.
• Methods have been shown to produce desired
product characteristics at clinical scale.
• P.I. is physician with patient care focus, with little or
no experience with cell therapy regulations.
• Staff has little or no experience with product.
Implementation Strategy
• Utilize formal change control process.
• Assess regulatory status of product type to be
produced; obtain approvals as needed.
o IND required?
o 21 CFR 1271 GTP regulations?
o IRB submission?
• Initiate a detailed Service Agreement.
• Educate CT Lab management and staff.
• Adapt manufacturing process to CT Lab’s
Quality Management Plan.
• Incorporate new investigators into the Cell
Therapy team.
Implementation Strategy - Ground Rules
• Principal Investigator is responsible for writing and
monitoring the clinical protocol.
• Cell Therapy Lab has input into production methods
and materials used.
• Principal Investigator will follow CT Lab’s Quality
Management Plan (QMP).
• SOP’s written and followed for all operations.
• Deviation tracking / Process Improvement system
utilized.
• Outcome analysis performed at regular intervals.
• Equipment maintenance; document control; training
documentation; annual SOP review; product release;
aseptic processing procedures followed.
Implementation Strategy – Facility
• Decide whether cleanroom facility is needed:
o More than minimal manipulation, open systems – yes.
o Minimal manipulation, closed systems –no.
• Determine impact on existing processing schedule.
• Lease (dedicated) CT Lab space to P.I.
• CT Lab staff responsible for all facility cleaning,
maintenance, and environmental monitoring.
• P.I. (and staff) follows CT Lab gowning procedures,
raw material flow, personnel flow, and waste disposal
procedures.
Implementation Strategy – Equipment
• Transfer all equipment to CT Lab “ownership”.
• CT Lab responsible for:
o
o
o
o
o
o
o
calibration / certification program
preventive maintenance
cleaning schedules
usage logs
spare parts
operation manuals
O & M SOP
• Convert re-useable equipment to disposable.
• CT Lab maintains vendor relationships.
Implementation Strategy – Raw Materials
• Order materials using CT Lab policies and
procedures.
o
o
o
Create raw material specifications.
Obtain Certificates of Analysis.
Inspect (test) and release prior to use.
• Convert to sterile infusion–grade (FDA approved)
reagents.
• Change suppliers if necessary.
• Dedicated supply inventory (if possible).
• Store segregated in same storeroom as all other
supplies.
Implementation Strategy – Staffing
• P.I. provides experienced Technologist to assist
with technology transfer and clinical processing.
• CT Lab provides staff to assist during processing.
• CT Lab provides staff to review charts and
approve product release.
• Include P.I. (and staff) in CT Lab meetings, other
communications.
• CT Lab management has input into performance
appraisal of all processing staff.
Implementation Strategy - Training
• P.I. trains support staff (technical operations).
• CT Lab staff trains P.I. (and staff) to follow all
relevant institutional policies and procedures,
including aseptic processing, lab safety, and patient
confidentiality guidelines.
• Use CT lab’s training documentation system.
Implementation Strategy - Methods
• All operations are SOP driven.
• P.I. to provide technical details.
o P.I. authors SOP’s.
o P.I provides published references for methods chosen, if
possible
o CT Lab converts SOPs and forms to CT Lab format.
o Create worksheets and forms as needed to document
procedural details.
o Add new SOPs and forms to controlled document system.
• CT Lab dictates aseptic processing procedures.
• PI and CT Lab conduct process validation.
Implementation Strategy – QC Assays
• Define release criteria
o Contract testing with CLIA-certified laboratory.
o Write and validate test methods.
• Define product characterization testing
o Limit to what might effect treatment or might help
monitor process.
• Decide research questions
o CT Lab focuses on product testing; P.I. responsible for
pre and post-infusion patient monitoring.
• Create protocol-specific sampling plan
Implementation Strategy - Records
• Build a Master Production Record:
o Worksheets (batch record)
o Sampling Plans
o Requisitions
o Infusion forms
o Labeling (product and QC samples)
o Test result forms
o Certificate of Analysis
o Product Release checklist
• Keep patient records on site at CT Lab with all other
patient charts.
• Follow CT Lab record retention policies.
Implementation Strategy – Financial
• Fee for Service contract.
• Invoice P.I., not patient.
• CT Lab contributes process development and
validation costs. Invoice for start-up costs over
time, if necessary.
• Monthly lease price covers facility and equipment
maintenance costs, environmental monitoring,
utilities (percentage of total).
• Invoice raw material costs +20% monthly.
• Bill per procedure for Technologists’ time.
Maintenance Strategy
• Cross-train CT Lab staff to perform all operations.
• Meet monthly with operations staff to monitor
process improvement objectives.
• Meet quarterly with all management, operations,
and QA staff to discuss:
o
o
o
o
o
Patient outcomes
Processing outcomes
Deviations / CAPAs
Non-conforming products
Staff training
• Report adverse events and core GTP deviations to
FDA as required.
Challenges
•
•
•
•
•
•
Convincing clinicians to follow SOPs
Obtaining outcome data
Establishing continuous improvement mindset
Enforcing aseptic processing guidelines
Concurrent documentation
QA meeting attendance
Successes
• U.C. performs ≈ 12 -18 autologous islet transplants
per year for chronic pancreatitis patients.
• Converted from re-useable product contact
equipment to sterile, single use disposables.
• Processing now being performed in compliance with
comprehensive Quality Management Plan.
• Greater percentage of patients are insulin
independent post transplant since Hoxworth began
assisting.