CRED Course: Regulatory Challenges of Successfully Developing ATMPs

A Workshop on the Regulatory Challenges of Successfully Developing Advanced Therapy Medicinal Products 11 July 2017 TOPRA Office, London

9.00 9.30

Registration

TOPRA Introduction

Samantha Alsbury Head of Professional Development, TOPRA Julie Foulkes Freelance Regulatory Affairs Advisor

9.35

Welcome and Introduction

Chair: Julie Foulkes, Freelance Regulatory Affairs Advisor 9.40 Introduction to ATMPs • What are ATMPs…and what are not • ATMP classification • ATMP- Device combinations • Approved products • Assessment processes • Industrial landscape 10.30 CMC and Quality considerations for ATMPs – Part 1 11.00 Tea and Coffee break 11.15 CMC and Quality considerations for ATMPs – Part 2 Food for Thought (examples of ATMP challenges). • Defining the drug substance • Short shelf life products • Limited product quantities • TSE, CJD, and viral safety • Comparability • Process validation • EU legislation & guidance overview • Pharmacopoeial standards Module 1 & Module 3 guidance •

Alison Wilson Consultant Cell Data Services

Alexis Cockroft Biopharm CMC Regulatory Affairs GlaxoSmithKline

Alexis Cockroft Biopharm CMC Regulatory Affairs

12.00 Non clinical development of ATMPs • General requirements for ATMPs •

Michaela Sharpe Cell & Gene Therapy

Challenges with preclinical development

12.45 Discussion •

Delegates have the chance to share experiences and ask questions

13.00 Lunch Chair: Alexis Cockcroft, GlaxoSmithKline 14.00 Experience in Clinical Development of ATMPs • General requirements for ATMPs • Experience with ATMP clinical trials • Regulatory challenges of ATMP CTAs • GCP guidelines for ATMPs

Bridget Heelan PAREXEL International

14.45 Environmental Risk Assessments for GMOs in Clinical Trials • Classification of GMOs • CTAs and the diversity of requirements across the EU

Julie Foulkes Freelance Regulatory Affairs Advisor

15.15 Tea and Coffee Chair: Alison Wilson, Cell Data Services 15.30 Regulatory Challenges and Pitfalls •

Bj ӧ rn Carlsson

Non-clinical assessment and issues of relevant models • Experience to date with ATMPs • ATMP procedures • EMA advisory support – what does the future hold • Common issues with assessments

LÄKEMEDELSVERKET Medical Products Agency

16.15 Discussion •

Delegates have the chance to share experiences and ask questions

16.45 Close of Day

TOPRA Conferences and Courses 2017 Dates are subject to change and will be confirmed on www.topra.org , TOPRA courses for 2017 will include:

Date

Category

Course/conference

Location

15 June

CRED

SmPC, Patient Information Leaflet and Labelling

London, UK

27 June

Horizons

Dealmaking in a Changing Regulatory Landscape – Joint meeting with PLG

London, UK

6 July

Horizons

TOPRA Summit

London, UK

11 July

CRED

Regulatory Challenges of Successfully Developing ATMPs

London, UK

13 July

Basics

Basics of Medical Technology Regulatory Affairs

Dublin, Ireland

26-28 July

Masterclass

Design Development and Certification of Medical Devices

London, UK

8 August

Basics

Basics of Pharmaceutical Regulatory Affairs

London, UK

6-8 September

MSc Module

Module 2: Regulatory Strategy for a New Chemical Active Substance: Nonclinical Development

Chesham, UK

7 September

CRED

Drug-Device Combination Products

Malmö, Sweden

2-4 October

Symposia

Human Pharmaceuticals Symposium

London, UK

3-4 October

Symposia

Veterinary Symposium

London, UK

3-4 October

Symposia

Medical Devices Symposium

London, UK

11 October

CRED

Generics: Understanding the Regulatory Considerations

London, UK

13 October

CRED+ Workshop Seeking Scientific Advice

London, UK

18-19 October

CRED

Chemistry, Manufacturing & Controls

London, UK

6-8 November

Masterclass

Clinical Evaluation of Medical Devices

London , UK

8 November

Awards

Awards for Regulatory Excellence

London, UK

9-10 November

CRED+

Health Technology Assessment as Part of Regulatory Strategy

London, UK

13-17 November

Foundation

Introduction to Pharmaceutical Regulatory Affairs (MSc Module 0)

Prague, Czech Republic

22-23 November

CRED

Clinical Trials

London, UK

27-29 November

MSc Module

Module 4: Regulatory Strategy for a New active substance – Global Clinical Development

Chesham, UK

7 December

Basics

Basics of Pharmaceutical Regulatory Affairs

London, UK

13-14 December

CRED

Regulatory Operations

London, UK

November

Horizons

Paediatrics Update in collaboration with the European Commission

Brussels, Belgium

November/December Horizons

TOPRA joint meeting with the Heads of Medicines Agencies

EU

Continued overleaf

Key

Basics

Courses aimed at those who are exploring EU regulatory affairs and who are taking their first steps in the profession. These courses provide an overview of regulatory affairs (pharmaceutical, medical devices and veterinary medicines) and are also suitable for those working in associated areas, such as manufacturing and marketing, as well as support staff. Courses aimed at those who are establishing a regulatory foundation and who typically have 0–2 years experience in regulatory affairs. These include our residential Introductory courses held in Spring and Autumn and also our Fundamentals of the EU eCTD course. Continuing Regulatory Education and Development (CRED) courses are a series of one-day/two-day interactive workshops to enhance your knowledge in specific regulatory areas. They are suitable for those who are consolidating their regulatory competencies (2–5 years’ experience). The CRED+ courses focus on topics in greater depth and at a more advanced level and are aimed at those with more than 5 years’ experience who are driving their regulatory career. Masterclasses are 3-day workshops addressing specific regulatory subjects and are suitable for those who are at the stage of driving their regulatory career (5+ years’ experience). They are available as standalone courses or are taken as modules to form the MSc in Pharmaceutical Regulatory Affairs. Horizons conferences are open to all but are aimed at those who are at the stage of influencing the regulatory profession. They provide a forum for discussion and debate on current regulatory topics. Held since 2004, the annual TOPRA Symposium is a vibrant forum where representatives of industry and regulatory agencies come together to discuss and understand today’s regulatory issues and debate the future plans for regulation. The three symposia – pharmaceuticals, medical devices and veterinary medicines – are open to all those working in the regulatory profession.

Foundation

CRED

CRED+

Masterclass/ MSc

Horizons

Symposia

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ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

CRED A Successful ATMP Regulatory Development Programme

Introduction to ATMPs

11 July 2017

Alison Wilson CellData Services

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

1

Learning Outcomes

 Appreciation of background to ATMP Regulation

 Understanding of relationship to other EU legislation

 Understanding of definitions and classification

 Knowledge of differences in procedural aspects between ATMPs and other medicinal products

2

Overview

● What are ATMPs…and what are not ● ATMP classifications ● ATMP - Device combinations ● Approved products ● Assessment processes ● Other relevant legislation ● Industrial landscape

3

What are ATMPs

● Medicinal products – per 2001/83/EC ● Contain cells, tissues or genes ● Cells may be viable or non-viable

● Cells may be autologous, allogeneic or xenogeneic ● Excludes cell derivatives: products based on e.g.: – Growth factors – Proteins Not ATMPs

4

ATMP Regulation Overview

Defines ATMPs and extends 2001/83/EC

Tissue engineering products to be classified de jure as medicinal products – full provisions of mp framework to be applied Mandatory centralized marketing authorization

Post authorization follow up and risk management

Provides SME incentives

Amendment of Annex 1 to 2001/83/EC: specific data requirements for ATMPs (2009/120/EC)

Establishes an expert committee (CAT) for MAA assessment and scientific advice

5

ATMP Regulation: special processes

● Classification – Is product an ATMP? – What kind of ATMP? ● Certification – Assessment of quality and/or non-clinical data prior to MAA – SME only ● Risk-based approach – Opportunity to design development process – Justification for studies performed / omitted

6

ATMP Incentives

Article 16.2: ● Scientific Advice fee reductions of 90% (SME) ● SA fee 65% reduction (other ATMP developers) Article 19: ● MAA fee reduction of 50% if specific public health interest (SME & hospitals) ● First year post-authorisation fees also 50%

7

ATMP CLASSIFICATION

8

Gene therapy medicinal product (2001/83/EC Annex Part IV 2.1)

A biological medicinal product which has the following characteristics: • it contains an active substance which contains or consists of a recombinant nucleic acid used in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a genetic sequence • its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence

Gene therapy medicinal products shall not include vaccines against infectious diseases

9

Somatic Cell Therapy (2001/83/EC Annex Part IV 2.2)

A biological medicinal product which has the following characteristics: (a) contains or consists of cells or tissues that have been subject to substantial manipulation so that biological characteristics, physiological functions or structural properties relevant for the intended clinical use have been altered, or of cells or tissues that are not intended to be used for the same essential function(s) in the recipient and the donor and (b) is presented as having properties for, or is used in or administered to human beings with a view to treating, preventing or diagnosing a disease through the pharmacological, immunological or metabolic action of its cells or tissues

10

Tissue Engineered Product EC No 1394/2007 Article 2.1(b)

A product that: • contains or consists of engineered cells or tissues, and • is presented as having properties for, or is used in or administered to human beings with a view to regenerating repairing or replacing a human tissue

11

What is “engineered?”

Engineered” = cells or tissues that • Have been subject to substantial manipulation, so that their original biological characteristics, physiological functions or structural properties relevant for the intended regeneration, repair or replacement, are altered; OR • Are not intended to be used for

Autologous heterogeneous bone marrow stem cells

Non-manipulated

the same essential function or functions in the recipient as in the donor

For amyotrophic lateral sclerosis

Trophic factor secretion

 cells/tissues used for a different function are “engineered” and therefore regulated under the ATMP Regulation even if they have not been substantially manipulated

ENGINEERED

Neuron regeneration

TEP

12

Examples of processes not considered “substantial manipulation” (1394/2007/EC Annex I)

Cutting

• Cell separation • Cell concentration • Purification • Filtering • Lyophilisation • Freezing • Cryopreservation • Vitrification

Grinding

Shaping

Centrifugation

Soaking in antibiotic or antimicrobial solutions

Sterilisation

Irradiation

In vitro culture of cells is always considered to be manipulation = engineering

 Cell expansion is NOT included

13

Combined ATMP

EC (No) 1394/2007 Article 2.1(d) An ATMP that:

* incorporates, as an integral part of the product, one or more medical devices within 93/42/EEC or 90/385/EEC and * its cellular or tissue part must contain viable cells or tissues, or * its cellular or tissue part containing non-viable cells must be liable to act upon the human body with action that can be considered as primary to that of the device

ie the cells or tissues are the active substance

14

Definition - expanded

Integral part of the product

• Device is implanted with cells – not a syringe / infusion pump etc

One or more medical devices

• Meets legal definition of medical device in MDD or AIMD

• Article 2.2: default primary mode of action

Viable cells or tissues

• Pharmacological / immunological / metabolic actions of tissue/cells

Non-viable – primary action

15

Combined … or not?

Not Combined

Not Combined

Combined

Combined

Autologous fibroblasts and keratinocytes

Viable, autologous keratinocytes and melanocytes on acellular

Expanded endothelial

Expanded chondrocytes on synthetic biodegradabl e scaffold

co-culture seeded on transgenic porcine acellular

cells in porcine gelatin matrix

human dermal matrix

dermal matrix

Burns, chronic wounds

Wound healing

Cartilage repair

Vascular injury

16

ATMP Definition Defaults

Pharmacological, immunological or metabolic action of viable cells or tissues are considered as the principal mode of action of the product

ATMP containing both autologous and allogeneic cells shall be considered an allogeneic product

Products meeting definition of both SCT and TEP shall be considered a TEP

Products meeting definition of SCT or TEP and GT shall be considered a GT product

17

Classification decision steps

Is it a medicinal product

Does it contain genes, cells or tissues

GT? SCT? TE ?

Is it an ATMP

Does it contain scaffold, matrix etc

Is it a combined ATMP

18

ATMPs approved to date

Product

Drug Substance

Indication

Type of ATMP

Date

Chondro Celect

autologous selected chondrocytes

Cartilage repair

Tissue engineering

2009

Familial lipoprotein lipase deficiency

Glybera

alipogene tiparvovec

Gene therapy

2012

autologous activated blood mononuclear cells

Metastatic prostate cancer

Cellular immunotherapy

Provenge

2013

Tissue engineering (Combined)

MACI

autologous cultured chondrocytes

Cartilage repair

2013

Limbal stem cell deficiency

Holoclar

autologous corneal epithelial/stem cells

Tissue engineering

2015

Metastatic melanoma

Gene therapy

Imlygic

talimogene laherparepvec

2015

autologous CD34+ cells transduced with human ADA gene

Gene therapy

Strimvelis

ADA-SCID

2016

Somatic cell therapy

Zalmoxis

allogeneic T-cells & suicide gene

Adjunct to HSCT

2016

autologous spherical chondrocyte aggregates

19

Cartilage repair

Tissue engineering

Spherox

? 2017

ASSESSMENT PROCEDURES

20

Assessment Processes

● For MAA – centralised procedure mandatory ● Accelerated assessment, Conditional MA, adaptive pathways, PRIME, orphan route – all available ● Paediatric development requirements apply ● No difference from standard applications ● ATMP-specific options: – Pre-review of quality & safety: certification procedure – Risk-Based Approach to justify dossier content

21

Committee on Advanced Therapies

● Expert committee – scientific aspects related to ATMPs ● Pool of Community expertise ● Multi-disciplinary – Biology – Biotechnology – Surgery – Medical devices – Ethics – Patient representatives – Research / clinical representatives ● Provide draft Opinions to CHMP

22

EMA Procedures - to May 2017

MAA Procedure

#

Submitted

16

Positive Opinion

10

Negative Opinion

4

Withdrawal

4

Ongoing

2

Classification Requests

253

Certification Procedures

9

Scientific Advice Procedures

241

PRIME requests

12/31

Source: CAT Monthly Report May 2017

23

Clinical Trials

● Same process as other medicinal products ● VHP available ● Extended CTA assessment timescales in current directive and new Regulation procedures – Directive: 60 days + 30 + 90 (expert committee) – Regulation: 45 days + 50 days for Part I assessment ● Gene therapies: GMO assessment reviewed nationally by each MS

24

EU guidelines specific to ATMPs

ICH

Std MP

Gene

Cell

Ph Eur

25

Cell-based products guidelines (1)

Human cell-based medicinal products ● Over-arching guideline ● Multidisciplinary ● For MAA requirements ● Specific guidance on Annex Part IV requirements – Identity, purity, potency, biomaterials – Characterisation & validation – Non-clinical – Clinical – Pharmacovigilance & risk management

26

Cell-based products guidelines (2)

● Clinical development of TE products ● CJD risk ● Potency (cancer immunotherapy) ● Xenogeneic cells ● Reflection Paper: stem cells ● Reflection Paper: ACI products ● Safety & efficacy follow-up: risk management of ATMPs (including GT)

27

Gene Therapy Products Guidelines (currently 13)

● Quality, non-clinical and clinical aspects of medicinal products containing GM cells ● Quality, non-clinical and clinical aspects of gene therapy medicinal products ● Environmental risk assessment ● Design modifications ● AAV vectors ● Insertional mutagenesis risk ● Germline integration risk ● Virus shedding

28

OTHER LEGISLATION RELEVANT TO ATMPS

29

Quality and safety of human cells and tissues

● EU Cells & Tissues Directives ● 2004/23/EC … on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues ● All clinical use of human tissues subject to EU directive 2004/23/EC, except for: – tissues and cells for autologous use within the same surgical procedure – blood and blood components (Directive 2002/98/EC) – organs or parts of organs (Directive 2010/53/EU) ● Applies equally to autologous and allogeneic use

30

Implementing Directives under 2004/23/EC

Directive Coverage 2006/17/EC Donation, procurement, donor testing 2006/86/EC Processing, preservation, storage, distribution 565/2015 Single European Code 566/2015 Import of human tissue – equivalent standards

31

Overlap with ATMP Regulation

2006/17/EC

2006/86/EC

Human tissue product

565/2015/EU

566/2015/EU

Human cells/tissues

2006/17/EC donation, procurement, testing

2006/86/EC AEs, coding, traceability

ATMP

565/2015/EU

566/2015/EU

32

INDUSTRIAL LANDSCAPE

33

Industrial Landscape

● Who makes ATMPs…and why is this important? ● Significant proportion are hospitals / academic groups ● Issues with

– Access to information – Regulatory assistance – Access to SME incentives

● Translation to commercial development ● Cost for SME – even with fee reductions

34

Types of ATMP Developer - global

35

Source: House of Lords Science & Technology Committee Report July 2013

Clinical trials of advanced therapies

ClinicalTrials.gov, n=1342 (2014)

from: Heathman et al. Regen Med 2015. 10(1) 49-64

36

UK Clinical Trials 2016

70%

30%

Allogeneic

Autologous

63%

37%

Non-GM

GM

60%

40%

Research Ins

Industry

37

Source: Cell & Gene Therapy Catapult Clinical Trials Database May 2017 (amended)

UK Clinical Trials by indication

38

Source: Cell & Gene Therapy Catapult Clinical Trials Database May 2017

Learning Outcomes: Recap

 Appreciation of background to ATMP Regulation  Understanding of definitions and classification  Understanding of relationship to other EU legislation  Appreciation of development landscape and product types in clinic

39

Contact Details

Alison Wilson Principal Consultant ajwilson@celldataservices.co.uk +44 1430 801015 / +44 7939 667943

40

11 th July 2017

CMC and Quality Considerations of ATMPs

Alexis Cockroft

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

PART 1:

GENERAL REQUIREMENTS FOR ATMPS

(Quality/CMC)

EU legislation

Directive 2001/83/EC – Annex I, Part IV

Advanced therapy medicinal product - ATMP Regulation 1394/2007/EC

(a) ‘Advanced therapy medicinal product’ means any of the following medicinal products for human use:

— a gene therapy medicinal product ...,

— a somatic cell therapy medicinal product ...,

— a tissue engineered product ...

(d) ‘ Combined advanced therapy medicinal product ’ means an advanced therapy medicinal product that fulfils the following conditions:

— it must incorporate, as an integral part of the product, one or more medical devices...

— its cellular or tissue part must contain viable cells or tissues, or

— its cellular or tissue part containing non-viable cells or tissues must be liable to act upon the human body with action that can be considered as primary to that of the devices referred to.

Directive 2001/83/EC – Annex I, Part IV - Genetically Modified Cells

3.2.1.5. In the case of genetically modified cells, the starting materials shall be the components used to obtain the genetically modified cells, i.e. the starting materials to produce the vector, the vector and the human or animal cells. The principles of good manufacturing practice shall apply from the bank system used to produce the vector onwards.

Directive 2001/83/EC – Annex I, Part IV - Traceability

3.1. Specific requirements for all advanced therapy medicinal products A description of the traceability system that the marketing authorisation holder intends to establish and maintain to ensure that the individual product and its starting and raw materials, including all substances coming into contact with the cells or tissues it may contain, can be traced through the sourcing, manufacturing, packaging, storage, transport and delivery to the hospital, institution or private practice where the product is used, shall be provided. The traceability system shall be complementary to, and compatible with, the requirements established in Directive 2004/23/EC of the European Parliament and of the Council ( 1 ), as regards human cells and tissues other than blood cells, and Directive 2002/98/EC, as regards human blood cells .

Directives 2001/18/EC and Directive 2009/41/EC

Genetically Modified Organisms and Genetically Modified Micro-organisms

Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/220/EEC

Directive 2009/41/EC of the European Parliament and of the Council of 6 May 2009 on the contained use of genetically modified micro-organisms

[See later...]

EMA guidances overview

Cell and gene therapy guidances (EMA)

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/gener al/general_content_000298.jsp&mid=WC0b01ac05800862bd

Guideline: investigational medicinal products - EMA

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/05/WC500127370.pdf

Cell and gene therapy guidances (USA) - US FDA

http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegul atoryInformation/Guidances/CellularandGeneTherapy/default.htm

Pharmacopoeial standards

5.14. Gene transfer medicinal products for human use – Ph Eur

(No change for Ph Eur 9.2)

5.14. Gene transfer medicinal products for human use – e.g: GM cells

<1046> Cellular and Tissue- Based Products - US Pharmacopoeia

(No change for USP 40

<1047> Gene Therapy Products - US Pharmacopoeia

<1043> Ancillary Materials - US Pharmacopoeia

Ph Eur 5.2.12 Raw Materials - European Pharmacopoeia – General Text

Raw Materials – Other Resources

PAS 157: Evaluation of materials

of biological origin used in the

production of cell-based

medicinal products – Guide (EU

and US specific) – available

online as a free download

http://shop.bsigroup.com/forms

/PASs/PAS-1572015/

Structure of Module 3 for products containing genetically modified cells

Module 3 structure - accommodating a vector

Module 3 structure – 3.2.S.2.3 Control of Materials substructure

3.2.S.2.3 Control of Materials

1 Control of Source and Starting Materials of Biological Origin 2 Control of Source and Starting Materials of Non-Biological Origin 3 Gene Therapy Vector

3.1

General Information

3.2

Manufacturer(s)

3.3

Description of Manufacturing Process and Process Controls

3.4

Source, history, and generation of the cell substrate

3.5

Cell banking system, characterisation, and testing

3.6

Control of Critical steps and Intermediates

3.7

Process Validation and/or Evaluation

3.8

Manufacturing Process Development

3.9

Characterisation

3.10

Specification

3.11

Analytical Procedures (including dev)

3.12

Validation of Analytical Procedures

3.13

Batch Analyses

3.14

Justification of Specification

3.15

Reference Standards or Materials

3.16

Container Closure System

3.17

Stability

EU Module 1: Information for the MAA application form

Product Information - EU MAA

Invented name

Strimvelis

Common name:

autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence

(Drug Substance)

Immediate Packaging

bag (EVA)

Content

Patient specific up to 50 mL max

Pack size

1 or more bags each with 1 luer spike interconnector

Pharmaceutical Form

Dispersion for Infusion

Strength

1-10 million cells per mL

Route of Administration

Intravenous use

Standard Terms - EDQM - Pharmaceutical Dose Forms

Standard Terms - EDQM – container and closure

PART 2: FOOD FOR THOUGHT

(a few examples of ATMP challenges)

Strimvelis: Gene Therapy for ADA-SCID

Strimvelis Manufacturing Process (Gene Therapy for ADA-SCID)

Vector Manufacturing Process

All production at CMO (MolMed Spa.)

- Manufacturing site co-located with hospital/treatment site

Bone Marrow Extraction

CD34+ Cell Separation & Transduction Process

Patient Infusion

Real time release

30 Property of GlaxoSmithKline

Defining the drug substance

What is the Active Substance and Strength?

EU Directive 2001/83/EC:

Article 1, 3a. Active substance:

Any substance or mixture of substances intended to be used in the manufacture of a medicinal product and that, when used in its production, becomes an active ingredient of that product intended to exert a pharmacological, immunological or metabolic action with a view to restoring, correcting or modifying physiological functions or to make a medical diagnosis.

Article 1, 22. Strength of the medicinal product:

The content of the active substances expressed quantitatively per dosage unit, per unit of volume or weight according to the dosage form.

What is the Active Substance? - Genetically Modified cells – Gene Therapy

EU Directive 2001/83/EC, Annex I, Part IV

Specific Requirements Regarding Module 3

3.2. Specific requirements for gene therapy medicinal products

3.2.1.2. Gene therapy medicinal product containing genetically modified cells

...

The active substance shall consist of cells genetically modified by one of the products described in section 3.2.1.1 ...

3.2.1.1. ...

...nucleic acid sequence(s) or genetically modified microorganism(s) or virus(es) ...

Active Substance definition - Strimvelis

Proposed Active Substance

Description

Originally proposed:

Haematopoietic stem cells which contain the ADA transgene

Genetically modified CD34+ cells

Haematopoietic (multi- and oligo-potent) progenitor cells which contain the ADA transgene

Proposed by CAT/CHMP:

Genetically modified CD34+ cells:

CD34+ cells which contain the ADA transgene

Autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence

Non-genetically modified CD34+ cells:

CD34+ cells which do not contain the ADA transgene

Active Substance (continued)

The rationale:

The product is not only a gene therapy product but also a haematopoietic cell transplant. Efficacious treatment outcome therefore depends on two aspects

1) successful gene transfer and 2) successful haematopoietic cell transplantation.

For patient safety, successful haematopoietic cell transplantation is paramount at the time of treatment.

Short shelf life products

Guideline on Human cell-based medicinal products - EMA (EU)

4.2.4 Quality control 1. Release criteria

...If certain release tests cannot be performed on the active substance or finished product, but only on key intermediates and/or as in-process tests, this needs to be justified . In these cases an adequate quality control has to rise from the manufacturing process, supported by the results of the clinical studies. These exceptions may include the following: ...A complete release testing cannot be finalised before the product is administered to the recipient due to time restrictions (e.g. in case of autologous products, which are administered immediately after completion of the production and initial testing). However, a critical set of essential tests that can be performed in the limited time prior to clinical use must be defined and justified. Whenever feasible, retention samples should be stored for future analysis.

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003894.pdf

Quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells

Guideline text:

5.4. Quality Controls Release criteria

When the shelf-life of the product does not allow a complete program of control testing for release purpose, a reduced release testing program may be carried out. In such cases, the missing information at release level should be compensated by an appropriate in process testing and a more extensive process validation .... Such a reduced release testing program should be clearly described and justified. The absence of identity and potency testing is unlikely to be considered justifiable .

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/05/WC5001268 36.pdf

Real Time Release Testing (ICH Q8)

Real Time Release Testing:

The ability to evaluate and ensure the quality of in-process and/or final product based on process data, which typically include a valid combination of measured material attributes and process controls.

Control Strategy

..Enhanced understanding of product performance can justify the use of alternative approaches to determine that the material is meeting its quality attributes. The use of such alternatives could support real time release testing..

..Real time release testing can replace end product testing, but does not replace the review and quality control steps called for under GMP to release the batch.

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2 _Guideline.pdf

Real Time Release - Guideline on Real Time Release Testing (EMA)

Real Time Release Testing (RTRT): The ability to evaluate and ensure the quality of in- process and/or final product based on process data, which typically include a valid combination of measured material attributes and process controls (ICH Q8 (R)). Batch release: Approved RTRT may form a basis but more aspects need to be taken into account in the decision of a Qualified Person to release a batch. These aspects could include batch results of testing for an attribute not subject to RTR testing as well as specific GMP requirements. Application of RTRT to biological/biotechnological products Alternate approach to routine end product testing could be considered ....provided that it can be demonstrated that acceptable level would be maintained in the final product level. Product/process understanding, in-process control and/or attribute testing at an earlier step in the process are elements that can be used to justify the replacement of end product testing on a routine basis by RTRT. A justification based on a combination of routine testing and validation approaches is ... possible... In this situation, routine testing at an earlier step, before a purification step which has been demonstrated to appropriate clearance capability with regards to the given impurities, could also be used to justify the lack of end product testing of these quality attributes on a routine basis.

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/04/WC500125401.pdf

Strimvelis Summary of Product Characteristics

Shelf life 6 hours

4.4 Special warnings and precautions for use ...Stage two quality control results will only be available after the product has been infused

US Code of Federal Regulations - test completion prior to release

“No lot of any licensed product shall be released by the manufacturer prior to the completion of tests for conformity with standards applicable to such product,” (21 CFR 610.1), which include tests for potency, sterility, purity, and identity (21 CFR Part 610, Subpart B). These requirements apply to all biological products, including autologous and single patient allogeneic products, where a lot may be defined as a single dose.

http://www.ecfr.gov/cgi-bin/text- idx?SID=d631a6660ffb43b62ee30989f2771115&mc=true&node=pt21.7.610&rgn=div5#se21.7.610_11

http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guid ances/CellularandGeneTherapy/UCM243392.pdf

US – Example - Mycoplasma

Mycoplasma Due to the limited dating period of many ex vivo genetically modified cellular products, it is frequently not feasible for a sponsor to perform the recommended culture-based assay .. for release testing. In those cases, we recommend the use of polymerase chain reaction (PCR)-based mycoplasma assays or another rapid detection assay during product development. As part of your BLA, you should submit appropriate data to demonstrate that the PCR or alternative test has adequate sensitivity and specificity.

http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidan ces/CellularandGeneTherapy/ucm078694.pdf

http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidan ces/Xenotransplantation/ucm092705.pdf

Other Commercial ATMPs (EU)

Holoclar:

6.3 Shelf life

36 hours.

ChondroCelect (withdrawn):

6.3 Shelf life

48 hours.

Limited product quantities

Guideline on Human cell-based medicinal products - EMA (EU)

4.2.4 Quality control 1. Release criteria

...If certain release tests cannot be performed on the active substance or finished product, but only on key intermediates and/or as in-process tests, this needs to be justified. In these cases an adequate quality control has to rise from the manufacturing process, supported by the results of the clinical studies. These exceptions may include the following: ... The amount of available product is limited to the clinically necessary dose (e.g. due to very limited cell numbers at collection or low proliferation rates). The release of the product should be justified by the validation of the cell manipulation process and the in-process controls.

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003894.pdf

Guideline on Human cell-based medicinal products - EMA (EU)

4.2.5 Validation of the manufacturing process

..In case of limited sample sizes (e.g. autologous preparations for one single administration), it is recommended that a more extensive validation is performed with cell preparations of comparable characteristics but available in sufficient amounts for validation purposes.

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003894.pdf

Strimvelis Summary of Product Characteristics

4.2 Posology and method of administration The patient must be able to donate adequate CD34 + cells to deliver the minimum 4 million purified CD34 + cells/kg, required for manufacture of Strimvelis.

Posology The recommended dose range of Strimvelis is between 2 and 20 million CD34 + cells/kg.

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003894.pdf

TSE, CJD and viral safety

Note for guidance on minimising the risk of transmitting TSE

Note for guidance on minimising the risk of transmitting TSE

Minimising the risks of transmission of TSE is based upon three complementary parameters: — the source animals and their geographical origin, — nature of animal material used in manufacture and any procedures in place to avoid — cross-contamination with higher risk materials, — production process(es) including the quality assurance system in place to ensure product consistency and traceability . Risk assessment – ...the measures taken to manage the risk of transmitting animal TSEs via medicinal products represent risk minimisation rather than risk elimination. ..the basis for regulatory compliance should be based on a risk assessment, taking into consideration all pertinent factors as identified in this Note for Guidance

http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:52011XC0305(04)&rid=1

Raw Materials – TSE – Other Guidance

Legislation and Guidance

WHO Guidelines on Transmissible Spongiform Encephalopathies in relation to Biological and Pharmaceutical Products European Commission Decision 2007/453/EC of 29 June 2007, 2009/830/EC and subsequent amendment to 2007/453/EC (2012/111/EU), establishing the BSE status of Member States or third countries or regions thereof according to their BSE risk. EMA/CHMP/BWP/303353/2010 CHMP position statement on Creutzfeldt-Jakob disease and plasma-derived and urine-derived medicinal products (2011). EMA/CHMP/BWP/353632/2010 CHMP/CAT position statement on Creutzfeldt-Jakob disease and advanced therapy medicinal products (2011)

Viral safety

Guideline on Virus Safety Evaluation of Biotechnological Investigational Medicinal Products http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guidel ine/2009/09/WC500003795.pdf Q5A(R1) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Qu ality/Q5A_R1/Step4/Q5A_R1__Guideline.pdf {Gene and Cell Therapy products are not in scope but the principles are applicable at least in part}. • Cell line qualification: testing for viruses • Raw materials of biological origin • Testing for viruses in unprocessed bulk

• Validation of virus reduction • Virus safety risk assessment • Re-evaluation of viral safety during development

Guideline on the use of porcine trypsin used in the manufacture of human biological medicinal products

12. Regulatory Aspects

The Marketing Authorisation Holder/Applicant of the medicinal

product should have sufficient information on the trypsin to allow a

comprehensive risk assessment and provide a sufficient data

package to the competent authority for assessment. This should

include a description of testing methods and the stage at which

virus testing is performed, as well as the volumes and sensitivity of

the virus tests. Study reports validating virus reduction steps should

be provided according to Guideline CPMP/BWP/268/95. In the case

of a change of supplier of trypsin, data ...should be provided for the

new trypsin.

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/02/WC500162147.pdf

Note for Guidance on the use of bovine serum in the manufacture of human biological medicinal products

10. Dossier requirements for Marketing authorisation application/variations

All data relating to the content of the certificate required by the serum user, the identification of different sources, the tests and controls carried out on each batch of serum, the name of the company performing the controls, the criteria of acceptance or rejection of the batches by the serum supplier and the serum user should be included in the marketing authorisation dossier. A change in serum supplier or a change in any inactivation/removal process should be the subject of a variation for which appropriate comparability data for the drug substance / drug product will be required as appropriate... When changing from non-irradiated to irradiated serum or when a new irradiation plant (addition or replacement) is introduced, the variation application should also include relevant information on the virus validation study...

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/06/WC500143930.pdf

Other considerations – e.g. hypersensitivity

4.4 Special warnings and precautions for use

Strimvelis should be used with caution in patients with hypersensitivity to ...bovine serum albumin.

Holoclar: Patients with a known hypersensitivity to ... foetal bovine serum must not be treated

4.3 Contraindications

ChondroCelect: Hypersensitivity to ...bovine serum.

Comparability

Draft Guideline on Quality, non- clinical and clinical aspects of gene therapy medicinal products 4. Quality 4.4 Process development and process validation for drug substance and drug product ...Approaches to determine the impact of any process change will vary, depending on whether this is at the drug substance or drug product stage and with respect to the specific manufacturing process step concerned. It will also depend on the extent of the manufacturer’s knowledge and experience with the process and development data gained . Appropriate, and fully justified comparability studies according to the principles outlined in ICH Topic Q5E for biotechnological/biological products should be conducted in order to demonstrate comparability of the pre- and post-change product. The criteria for determining comparability of GTMP medicinal products after manufacturing changes should be fully justified.

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/05/WC5001870 20.pdf

ICH Q5E: Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process

1. INTRODUCTION 1.4 General Principles

The goal of the comparability exercise is to ensure the quality, safety and efficacy of drug product produced by a changed manufacturing process, through collection and evaluation of the relevant data to determine whether there might be any adverse impact on the drug product due to the manufacturing process changes. The demonstration of comparability ...mean that the quality attributes of the pre-change and post-change product are ... highly similar and that the existing knowledge is sufficiently predictive to ensure that any differences in quality attributes have no adverse impact upon safety or efficacy of the drug product. If a manufacturer can provide assurance of comparability through analytical studies alone, nonclinical or clinical studies ...are not warranted....Where the relationship between specific quality attributes and safety and efficacy has not been established, and differences between quality attributes of pre- and post- change product are observed, it might be appropriate to include a combination of quality, nonclinical, and/or clinical studies in the comparability exercise.

Guideline: comparability of cell-based medicinal products

CAT Workplan: Development of ATMP specific guidelines

Key objectives

• Development of a guideline on comparability of cell-based medicinal products

Activities in 2017-2019

CAT activities to achieve the objectives set for this area:

• Finalise a concept paper on the above mentioned guideline, to be published by end 4Q 2017

• Publication of the draft of the Guideline for external consultation by 4Q 2018

• Finalise the Guideline in 2019

http://www.ema.europa.eu/docs/en_GB/document_library/Work_programme/2017/05/WC500227375.pdf

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