Logistics Challenges and Solutions for Cell and Gene ... · Depots for storage of GMO’s (genetic...

© 2019 Parexel International Corporation

Logistics Challenges and Solutions for Cell and Gene Therapy Trials

Andrea Zobel

Sr. Director Parexel Academy

[email protected]

[email protected]

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


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


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


Fast or deep frozen logistics

Manufacturer Patient

Site

Depot

Site

Fast or frozen

2 - 8°C/


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


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


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!


Case Studies


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!


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


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!


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


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


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!


Logistics challenges ofCAR-T Therapy


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


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


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


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


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


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


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


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


Thank you

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