How to Run a Large GMP Facility GMP Manufacturing in Texas –

How to Run a Large GMP Facility
GMP Manufacturing in
Texas –
Where Bigger is
expected to be Better!
Adrian Gee
Center for Cell & Gene Therapy
Baylor College of Medicine
Houston, Texas
• Introduction to CAGT & its History
• The challenges of growth
– Space
– Staff
– Workload
– Documentation
– Budget
– Regulatory
• Advice
Center for Cell & Gene Therapy
CAGT History
• Formed in 1998 as a partnership between Baylor, The
Methodist Hospital and Texas Children’s Hospital to share
cost & avoid duplication
• Dr Malcolm Brenner recruited as Director from St. Jude’s
Children’s Research Hospital, Memphis, TN
• Important to cover the spectrum from basic research to
Phase I – II clinical trials
• Total staff (including nursing etc.) ~400 ( ~ 40 Faculty)
The Start
~ 50 stem cell transplants per year
3 INDs for virus-directed cytotoxic T cells
Newly built GMP Facility
2 cell processors
~3 IND cell technicians
2 QC technicians
QA Manager
• 9 Clean Rooms
• Flow cytometry in clean area
• Cell storage in clean area
• Adjacent QC Laboratory
The Change
• 2009 – added 8
• Offered to build
new GMP
• 16th floor
• Opportunity to
• 19,000 sq ft
including offices
The New Facility
22 Clean Rooms (Class 10,000, ISO 7)
12 – Cell Processing
7 – Vector Production
3 Swing Rooms
Centralized Materials area
2 LN2 Banking Areas
1200sq ft QC lab
Flow Cytometry Lab.
QA Space
Filing space
Cell Processing Main
Vector Production Facility
Special Processing
Receiving & Storage
Quality Assurance
& Control
Offices &
HVAC Systems
Cell Processing Facility
20-30 air changes per hour
50% recirculated air
CPF Flow path
Cell Processing Facility
Single corridor design
HVAC Systems
Vector Production Facility
60 air changes per hour
100% exhausted air
VPF Flow path
Vector Production Facility
Clean & dirty corridors
Quality Control
Quality Control
Cell Processing
Released Supplies
Quality Assurance
Freezer Storage
Flow Cytometry
Vector Production
Materials Management
Traffic Pattern
Cell Processing
Gowning Flow
Offices &
Vector Production
Challenges – New Space Issues
– What are you going to make & for whom?
– How much space will really be needed?
– Ongoing expense
• Initial and ongoing qualification
– Equipment
• Cleaning
– Validation – how to do it?
– Single- or-unidirectional flow?
– Who will clean?
• Environmental monitoring
– Staff, equipment and expense
Challenges – Staff
– New staff
• Recruitment
• Exempt or non-exempt
• Training time
• Work existing staff to death! Particularly QC
• Exempt (no overtime) staff – difficult to
manage fairly
• Initial emphasis on QC training then expanded
Challenges – Workload
– New Protocols
and Products
• Space should be
• Need a
method to
introduce new
~50 INDs + Transplant products
Challenges – Workload
– New Protocols
and Products
• Space must be
• Need a
method to
introduce new
~50 INDs + Transplant products
Cells Produced
Products Manufactured
Hematopoietic Progenitor Cells (HPC)
Products Manufactured
Cytotoxic T cells (CTLS)
HPC, Marrow, Unmanipulated
CTLs – EBV directed
HPC, Marrow, Red cell depleted
CTLs – LMP2 directed
HPC, Marrow, Plasma depleted
CTLs – LMP1/LMP2-directed
HPC, Marrow, CD34 selected
CTLs – Adenovirus directed
HPC, Apheresis, Plasma depleted
CTLs – tri-virus directed
Marrow mononuclear cells (MNC) –
cardiac repair
CTL – EBV/Neuroblastoma directed
Marrow CD34-selected – cardiac repair
Marrow MNC – traumatic brain injury
Marrow MNC – stroke patients
HPC - Cord blood
CD34-selected, ex vivo expanded
For hearing loss & brain injury
Lymphoblastoid Cell Lines
Donor leukocytes (DLI)
CTL- Genetically modified (TGFβ etc)
Genetically-modified allodepleted donor
T lymphocytes
Lymphoblastoid cell lines +/- genetic
modification – Intermediate product
Tumor vaccines +/- genetic modification
TV – autologous – neuroblastoma-directed
TV- allogeneic – neuroblastoma-directed
TV- autologous – CLL-directed
Hepatic progenitor cells
Mesenchymal stem/progenitor cells
Pancreatic islet cells – allogeneic
Antigen presenting cells (APC)
GMP-grade EBV
NK Cells
APC – dendritic cells – Intermediate
APC – monocytes – intermediate product
APC – leukemic cell lines
New Protocol Implementation
• Binder includes
–Manufacturing flowchart
–Copy of Protocol
–CMC section from IND
–Presentation to staff
–IRB Approval
–SOP & worksheets
–Certificate of Analysis
–Product Label
Workload - Documentation
In order of frustration
Staff training records
Equipment records
Environmental monitoring
Standard Operating Procedures
Validation & Qualification
Audits – performance &
• Batch records
Workload - Monitoring
• Labor intense & expensive
• How much, where &
• Retrospective value of
viable counts?
• Correlation with product
Challenges – Budget
Money issues
• Large facilities = large running cost
– Staff, maintenance, calibration,
monitoring etc.
• Funding is tight
• Many costs not covered by traditional
• Helps to have high “internal” demand
• Possible sources: contracts, space
rental etc.
Challenges – Compliance
• Ongoing compliance is not an option!
• Understand what is really required
• Expectations for compliance in Phase 1 are
• Money for QA is often tight - but this is changing
• “Good” QA people are hard to find
• Option to close unused areas
• Prioritize tasks
• Deputize where possible
• Be realistic, not over-ambitious when planning
• Set expectations with the administration
• New staff, equipment, running costs etc.
• Potential income/losses
• Do not overbuild
• Understand the regulations
• Seek advice wherever it is available
• Implement growth in phases
Kia Ora!