regulatory aspects on extracellular vesicle -based ... vesicle-based new therapeutics development of...

Regulatory Aspects on Extracellular Vesicle-based

Paracelsus Medical University Salzburg | Strubergasse 21, A-5020 Salzburg | www.pmu.ac.at

SCI-TReCS

Spinal Cord Injury & Tissue Regeneration Center Salzburg

Regulatory Aspects on Extracellular Vesicle-based

Pharmaceutical Engineering

Dept. Blood Group Serology and Transfusion Medicine

Eva Rohde

� Blood Donation Management

� Prodoction of Blood Components (100k/year)

� Diagnostics: Immunohematology = Blood Group Typing

Serology & Molecular Biology (DonorPatient), Robotics

� Infectious Disease Diagnostik (Hepatitis A, B, C, HIV1/2, Syphillis,

Neopterin):

Immunology, Serology & Molekularbiology (Spender)

Activities 2001 - nowTransfusion Medicine Departments Graz & Salzburg, Austria

© Paracelsus Medizinische Privatuniversität | Lehrveranstaltung | Name des

Immunology, Serology & Molekularbiology (Spender)

� HLA-Diagnostics (Immunogenetics, HLA-Typing, Donor/Patient)

� Therapy:

Phlebotomia/ Transfusions / Diagnostics (Patients)

� Therapeutic Aphereses (gr.: ἀφαιρέιν, aphereio = take out from body):

stem cell harvesting prior to chemotherapeutic treatment

� Establishing (stem) cell-based therapiesR&D: Developing novel cell-based therapeutic strategies for tissue

regeneration and functional repair after organ injury

Extracellular Vesicle-based

New Therapeutics

Development of Emerging Investigational New Drugs (INDs)-based on Human

Cells or Derivatives Such as Extracellular Vesicles (EVs) raises several

(Unmet) Requirements:

1. Biomedical Complexity: Tissue Regeneration -> Open Questions 1. Biomedical Complexity: Tissue Regeneration -> Open Questions

2. Adequate Infrastructure: technical equipment according to

pharmaceutical manufacturing standards

3. Quality Management System: implementating manufacturing

procedures according to pharmaceutical standards

4. Complicated Regulatory Issues: EV-based Therapeutics

Pharmaceutical Categorization – Challenging

International Harmonization – Lacking

© Paracelsus Medizinische Privatuniversität | SCI-TReCS | Spinal Cord Injury and Tissue Regeneration Center Salzburg

Strictly Underlying Regulatory Aspects

Example:

Mesenchymal

Stromal

Progenitor Cells

MSPCs

Source: e.g. BM-aspirations

to produce advanced therapy

medicinal products (ATMPs)

-> special regulations with

regard to pharmaceutical

production and clinical testing

110cm

1 x 109 = human setting

2.8m2

1 x 106 = mouse setting,

10cm2

Pooled Human Platelet Lysate:

Studying the impact of platelets on regeneration

Schallmoser K, Strunk D Basic Cell Culture Protocols, Humana Press, 2013


3/2007

10/2009

MSPCs + pooled Human Platelet Lysate (pHPL)

= Bone Regeneration

Selected Publications


SCI-TReCS Start


SCI-TReCS Mandate

� SCI-related clinical research projects

� Providing best state of the art treatment and care of patients � Providing best state of the art treatment and care of patients

with spinal cord injury (SCI)

� Developing novel integrative therapeutic strategies for tissue

regeneration and functional repair after organ injury


SCI-TReCS Mission


Local Cinical/Basic Science Expertise

Vessels

EPCs

Bone

MSPCs

Spinal Cord

& Brain

Eye Skin

SCI-TReCS

Pelvic

Floor

J. Bauer,

Dept. Dermatology,

PMU/SALK, Salzburg

H.Reitsamer,

Dept. Ophtalmology,

PMU/SALK, Salzburg

S. C.-Despres, Experimental

Neuroregeneration &

L. Aigner, Mol. Reg. Med.

E. Trinka, Dept. Neurology,

PMU Salzburg

H. Resch Traumatology &

D. Strunk, Exp.&Clin.

Cell Therapy,

E. Rohde, Transf. Med. &

J. Bauer, Tendon&Bone

PMU Salzburg

D. Strunk, Exp.& Clinical

Cell Therapy,

E. Rohde, Dept. of

Transfusion Med

PMU Salzburg

G. Janetschek,

R. Zimmerman

Dept. of Urology,

PMU/SALK, Salzburg


SCI-TReCS Organigram


SCI-TReCS Approach


Regeneration after traumatic, toxic, metabolic or ischemic

organ injury can be promoted by the inherent healing

power of somatic stem cells or factors isolated from the

human body.

Regenerative Medicine

Spinal Cord Injuries? Tissues & Organs?


MSPCs ECFCs pHPL Exosomes / EVsMesenchymal Endotheliale pooled Human mRNA/miRNA/Protein

Stem- and Progenitor Colony Forming Platelet Lysate Containing Microvesicles

Cells Cells

100% 80%20%

1. Biomedical Complexity

Open Questions

UC-MSPCs in pHPL

IgGbFGFEGFHGFCTGFIGF-1TGF- βVEGF-A, -CPDGFFactor VMultimerinFactor VIIIMMPsα2-Macroglobulin

PlasminogenPAI-1CXCL-5MIP-1αRANTESCCL17IL-8P-SelectinVon Willebrand FactorThrombospondinFibrinogenIntegrin αIIbβ3Integrin αvβ3Fibronectin...............

Osteogenesis

NeovasculogenesisPLATELETS:ORGAN

REGENERATION

WOUND

HEALING

ANGIOGENESIS

REGENERATIVE

POTENCY of

NON-

HEMATOPOIETIC

(STEM) CELLS


Identity? Purity? Potency?

?Isolation Techniques – Quantification ?

Purity / Impurities?

?Mode of Action (MoA) – Nature of the Target–?

? Potency Assays (in vitro/in vivo)?

?Relevance of the selected animal models with

regard to the intended therapeutic use?

? Vesicle uptake – Homeostasis – Biodistribution ?

?Toxicity Testing?

? Non-clinical & Clinical Safety – 1° & 2° Pharmakokinetics – Safety Pharmakology Studies?

2. InfrastructureBasic Science & Development

including GMP Manufacturing Site

Constructions until X-XI/2013Constructions until X-XI/2013


Past (March 2013) & Current View

18

SCI-TReCS GMP-Laboratory


GMP Lab for (Stem) Cell &

Extracellular Vesicle production


3. QM → Manufacturing →

InvesMgaMonal New Drug → Clinical Trials

Autologous Cells/Hu Factors → Therapy/Testing → Regeneration?

→ via Good Manufacturing PracMceDevelopment of Cell-based / Vesicle-based Biological Medicinal Products

in line with the principles of GMP and with a stringent Quality Management


EV-based IND-Development:

Development of Emerging Investigational New Drugs (INDs)-based on Human

Cells or Derivatives Such as Extracellular Vesicles (EVs) raises several

Hurdles:

Investigational New Drugs (INDs) based on human cells or derivatives such as

extracellular (vesicles EVs)extracellular (vesicles EVs)

1. Biomedical Complexity: Tissue Regeneration -> Open Questions

2. Adequate Infrastructure: technical equipment according to

pharmaceutical manufacturing standards

3. Quality Management System: implementation of manufacturing

procedures according to pharmaceutical standards

4. Complicated Regulatory Issues: EV-based Therapeutics

Pharmaceutical Categorization – Challenging

International Harmonization – Lacking


Current legislation at least in United States and Europe (Asia, Africa and Australia?) does not provide

specific regulation of EV-based therapies, thus the definition of “biological medicine” is applicable for

EV-based therapeutics. -> There is a need to contact national authorities, to confirm this information!

EVs are classified as biological medicine according to (not yet harmonized international) legislation: “A

biological medicine is a medicine that contains one or more active substances made by or derived from

a biological cell. Some of them may be already present in the human body and examples include proteins

such as insulin, growth hormone and erythropoietin (valid for EVs also!). The active substances of

biological medicines are larger and more complex than those of non-biological medicines. Only living

organisms are able to reproduce such complexity.” (European Medicine Agency EMA/837805/2011).

4. Regulatory Issues: Pharmaceutical

Classification of EV-based Therapeutics

organisms are able to reproduce such complexity.” (European Medicine Agency EMA/837805/2011).

This pharmaceutical classification harbours special challenges with regard to pharmaceutical

manufacturing and preclinical safety testing. -> in parallel to other biologics

Independent of the source of EVs (cells, body fluids, tissues), minor changes in production processes can

have major impacts on clinical characteristics and manufacturers may face great challenges in

completely defining physicochemical, immunochemical and biological properties of EVs.

Following the standardized production the characterization of biological medicinal products has to be

done by a combined approach of testing the (expected) active substances (safety pharmacology,

pharmacodynamics and toxicology testing) and the final medicinal product together with a tight

assessment of the pharmaceutical production processes and associated controls.


The hospital exemption rule, as defined in the ATMP Regulation (EC) No 1394/2007, can be applied on

gene therapy/cell therapy/tissue engineered medicinal products …“which are prepared on a non-

routine basis according to specific quality standards (i.e. current good manufacturing practice, GMP), and

used within the same Member State in a hospital under the exclusive professional responsibility of a

medical practitioner… -> this is not valid for EV-based therapies (if they are classified as biologicals)

ATMPs are defined to contain living cells (having a nucleus -> not applicable for EVs) and/or not intended

to be used for the same essential … functions in the recipient as in the donor

4. Regulatory Issues: Hospital Exemption &

ATMPs & International Legal Framework

Advanced Therapy medicinal Products (ATMPs) are not considered to be comparable with conventional

pharmaceuticals such as chemical compounds with regard to their physicochemical, immunochemical

and biological properties -> this seems to be valid for EV-based therapeutics also

It is generally acknowledged that conventional non-clinical pharmacology and toxicology studies may

NOT be appropriate for cell-based medicinal products, i.e. ATMPs (page 3, EMEA/CHMP/410869/2006).

-> This would be nice, if applicable for EV-based therapeutics, too.

Therefore, preclinical safety testing prior to clinical application of ATMPs is separately regulated by

applying hospital exemption rules in Europe (EMA-CAT)/ United States FDA’s CBER (?) / Japan Pharma-

ceutical and Medical Device Agency? other continents?. -> Varying national rules, not yet harmonized!


Conclusion:

Scientific community and companies interested in EV-based pharmaceutical

development should contact the relevant national and international legal

bodies to discuss manufacturing and interventional strategies of EV-based

Investigational new Drugs (INDs) -> the earlier the better

Possibly, “Hospital Exemption” rules can be achieved for EV-based INDs, too,

especially, if EVs are harvested from ATMPs. Currently, EVs are classified als

biological medicinal productsbiological medicinal products

Regulations are made by human beings -> thus: quite complicated but may

be changed

In Contrast:

Unravelling wheter and how vesicle-mediated regulation can in fact be

employed to promote tissue regeneration ... is the REAL BIG ISSUE...


Thank you for your attention!

http://www.pmu.ac.at/en.html

And all Sponsors of the Paracelsus

Medical University Salzburg!


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