The new Regulation (EC)1394/2007 on Advanced Therapy … new... · 2015-04-15 · Human Tissues/Cells for Human Application incl. SCs excl. Blood Blood Components National Dir 2004/23/EC

Defi

nit

ion

s

I II III IV V VI VII IX X XI

Sc

op

e

Pla

cin

g o

n m

ark

et

Ma

nu

fac

t. &

Im

po

rt

La

be

llin

g &

L

ea

fle

t

Cla

ss

ific

ati

on

Wh

ole

sa

le D

istr

ibu

t.

VIII

Ad

ve

rtis

ing

Ph

arm

ac

ovig

ila

nce

Su

pe

rvis

& S

an

cti

on

s

Blo

od

& P

las

ma

The new Regulation (EC)1394/2007

on Advanced Therapy Medicinal Products

combined products

Paul-Ehrlich-Institut

Federal Agency for Sera and Vaccines

Ralf Sanzenbacher



Division of Medical Biotechnology

Section Tissue-Engineering & Somatic Cell Therapeutics

D-63225 Langen/Germany



Update on Cell Therapy and Tissue Regeneration Products in

Germany

3rd Annual Taipei International Symposium on human

Cell and Tissue-based Products, Oct 1st to 3rd, 2008

Topics

CELL-BASED PRODUCTS:

Responsibilities and History of PEI

Product examples

Quality issues

Ralf Sanzenbacher









Germany



London

Langen

Brussels

EU:

27 MS

http://images.google.de/imgres?imgurl=http://www.eu2008.fr/webdav/site/PFUE/shared/import/0601_La_Commission_europeenne/0601_Commission_europeenne1_Sc.jpg&imgrefurl=http://www.eu2008.fr/PFUE/cache/offonce/lang/en/accueil/union_europeenne/institutions_organes_agences/la_commission_europeenne/La_Commission_europeenne%3Bjsessionid%3DD08909498F15248746AB6AC5126770B2&h=469&w=703&sz=48&hl=de&start=1&um=1&usg=__fzq0axoEgHf1yvT88ds0awuEFcE=&tbnid=QaR1hv6TPNP3YM:&tbnh=93&tbnw=140&prev=/images%3Fq%3DEuropean%2Bcommission%2BBruessels%26um%3D1%26hl%3Dde

http://images.google.de/imgres?imgurl=http://www.fda.gov/oia/graphics/euflag.jpg&imgrefurl=http://www.fda.gov/bbs/topics/NEWS/2006/NEW01383.html&h=349&w=519&sz=37&hl=de&start=5&um=1&usg=__vK7x886yvVKKEb-M2ESg8ql7B6M=&tbnid=04HK_3BmDJBkiM:&tbnh=88&tbnw=131&prev=/images%3Fq%3DEuropean%2Bcommission%26ndsp%3D20%26um%3D1%26hl%3Dde%26sa%3DN

EMEAEuropean

Medicines Agency

PEI

Paul-Ehrlich-

Institut

Federal

Agency for

Sera and

Vaccines

BfArM

Federal

Institute for

Drugs and

Medical

Devices

BzgA

Federal

Centre for

Health

Education

DIMDI

German

Institute of

Medical

Documentation

and

Information

RKI

Robert Koch-

Institut

Federal

Institute for

Disease

Control and

Prevention

German Federal Ministry of Health

WHO

European

Commission

HMAHeads of

Medicines

Agencies

PEI: National and International Integration

EDQMEuropean Directorate for

the Quality of Medicines

ICHPaul-Ehrlich-Institut


History of the Paul-Ehrlich-Institut (PEI)

1896:

Institute for Serum Research

and Serum Testing (Berlin-Steglitz)

First Director: Paul Ehrlich

1906:

Georg-Speyer-Haus

(Frankfurt am Main)

1900 2000

1899:

Royal Institute for

Experimental Therapy

(Frankfurt am Main)

1947:


(Frankfurt am Main)

1990:

PEI moves to Langen

1994 Responsibility for Blood and Blood Derivates

2000 Accreditation as Notified Body for IVD Testing

Aug 2004 Responsibility for Clinical Trial Authorisation

1972 Establishment as Federal Agency

today

June 2005 WHO Collaborating Centre for Quality

Assurance of Blood Products and IVD

Sept 2005 Responsibility for Tissue Preparations

July 2004 Responsibility für Somatic Cell Therapy

and Gene Transfer MP

Medicinal Product Responsibility

of the Paul-Ehrlich-Institut (PEI)

Tissue

PreparationsAllergens Blood &

Plasma-

derived

Products

Sera,

Igs,

mAbs

Vaccines

(human,

vet.)

Advanced

Therapy

Products Cell

Therapy

Products

Gene

Therapy

Products

Tissue-

engineered

Products

http://www.pei.de



Tissue Preparations: Examples

Musculosceletal Tissue

Bone tissue

Femoral head

Soft tissues, tendon

(Dura mater)

Avitalised skin

Heart valves

Blood stem cells for

hematopoetic reconstitution

Foetal, embryonic, adult

Cornea



http://images.google.de/imgres?imgurl=http://www.kompetenznetze.de/Redaktion/Kompetenznetze/biotec-BioProfil-Funktionelle-Genomanalyse/Innovationshighlights/medien/bild__de__Nachwachsene-Herzklappen-Bioprofil,width%3D180,height%3D135.jpg&imgrefurl=http://www.kompetenznetze.de/navi/de/Services/innovationshighlights,did%3D94930.html&h=135&w=180&sz=9&hl=de&start=27&tbnid=idX8THnMndyQiM:&tbnh=76&tbnw=101&prev=/images%3Fq%3Dherzklappen%26start%3D18%26gbv%3D2%26ndsp%3D18%26svnum%3D10%26hl%3Dde%26sa%3DN

Liver

- Allogenic liver cell suspension for treatment of acute sepsis

or inherited metabolic liver failure

Type I Diabetes

-Allogenic pancreatic islets to restore insulin production

Skin

- Different skin cell suspensions for treatment of acute wounds

- Autologous adipose-derived stem cells for treatment of anal fistula

Immunotherapeutics

- CTLs or NK cell transfer for adoptive immuntherapy

Cell-based therapeutic Vaccines

- Peptide-loaded DC used as tumor vaccines

- Fused Tumor/DC hybrid cells

Adult stem cells

- MSC and HSC of different origin,

- e.g. for haematological indications like AML

- Treatment of anal fistula

Cell Therapy Medicinal Products: Examples



http://images.google.de/imgres?imgurl=http://www.bio-pro.de/imperia/md/images/artikelgebunden/rnd/cytonet_leberzellsuspension_166x390.jpg&imgrefurl=http://www.bio-pro.de/en/region/rhein/magazin/03132/index.html&h=390&w=166&sz=13&hl=de&start=1&um=1&tbnid=kYkeNYtdvoy7bM:&tbnh=123&tbnw=52&prev=/images%3Fq%3Dliver%2Bcell%2Bsuspension%26svnum%3D10%26um%3D1%26hl%3Dde

http://images.google.de/imgres?imgurl=http://content.answers.com/main/content/wp/en-commons/thumb/0/07/300px-Langerhanssche_Insel.jpg&imgrefurl=http://www.answers.com/topic/islets-of-langerhans&h=261&w=300&sz=38&hl=de&start=11&tbnid=mJavYKY789BjHM:&tbnh=101&tbnw=116&prev=/images%3Fq%3Dlangerhanssche%2Binsel%26gbv%3D2%26svnum%3D10%26hl%3Dde%26sa%3DX

EpiDex

(Euroderm, Germany)



www.euroderm-biotech.com

www.organogenesis.com

www.apligraf.com

Apligraf

(Organogenesis, USA)

Human Tissue Engineered Products: Skin Replacement

TisCover

(A-Skin, NL)

week 24ulcerwww.A-skin.nl

Human Tissue Engineered Products: Cartilage Repair 1st, 2nd, 3rd Gen



BioSeed-C

(BioTissue Technologies, Germany)

www.biotissue-tec.com

www.codon.de

Chondrosphere

(co.don AG, Germany)

www.tetec-ag.de

Novocart / Novocart 3D

(TETEC AG, Germany)

www.merz-pharma-austria.at

Hyalograft-C

(Fidia Advanced Biopolymers, Italy)

Carticel / MACI

(Genzyme, USA)

ChondroCelect

(TiGenix, Belgium)

www.medicalPhoto.com

http://www.medicalphoto.com/

Lifeline

(Cytograft, USA)



www.cytograft.com

www.vasotissue.com

(Vasotissue, Germany)

Human Tissue Engineered Products: Vessel Replacement

http://www.cytograft.com/pic_beating.html

Cartilage repair

- Autologous chondrocyte transplantation (ACT, ACI)

Skin regeneration

- Acute wounds, diabetic foot skin ulcers, veinous ulcer

- different cell types (keratinocytes, fibroblasts)

in combination with a sheet-like matrices/scaffolds

- MSC-like cells for hair regeneration (androgenetic alopecia)

Bone regeneration

- Osteogenic or bone-marrow-derived stem cells combined

with scaffolds or biomaterials

Cardiovascular regeneration

- Hematopoetic stem cells for heart regeneration

- Engineered autologous/allogeneic blood vessels or heart valves,

- Endothelialised stents

Complete organ engineering

Artificial lymph node

Artificial liver

Human Tissue Engineered Products: Examples



http://www.integra-ls.com/

http://images.google.de/imgres?imgurl=http://p3.focus.de/img/gen/T/E/HBTEANnaijh_Pxgen_r_450xA.jpg&imgrefurl=http://www.focus.de/gesundheit/ratgeber/haarausfall/therapie/haartransplantation/knifflige-sache_did_12791.html&h=300&w=450&sz=68&hl=de&start=72&um=1&usg=__9tM2fZXL__Low1cf9bsGcH5QfKk=&tbnid=ZQscKke-I04c0M:&tbnh=85&tbnw=127&prev=/images%3Fq%3Dhaarfollikel%26start%3D60%26ndsp%3D20%26um%3D1%26hl%3Dde%26sa%3DN

Medical

Biotechnology


Basic Scientific Research

Retrovirology ( HIV / SIV and HERV / PERV )

Gene Therapy ( Vector development / gene therapy )

Cell Therapy/TE ( Intracellular signaling, stem cell differentiation )

Working Groups

Gene Therapy Working Party

Working Party on Cell-based Products

WHO Clinical Gene Therapy Monitoring Group

others

Product Responsibility for

Gene Transfer Medicinal Products (vectors, DNA, gen. mod. cells or micro-organisms)

Somatic Cell Therapy MPs (human cells; immunotherapy)

Tissue Engineering MPs (human cells including stem cells)

Xenogeneic Cell Therapy MPs (xenogeneic cells)

Tissue Preparations (allogenic tissue)

Division 6 - Medical Biotechnology (I)

Advisory Servicefor Authorities, Organisations

Manufacturing Advice/Inspections

Scientific Advice

MAA Assessment

Clinical Trial

Advice/Inspections/Approval

Centralised

Departments/

Sections

Inspections

Virus safety Microbological safety

Biostatistics

Pharmacovigilance

Questions

Advices

Applications

….

Vaccines

Product-specific

Departments/

Sections

Blood Products

Clinical Trials

Immunology

Division 6

PTL

Core Team

Sponsor

EMEACTA/SA

/MAA

Cancer Vaccines

Division 6 - Medical Biotechnology (II)



Human

Tissues/Cells

for Human

Application

incl. SCs

excl.

Blood

Blood Components

National

Accreditation SystemDir 2004/23/EC

Processing, Preservation,

Storage, Distribution,…

Tissues, Cells

Tissue Preparations

(bone, heart valves, cornea)

SCs for Haematopoietic Use

Autologous Grafts within

same Surgical Procedure

ATMPs

Centralised MAMedicinal Products



Parts of Organs

for Homologous Use

Dir 2004/23/EC

Donation

Procurement

Testing

Reproductive Cells

Dir 2006/17/EC

Dir 2006/86/EC

The Regulatory Levels in the EU on Human Tissues and Cells

(EC)1394/2007

on ATMPs

Dir 2001/83/EC

not industrially prepared

produced using well known process

not “prepared“

industrially prepared

produced using novel process

new active substance

specific indications

Not regulated

Gene transfer MP

Somatic Cell Therapy MP

Tissue-Engineering MP

Human Tissue Preparations (PEI since ) national by PEI

Manufacturing

Authorisation Clinical trial Marketing authorisation

Requirements and CA„s for Placing on the German Market

Human Tissue / /

local authority,

PEI on request

Approval by

PEIcentralised by

EMEA

Approval by

PEI from 12/2012

centralised by

EMEA from 12/2012

local authority,

PEI on request

since 9/2006

local authority,

PEI on request

since 1997 (except

Cornea)



Status 31.12.2007

Involvement of PEI as Rap/CoRap in Centralized European

Licencing Procedures of Biomedical MPs



10

14

9

12

4

9

22

6

8

1

112

9

121211

11

4

11

4

1231

3121

6

22

6

1

13

3

322

3

24

4

4

41

9

1

10

4

4

6

6

11

13

1 10

10

20

30

40

50

60

70

DE (=PEI) BE DK ES FI FR IE IT NL NO SE UK HU AT PL

advanced therapeutics C.

advanced therapeutics R.

antibodies R.

antibodies C.

blood products R.

blood products C.

vaccine R.

vaccine C.

Involvement of PEI in EMEA Scientific Advices [Hum] for

Biomedical Medicinal Products



0

10

20

30

40

50

60

70

80

90

100

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Perc

en

t

0

10

20

30

40

50

60

70

80

90

100

Ab

so

lute

Nu

mb

er

EudraCT Clinical Trial Applications in the EU(3Q 2005 to 3Q 2008)



Somatic cell therapy MPs 3Q 2005 3Q 2006 3Q 2007 3Q 2008

(trials / original products) ( 25 / 13 ) ( 73 / 59 ) (132/112) (213/171)

cancer immunotherapy 3 23 45 70

cardio-vascular 4 17 31 44

skin/liver/lung/eye/diabetes/

intestine/bone TE 5 12 28 48

neurological 1 4 5 6

lymphohistiocytosis (HLH) – 1 1 1

AIDS – 1 1 1

infertility – 1 1 1

13 59 112



171

EudraCT Clinical Trial Applications in the EU(3Q 2005 to 3Q 2008)

Gene therapy/transfer MPs 3Q 2005 3Q 2006 3Q 2007 3Q 2008

(trials / original products) ( 19 / 9 ) ( 51 / 23 ) ( 69 / 35 ) (124 / 59)

cancer 4 13 20 29

cardio-vascular 2 3 4 6

metabolic diseases (diabetes) – – – 1

autoimmune diseases 1 2 2 4

HIV vaccine 2 2 2 7

infectious disease

(chronic Hepatitis C) – – 1 2

neuronal – 1 3 5

vaccines (monovalent, combi-) – 2 3 5

9 23 35 59





Procedures for tissue/cell-products at PEI Div 6(2004- 2Q/2008)

(without Therapeutic Tumor Vaccines)(without non-manipulated HSC)

centralised national

0 0

2

67

6

2

6 6

4

01

0

12

0

8

20

{59}

8

12

15

22

15

0

6

9

1110

00

4

01

0

5

10

15

20

25

2004

2005

2006

2007

2008

0

MAA

MP Development Phases and Scientific Advice

national SA

briefing meeting EMEA

ITF, GTWP/CPWP EMEA SA

Discussion of

scientific principles

& classification

Discussion of

specific questions for MAA

formal answered by CHMP

Discussion of

scientific principles,

development strategies

product specifications



From bench to bedside:

How much do we need to know?



Issues to be adressed for approval of cell-based MPs

Procurement

Transport

Manufacturing

Administration

Non-clinical



Transport

Clinical

CBMPs – Quality aspects



Starting material – How to guarantee „external“ control of cell sourcing?

✘ Limited time and amount of tissue available for testing

of acceptance criteria

✘ Control of donation:

Intensive donor screening must

substitute for virus inactivation

✘ Getting consent in time

✘ Banking and history of cell lines

✘ Training of procurement team for specific needs

✘ Microbiology of cell procurement

✘ Assure consistent isolation of cells/tissues

✘ Linking different traceability systems, e.g in hositals

2006/17/EC Selection criteria for donors based on…

risk evaluation related to application of

product and established criteria

Medical/behavioural history (questionnaire, interview)

Physical examination

Testing

HIV-1/-2 anti-HIV-1/2

HBV HBsAg

anti-HBc further tests when anti-HBc+ and HBsAg-

HCV anti-HCV-Ab

Syphilis validated specific

or non-specific test

HTLV anti-HTLV only for high-risk donors

RhD, HLA, Malaria „may be required“

CMV, Toxoplasma, EBV,

Trypanosoma cruzi

ANNEX II Laboratory tests for donors of tissues/cells (except reproductive cells)

-test on serum/plasma

-qualified/authorized lab

- validated tests

Also for autologous donors when cells are stored or cultured !

Technical requirements for the

donation, procurement and testing of human tissues and cells

Directive 2006/17/EC






Reagents, other materials, excipients – Where to get ?

– How to test?

– How control costs?

✘ Certificates for animal-derived reagents (eg, origin, TSE, adv. agents)

✘ Change to non-animal derived products not always

possible or may have major impact on product

✘ For many reagents no pharmaceutical grade available

✘ Identity testing on small batches, e.g. collagenase

Challenges in microbial safety of CBMPs

Sterility of source material can not be guaranteed

Comparabe to transfusion medicine where 0.2 to 0.5 %

of cellular blood components (Thrombocytes)

are bacterially contaminated, e.g. Staph. epidermidis

Skin as tissue source

Increasing incidence of multi-resistent hospital strains

(MRSA, Acenetobacter, Vancomycin-resistent Enterococci)

Non- sporocidal disinfection procedures

Source material cannot be sterilised

Final products cannot be sterilised

e.g. by heat, gas, γ-rays, filtration, 0.2 µm filters

Use of antibiotics only masks bacterial contamination,

concentration might be lower in patientPaul-Ehrlich-Institut


Sterility testing underlay “sampling error”

i.e. the potential result “The test sample is sterile!”

gives no significant information on the whole

volume of product/intermediate

Antibiotics in culture medium

Short shelf life of final product

Established methods for sterility testing are not always applicable:

- Conventional sterility testing (Pharm Eur (2.6.1.Sterility) takes14 day; turbidity

- Automated sterility testing (Pharm Eur 2.6.27) takes 7 days

Results are not available at time of release / application to patient




Limitations of Automated Culture Systems: Experiments at PEI

Growth of Pseudomonas fluorescensin BacT/Alert at 32°C, 34°C und 35°C

0,0

20,0

40,0

60,0

80,0

100,0

P. fluores.

32°C

P. fluores.

34°C

P. fluores.

35°C

Temperatur

Na

ch

we

isze

it (

h)

8x10E 5

8x10E 4

8x10E 3

8x10E 2

8x10E 1

8x10E 0

no growth at 36 and 34°C

T. Montag-Lessing, PEI

Sven Deutschmann, Roche Diagnostics




Consequences:

Need for a complex strategy in microbial safety of cell products

(taking over of experiences of transfusion medicine ?)

Need for specific assessment for product and manufacturing process as a

whole, including procurement

Need for development of novel reliable rapid test systems

Need for revision of current guidelines



Manufacturing – Product is the Process!

– Primary cells are not GMP grade!

✘ Ensuring consistency of final product

while allowing variability in some process

steps due to variability of primary cells

✘ Ensuring comparability upon process

changes / upscaling

✘ Process optimization automatisation sometimes not feasable

„Scale out manu-facturing“

training of staff

✘ In-process controls optimal tests: measure process variables

meaningful, realtime, rapid,

quantitative, objective, robust


How much „similarity“ do we need?



Example Cell culture expansion – Which parameters are critical / important?

– Which are needed / suitable as IPCs?

✘ Viability

✘ Population doublings, survival

✘ Morphology

✘ Confluency

✘ Functional stability / (de-) (re-) differentiation ?

✘ Senescence

✘ Genetic / epigenetic stability


http://www.biotissue-tec.com




Characterisation / Release Specifications

✘ Tumorgenicity (pre-neoblastic transformation, karyotype)

✘ Structural characteristics, if essential

✘ Stability

✘ ✘ Cell viability

✘ ✘ Identity (phenotypic and/or genotypic)

✘ ✘ Cell purity

✘ ✘ Impurities (product-/process-related, degradation products, adventitious agents)

✘ ✘ Potency

✘ ✘ Sterility

✘ Total cell number



✘ should be based on the intended biological effect

which should ideally be related to the clinical response

✘ can be in vitro or in vivo test

✘ can be surrogate marker

✘ can also be measured on mode of action (e.g. ectopic model)

✘ ideally in place when first IMD is produced

✘combination of assays may be needed during development

✘ markers for potency and purity should not be mixed

✘ reference to preclinical and clinical data may be needed

ICH Q6B: Potency is the quantitative measure of biological activity based on

the attribute of the product, which is linked to the relevant biological properties


✘ Need for on-site preparation step ?

✘ Need for „GMP-status“ at hospital ?

✘ logistics, critical time of delivery



Transport – How to keep the product „alive“ ?

✘ Fragility / short shelf life of cells and/or whole product

✘ Product is likely sensitive to temperature changes, light, vibration, pH shifts, ….

✘ Identification of a qualified shipping contractor

✘ Logistics at end user, e.g appropriate storage, cooling,…


Administration – Hospital as „final manufacturing facility“?

4.3. Non-Clinical Development

General aspects

– Conventional requirements of Dir 2001/83/EC for pharmacological

& toxicological testing may not always be appropiate; deviation

should be justified.

– Objectives of the non-clinical studies are to demonstrate proof-of-

principle, define the pharmacological & toxicological effects

predicitive of the human response.

– The goals of non-clinical studies include:

- provide information to select safe doses for clinical trials

- support route of administration & application schedule

- support duration of follow-up time

- identify target organs for toxicity

- identify parameters to monitor in patients



Issues to be adressed for approval of cell-based MPs

Procurement

Donor screening

Microbiology of procurement

Banking and history of cell lines

Traceability systemsTransport

Validation

Manufacturing

Antibiotics

Microbiological safety

Availability of GMP-grade materials

quality-related cell characterisation

(eg pre-neoblastic transformation, dedifferentiation)

Consistency

Valid predictive potency test

Robust fast release specifications

Administration

on-site preparation

logistics

Non-clinical

Selection of suitable (homologous)

animal models

evaluation of relevant function in vitro /in vivo

confined localisation

Biodistribution

secretion of other biologically active molecules

Tumorigenicity, immunogenicity Paul-Ehrlich-Institut


Clinical

ensure relevant function in

human microenvironment

validity of -dose finding

- endpoints

- comparators

long-term follow up

Cell-based Therapies – Progressive adjustment of regulatory

demands in the course of product development

Phase I

Phase II

Phase III

MAA

PreclinicalProcurement

authorisation

Manufact.

license

„Complete“

Clinical

QA, QC



fast evolving science and legislation

GMP

CBMPs - How to Deal with Challenges

Regulatory framework is (co)evolving constantly.

Keep track! Use expert counsel! Products and regulations might not fit together!

Interact early and constantly with regulatory bodies.

Prepare your questions precisely! Use data-driven approach!

Regulatory bodies will not do your product development!

Keep in mind: due to the novelty of products and regulations

regulatory procedures might move on slower than you expect.

Know your manufacturing process.

Keep it as simple as you can!

Install early an effective quality system!

Characterise your product as best as you can as early as you can.

Define potency! Think about consistency!

Prospectively think of comparability: Every change may have regulatory impacts!

Identify most relevant preclinical models.

Think prospectively of the clinical development program.

Highlight the advantages of your product compared to competitors.





Ralf Sanzenbacher






E-mail: [email protected]

Thank you for

your Attention,

and special thanks to

MAAaccepted

C. Schneider, PEI

T. Montag-Lessing, PEI


Germany



mailto:[email protected]

Documents

The new Regulation (EC)1394/2007 on Advanced Therapy … new... · 2015-04-15 · Human Tissues/Cells for Human Application incl. SCs excl. Blood Blood Components National Dir 2004/23/EC