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© 2019 Parexel International Corporation
Logistics Challenges and Solutions for Cell and Gene Therapy Trials
Andrea Zobel
Sr. Director Parexel Academy
Andrea.Zobel@parexel.com
academy@parexel.com
https://parexel-academy.com
© 2019 Parexel International Corporation2
Logistics View on Cell and Gene Therapies
1 PatientGMP Manufacturer
IMP
Cells
Autologous transplantation
n DonorsGMP Manufacturer
IMP
Cells
Allogeneic transplantation
PatientsGMP Manufacturer
IMP= Cell line
(Stem) Cell therapy
PatientsGMP Manufacturer
IMP= GMO
Gene therapy
dependent on country
n Patients
IMP: Investigational Medicinal Product
GMO: Genetically Modified Organism
© 2019 Parexel International Corporation
In general, the ATMP in a clinical trial is an IMP and the regulations for IMPs must be followed
but the nature of the product causes additional challenges:
Shelf life: very short shelf lives of 24 hrs to 96 hrs
Storage and shipment conditions: protection of product and environment, often frozen
Traceability: as for IMP but longer archiving, donor documentation, procurement report
Labelling/Packaging: additional label requirements for cells, ATMPs and shipping container
Environmental safety: dangerous goods classification could be applicable
Import/Export: local regulations applicable, in many countries not established for these new
products
Training: special training required for all involved parties
3
Logistics Challenges of ATMP Clinical Trials
© 2019 Parexel International Corporation
Logistics Planning
Concept, vendors, supply chain network for autologous and/or time critical therapies
Concept, vendors for biomarker analytics, PK, companion diagnostics
Storage
GMP storage vendors for - 20°C, -80°C, liquid nitrogen (LN2) or other temperature ranges
Depots for storage of GMO’s (genetic modified organisms)
Distribution
Shipper solutions and tracking for ambient, refrigerated, dry ice and LN2
Import/export licenses and execution of imports
Laboratory
Laboratory services during study and in long-term follow-up
End-to-end sample management: Patient’s consent for analytical tests
4
Clinical Supply for Cell & Gene Therapy Trials
© 2019 Parexel International Corporation
Fast or deep frozen logistics
Manufacturer Patient
Site
Depot
Site
Fast or frozen
2 - 8°C/
© 2019 Parexel International Corporation6
Storage of ATMPsCell Therapies
GMP/GCP licensed and experienced depots required
Storage capacities in new temperature ranges e.g. 50°C, 60°C
Qualification need of storage rooms with new temperature ranges- Time!!
Limited capacities in depots for LN2 storage today
Gene Therapies
GTMP/GMO licenses required acc. to local law
Consider ERA (Environmental Risk Assessment),
deliberate release or contained use classification
Dedicated, labelled storage areas, biosafety officer?
Spill kits incl. protective clothing, disinfectant, absorbent
material, biohazard incineration bags
© 2019 Parexel International Corporation7
Distribution of ATMPsCell Therapies
Selection of special couriers out of qualified courier network
For living cells: site selection by distance and reachability from
manufacturing site
Tracking for time and temperature critical cell products
Ambient controlled shipments within hours
15 to 25°C, 2 to 8°C, -15 to -25 °C, other frozen temperature ranges, dry
ice, liquid nitrogen
Gene Therapies
Import/export execution of GMO’s incl. import license applications
Special couriers for GMO/ dangerous goods shipments
Restriction of storage time at depots and sites
Reverse logistics of unused GMO’s and contaminated materials
© 2019 Parexel International Corporation
IMP requiring manufacturing:
Clinical site = GMP manufacturing site or
Central site’s qualified person or quality manager oversees decentralized sites
IMP requiring reconstitution:
Material e.g. solvents and equipment specified or provided
IMP requiring storage:
Storage equipment e.g. deep freezers, liquid nitrogen,
GMO lab,
Ability to thaw, preparation before treatment
IMP ready to use:
Location within reachable distance to sender
Ideally capability for certified destruction of unused IMPs
8
ATMPs at the Clinical Site
Safety classification/license dependent on product
For all cases detailed process descriptions,
quality system and training of site staff
required!
© 2019 Parexel International Corporation
Case Studies
© 2019 Parexel International Corporation
Case Study Gene Therapy
Storage at -20°C acc. local GMO regulations Thawing, administration
AAV carrying human gene Y
IMP, -20°C, 6 months
Long-term Safety and Tolerability of Intracerebral Gene Therapy of patients with gene deficiency Y
Main Challenges:
to find patients for the orphan indication
availability of GMO regulations in countries with patient population
understanding of IMP by importers, couriers, depots, sites
- 20 °C storage and distribution capabilities
© 2019 Parexel International Corporation 11
Outcome Case Study Gene Therapy
Results of feasibility:
Majority of patients are located in countries with strict GMO regulation e.g.
Brazil with GMO license requirement for depots
Although GTMPs exempted from GMO law in Germany, federal authorities
allow only short term storage at depots and sites - 3 days!
Training need for all involved parties, e.g. import brokers and GTC staff not
even able to classify ATMP
Limited or no availability of -20°C freezers and GMO licenses at depots and
clinical sites
Storage at -20°C acc. local GMO regulations Thawing, administration
AAV carrying human gene Y
IMP, -20°C, 6 months
Long-term Safety and Tolerability of Intracerebral Gene Therapy of patients with gene deficiency Y
Study not
feasible in the
current regulatory
environment!
Long timelines to
get licenses and
set-up the supply
chain at -20°C!
© 2019 Parexel International Corporation 12
Case Study Autologous Cell Therapy
Labeling, release, administration
5 weeks culture, Shelf-life 48 hrs
IMP, 15 – 25°C, 24 hrs
Tumor, 2-8 °C
Phase 2 Trial: Cell transfer using autologous tumor infiltrating lymphocytes
Surgical removal of metastatic tumour
Main Challenges:
Release process and administration before availability of data
Traceability of product from and to the patient
Detailed processes to assure correct assignment of ATMP to patient
Identification of sites reachable within 24 hrs from the manufacturing site
© 2019 Parexel International Corporation 13
Outcome for Case Study Autologous Therapy
Labeling, release, administration
5 weeks culture, Shelf-life 48 hrs
IMP, 15 – 25°C, 24 hrs
Tumor, 2-8 °C
Phase 2 Trial: Cell transfer using autologous tumor infiltrating lymphocytes
Surgical removal of metastatic tumour
Result:
Detailed shipment plan for each site developed
Short ATMP release process at site developed
Short shelf life approach for stability and sterility testing
Traceability system to assure correct assignment of ATMP to patient
Within 24 hrs from the manufacturing site only a few sites had been identified
These sites had less patients than required
24 hrs shelf
life is too
short for
conducting
the trial with
sufficient
number of
patients!
© 2019 Parexel International Corporation 14
Case Study Cell Therapy
Surgery, administrationCell line, patient preparation
IMP, 15 – 25°C, 40 hrs
Phase 3 Trial: Cell transfer in inflammatory bowel disease patients
Main Challenges:
48 hrs shelf-life, but 8 hrs required at site for patient preparation
Time-consuming import and release process in countries with large patient
population
Only one manufacturing site in EU, delay of second site in US
© 2019 Parexel International Corporation15
Case Study: shelf life of cells determines sites and logistics
Production sites Specialist courier Countries/sites
1 in USA planned1 in Europe active
IMP Stem cells and placeboDose: 4 vials = 1 treatmentPackaged & labelled per GMP
48 hours shelf life at 15-25º C
Logistics plan for countries/sites
Pick up and TransportationTemperature controlled
Belgium, Czech, Hungary, France, Italy, Poland, Spain
IsraelCanada, USJapan
Max. 40 hours
Clinical Supply Oversight
© 2019 Parexel International Corporation 16
Study Execution
Surgery, administrationCell line, patient preparation
IMP, 15 – 25°C, 40 hrs
Phase 3 Trial: Cell transfer in inflammatory bowel disease patients
Solutions:
Identification of towns reachable within 40 hrs from the manufacturing site
Site selection within these regions, final selection and detailed plan for pick-
up and delivery
Import and quality release at site in certain countries before administration
Active Tracking for supply chain visibility
>190 successful
shipments and
treatments of
patients!
© 2019 Parexel International Corporation
Logistics challenges ofCAR-T Therapy
© 2019 Parexel International Corporation
Gene Therapy Medicinal Product (GTMP)
Somatic Cell Therapy Medicinal Product (CTMP)
18
CAR-T cells are a combination of cell and gene therapy
Scientific Recommendation on classification of Advanced Therapy Medicinal Products [Article 17 - Regulation (EC) No 1394/2007]
www.ema.europa.eu/ema/pages/includes/document/open_document.jsp?webContentId=WC500070338
Autologous CAR-T > Allogeneic CAR-T
© 2019 Parexel International Corporation
In general, the regulatory expectation for CAR-T is the same as for any other
biological medicinal product:
Product quality should be controlled relative to:
Identity- Purity - Biological activity - Safety (microbial, viral, TSE)
Product characterization and release testing:
Short shelf-life approach(Traditional sterility testing takes 14 days; some products have
shelf life of <3 days!)
Justification of release without full test results, testing of process intermediates, rapid
sterility testing, strategy for dealing with out specification results post-administration
Initial reference material from non-clinical studies, later from clinical studies with
qualification against old references
19
The quality challenge
© 2019 Parexel International Corporation
Case Study CAR-T Therapy
Main Challenges:
Identification of sites reachable within 48 hrs from the manufacturing site
Management and tracking of autologous CAR-T cell cryogenic shipments from
manufacturing site to patients at sites
Import of genetically modified CAR-T cells
Management of lab samples and tumour biopsies shipments from sites to selected
laboratories
15 yrs follow-up period for each patient with sample taking and analysis
Release, administration
CAR-T manufacturing 2 wks
IMP, LN2, fast!
PBMCs, 2-8°C, 48 hrs
Phase 2 Trial: CAR-T Therapy
Apheresis
© 2019 Parexel International Corporation
Active management of supply chain
Design and execution of operational and
logistics strategy
Tracking of specimens in/out from sites.
Strategic alliances with world class courier
services
IMP and leukapheresis management
Qualified Courier Strategy – Active Shipment Tracking
(GPS + temptale)Sample Tracking Tool
- eRequisition
Logistics Leader Role –Dedicated Functional Leader experienced in IMP
and sample logistics
Key Strategy Elements
Sites
Clinical Trial Supplies & Logistics
SIV Shipment
Leukapheresis
IMP for patient infusion
On-line accessioning tool for specimens
© 2019 Parexel International Corporation
Logistics Planning
Selection of couriers and shipment method for ambient controlled PBMC shipments within 48 hrs
and cryogenic CAR-T cell shipments
Feasibility and set-up of timetables for pick-up of PBMCs at sites and delivery to manufacturing
site including flight plans and tracking processes for selected sites
Set-up of laboratory tests, sampling material and sample tracking procedures
Distribution
Active Tracking of location and temperature of PBMC shipments
Management and tracking of autologous CAR-T cell cryogenic shipments from manufacturing site
to patients at sites
Management of lab samples and tumour biopsies shipments from sites to selected laboratories
Long Term Follow-up
Biosample Management System for biosamples within 15 yrs follow-up period
22
Logistics Plan for a CAR-T Trial
© 2019 Parexel International Corporation23
Problem: Limited manufacturing capacities
Current license holders have only e few manufacturing sites (typically in US, EU)
The consequence: critical ill patients are not treated and die!
Logistics limits feasibility of access
Solution: Decentralized Manufacturing
Standardized, GMP compliant manufacturing modules
Solution for better access to this life saving therapy
Can lower costs
Brings therapy close to patients
© 2019 Parexel International Corporation
Therapy was classed as a medical technology rather than a drug
Trials required only the permission of internal hospital ethics committees
Process can take as little as two months
China patients can begin after failing chemotherapy
US patients can begin when all other treatments have failed
CRISPR gene editing technology allowed
New regulations : Cell therapy products are treated like drugs, in alignment with policy in
the USA and European Union
20+ CAR-T IND’s have been filed with NMPA
24
Most patients treated with CAR-T in China
© 2019 Parexel International Corporation
Cell & Gene Therapy trial logistics is challenging but most are feasible
Regulatory and logistics environment is developing
Solutions for short shelf lives and limited number of manufacturing sites:
New cell preparations and decentralized manufacturing!
25
Conclusion and Outlook
© 2019 Parexel International Corporation
Thank you
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