NATIONAL PHARMACEUTICAL CONTROL BUREAU

MINISTRY OF HEALTH MALAYSIA

GUIDANCE DOCUMENT AND GUIDELINES FOR

REGISTRATION OF CELL AND GENE THERAPY PRODUCTS
(CGTPs) IN MALAYSIA

PREPARATION OF DRAFT GUIDANCE 1 March 2014

DISCUSSION/DISSEMINATION OF DRAFT GUIDANCE 28 January 2015

COLLATION OF FEEDBACK AND COMMENTS 26 June 2015 –

30 November 2015

FINAL GUIDANCE 30 December 2015

CONSIDERATION FOR ADOPTION 21 January 2016

1
 GUIDANCE DOCUMENT AND GUIDELINES FOR REGISTRATION
OF CELL AND GENE THERAPY PRODUCTS (CGTPs) IN
MALAYSIA

December 2015

NATIONAL PHARMACEUTICAL CONTROL BUREAU (NPCB)

Ministry of Health Malaysia
Lot 36, Jalan Universiti
46200 Petaling Jaya
Selangor Darul Ehsan.
Tel: +603-7883 5400
Facsimile: +603-7955 1030
Website: www.bpfk.gov.my
2
THIS GUIDANCE DOCUMENT IS ISSUED BY THE DIRECTOR OF
PHARMACEUTICAL SERVICES UNDER REGULATION 29, CONTROL OF
DRUGS AND COSMETICS REGULATIONS 1984. HE/SHE RESERVES THE
RIGHT TO AMEND ANY PART OF THE GUIDELINE WHICHEVER HE/SHE
DEEMS FIT.

All rights reserved.

No part of this document may be reproduced, stored in a retrieval system, or

transmitted, in any form or by any means, electronic, mechanical, microfilming,
recording or otherwise, without written permission from the Director of
Pharmaceutical Services, Ministry of Health, Malaysia.

3
FOREWORD BY SENIOR DIRECTOR OF PHARMACEUTICAL SERVICES
DIVISION, MINISTRY OF HEALTH, MALAYSIA

Development of biological medicines has been extremely rapid and the potential of
such products for improving health care on a global scale is immense. Cell and gene
therapies have been at the forefront of biotechnology research during the past
decade, providing for a cornucopia of new strategies for the treatment of diseases
such as immune-mediated chronic disease, some forms of cancer as well as for
repair and regeneration, and to this effect, many lives have been transformed.

The “Age of Cell Therapy” has arrived. With a robust pipeline of products in late
stages of clinical development and moving towards licensure whilst some products
already achieving regulatory approval, strongly indicates that the cell therapy
industry is poised to merge as a distinct healthcare sector. Cell therapy has the
potential to be the fourth pillar in health care, together with small molecules,
biologicals, and devices. Cell therapy fits within the large and even more diverse
regenerative medicines industry.

Regenerative medicines and cell-based therapies continue to engender bold

prognostications about how they could revolutionise healthcare. Living, delicate and
diverse cells are being incorporated as active agents and delivery for a broad range
of emerging therapeutic strategies. Stem cells represent seemingly limitless clinical
applications. Yet, along with this great promise come numerous challenges and
ground-breaking therapies cannot reach those who need them without successful
commercialisation. Their extreme intrinsic complexity in terms of substance,
characterization, manufacture, their dynamic mode of action, potential risks and the
“idiosyncrasies”, require us to perhaps think and act in new ways vis-a-vis a new
regulatory paradigm to ensure consistency, quality, safety and efficacy.

Gene therapies have travelled a difficult road so far, with a mixture of promise and
disappointment. But their story is far from over. Increasing evidence suggests that
gene therapy can provide long-term therapeutic effects for patients suffering from
genetic and complex disorders. Consequently, momentum in the field is building up,
resulting in the first gene therapy product licensure in the European Union in 2012.

The history of biopharmaceutical sector is one of continual invention and reinvention,

of regulation / business models that have adapted to weather uncertain product
features and shifting economic fortunes. Taking full advantage of the unique
properties of these cells and genes will require advances in or knowledge and
expertise of their inner workings as well as development of new approaches to their
large scale production and associated regulatory scrutiny and oversight. We must
also take time to orchestrate our efforts towards producing high quality talent,

4
regulation, deep expertise and up-skilling of evaluators / regulators to meet our
capacity building initiatives.

The regulatory framework for cell and gene therapy products (CGTPs) attempts to
address the unique characteristics of these products through a suitably adjusted set
of principles. CGTPs are subject to the same Investigational New Drug (IND) and
product registration / approval process as any other biologics. It is hoped that a
productive balance between the need to protect public health while enhancing
access can be attained.

The development of CGTPs guidance document and guidelines for registration in

Malaysia had engaged relevant stakeholders from various government agencies,
research/academic and treatment institutions, pharmaceutical industries,
manufacturers / importers via the formation of the Technical Working Group (TWG-
CGTPs), chaired by National Pharmaceutical Control Bureau (NPCB), Ministry of
Health Malaysia. The challenging task has been culminated in the publication of this
guidance document. The regulation fundamentally support good clinical care by
increasing safety and control, and enable good science by improving the quality and
reliability of data in addition to intensive monitoring for safety and efficacy and most
importantly is pragmatic. These outcomes are in everyone’s interest.

To complement Malaysia’s aim to achieve scientific excellence, innovations and to

fully exploit the potential of biotechnology, new research endeavours in personalized
medicines and stem cell therapy to promote new sources of growth and decrease
dependence on outside sources. Hence, under the Bioeconomy Transformation
Programme (BTP), Stem Cells and Regenerative Medicines has been identified as
one of the 10 Entry Point Projects (EPPs). I am convinced that we must strengthen
and enhance our efforts and partnerships at an international level - constantly review
our capacity building initiatives to meet targets and consistently build on niche areas
of specialties.

Biotechnology has opened up a new and exciting vista to regulators alike, towards
paradigm-shifting to healthcare field looking at areas of unmet need. This calls for a
plausible match of the regulatory oversight with biotechnological advancements and
innovations to ensure adequate quality, efficacy and safety of novel products. Thus, I
believe that regulatory science and regulation that is transparent, science based and
forward-looking is key. Science, even with broad-band, takes time and due diligence,
indeed, the regulation of CGTPs is still evolving, as befits a relatively young
developing field.

5
As reforms move forward, worldwide regulatory convergence and sharing of
knowledge and experience will be vital to effective regulation, since safety issues
have no borders. The success of CGTPs depends on putting our patient’s needs
and safety first as our primary objective of public health protection, together with
committed stakeholder and the government’s keen interest/support - a win-win
outcome is envisaged. In corollary, this will further enhance and promote a
dynamic and competitive knowledge-based economy for healthcare biotechnology
in Malaysia.

DATO’ EISAH A. RAHMAN

Senior Director of Pharmaceutical Services Division
Ministry Of Health, Malaysia
January 2015

6
FOREWORD BY CHAIRMAN OF TECHNICAL WORKING GROUP ON CELL AND
GENE THERAPY PRODUCT

It has been proclaimed that regenerative medicine would serve as the fourth pillar to
support healthcare needs, following the establishment of pharmaceutical, biological
and medical device products. The advent of cell and gene therapies as products of
translational science in regenerative medicine presents challenges to regulators
worldwide. Several cell therapy products have been approved for marketing, namely
ChondroCelect® in the European Union and Carticel® in the United States. The
European Medicines Agency (EMA) has granted a marketing authorisation for a
gene therapy product, Glybera®.

Talks on regulation on cell and gene therapy products (CGTPs) in Malaysia have
been gathering steam since 2009. A series of internal discussions within the National
Pharmaceutical Control Bureau (NPCB) led to the formation of a Technical Working
Group (TWG) in 2012, tasked to formulate strategies on regulation of CGTPs in
Malaysia. The TWG is represented by all stakeholders from government agencies,
research and treatment institutions, pharmaceutical product
manufacturers/importers, including those from the local cell based industry. The
discussions mainly addressed the Ministry of Health’s concern on unregulated use of
CGTPs leading to adverse health implications.

Although the regulation of CGTPs requires an inter-agency approach even within the
Ministry of Health and calls for arduous coordination among relevant agencies such
as NPCB and the Medical Practice and Development Divisions, I am immensely
proud that the challenging journey has now culminated in the publication of this
guidance document. As such, I hope the recommendations contained within this
document serve well as a future direction to regulators, product developers and
medical practitioners alike in facing the new era of regenerative medicine.

I wish to convey my deepest gratitude to the NPCB team led by the Section for
Biologic Product Registration for their laborious effort in formulating this document.
Many thanks to all stakeholders for their critical opinions throughout the drafting
process. Congratulations to all on a job well done!

TAN ANN LING

Director of Regulatory Pharmacy
National Pharmaceutical Control Bureau
Ministry of Health Malaysia
August 2015

7
NPCB EDITORIAL TEAM

PRIMARY AUTHOR

ARPAH BT. ABAS

Head of Biologics Section, until May 2015
Centre for Product Registration

SECRETARIAT

DR AZIZAH AB. GHANI

Head of Biologics Section, May 2015 – present
Centre for Product Registration

DR YVONNE KHOO SIEW KHOON

Senior Principal Assistant Director
Cell and Gene Therapy (CGTP) Unit
Biologics Section
Centre for Product Registration

AMIRUL MOHD MAHFUZ BIN MANNAN

Senior Assistant Director
Biologics Section
Centre for Product Registration

HAZUREEN BT. MOHD HALIMI

Assistant Director
Biologics Section
Centre for Product Registration

OTHER CONTRIBUTORS

SAMEERAH BT. SHAIK ABDUL RAHMAN

Head of Centre for Post Registration of Products

DR KAMARUZAMAN B. SALEH
Head of Centre for Investigational New Product

NORAISYAH MOHD SANI

Senior Principal Assistant Director
Centre for Post Registration of Products

KHAIRULANWAR BIN BURHANUDDIN

Principal Assistant Director
Centre for Investigative New Product

8
CHIONG YUH LIAN
Principal Assistant Director
Centre for Quality Control

FAZILLAHNOR BINTI AB. RAHIM

Principal Assistant Director
Centre for Compliance and Licensing

ACKNOWLEDGEMENTS

Members of Technical Working Group on Cell and Gene Therapy Products

(TWG-CGTPs)

Mr Tan Ann Ling Chairperson of TWG-CGTPs

Ms Anis bt. Talib NPCB
Ms Siti Aida bt. Abdullah NPCB
Dr Tajuddin bin Akasah NPCB
Ms Noorizam bt. Ibrahim NPCB
Mr Sulaiman b. Ahmad NPCB
Ms Rokiah Isahak NPCB
Ms Noorul Akmar Mohd Nur NPCB
Mr Wan Othman b. Wan Ismail NPCB
Ms Nurulfajar bt. Mohd Jamid NPCB
Ms Vidhya Hariraj NPCB
Ms Yam Pei Ching NPCB
Nurul Nashriq Md Hamsin NPCB
Mr Mohd Latiffi b. Abdul Aziz NPCB
Ms Syuhadah bt. Mohamed Hassan NPCB
Ms Fadhilah Hasbullah NPCB
Ms Nur Amani Shaari NPCB
Ms Tan Shin Yee NPCB
Ms Ong Kah Men NPCB
Dr Salmah bt. Bahri Director of Pharmacy Enforcement,
MOH Malaysia
Tn Hj. Mohd Zulkifli b. Abdul Latif Pharmacy Enforcement Division,
MOH Malaysia
Ms Astrina Abdul Salam Pharmacy Enforcement Division,
MOH Malaysia

Ms Nurhazwani Mohd Noor Pharmacy Enforcement Division,

MOH Malaysia
Mdm Abida Haq bt. Syed M. Haq Director of Pharmacy Practice &
Development, MOH Malaysia

Datin Dr Faridah Aryani bt Md. Yusof Pharmacy Practice & Development

9
 Division, MOH Malaysia
Haarathi Chandriah Pharmacy Practice & Development
Division, MOH Malaysia
Professor Datuk Dr A Rahman A Jamal Chairperson of National Stem Cell
Research and Ethics Subcommittee
(NSCERT)
Professor Dr Tunku Kamarul Zaman b. Director of University Malaya Medical
Tunku Zainol Abidin Centre (UMMC)
Professor Dato’ Dr Ruszymah bt. Hj. Universiti Kebangsaan Malaysia (UKM)
Idrus Medical Centre
Dr Angela Ng Min Hwei Head of Tissue Engineering Centre, UKM
Dr Yogeswaran A/L Lokanathan Tissue Engineering Centre, UKM
Dr Shiplu Roy Chowdhury Tissue Engineering Centre, UKM
Dr Ahmad Razid bin Salleh Director of Medical Practice Division,
MOH Malaysia
Dr Afidah Ali Medical Practice Division, MOH Malaysia
Dr Mohamed Ahsan bin Mohamed Ismail Medical Practice Division, MOH Malaysia
Dr Nur Ita Jusnita binti Rusli Medical Practice Division, MOH Malaysia
Dr Inderjeet Kaur Gill Medical Practice Division, MOH Malaysia
Dr Muzakiah binti Abd. Shukor Medical Practice Division, MOH Malaysia
Datin Dr Rugayah Bakri Medical Development Division,
MOH Malaysia
Dr Noor Aziah bt. Zainal Abidin Medical Development Division,
MOH Malaysia
Ms Noormah bt. Mohd Darus Medical Development Division,
MOH Malaysia
Dr Izzuna Mudla bt. Mohamed Ghazali Medical Development Division,
MOH Malaysia
Mr Yusuf b. Mohd Johari Medical Device Authority, MOH Malaysia
Dr Zubaidah Zakaria Institute of Medical Research (IMR),
MOH Malaysia
Dr Ezalia bt. Esa IMR, MOH Malaysia
Dr Noryati Abu Amin Director, National Blood Centre,
MOH Malaysia
Dr Roshida Hassan National Blood Centre, MOH Malaysia
Dr Nor Nazahah Mahmud National Blood Centre, MOH Malaysia
Dr Goh Pik Pin Director, Clinical Research Centre (CRC),
MOH Malaysia
Dr Sujatha Doraimanickam CRC, MOH Malaysia
Dr Lai Wei-Hong CRC, MOH Malaysia
Dr Mohd Akhmal Yusof CEO, Clinical Research Malaysia (CRM)
Dr Mohamed Ali b. Abu Bakar CRM
Mr Perumal a/l Chinaya CRM
Matron Wakia Wahab CRM
Dr Gopirajan a/l J. Rasamy CRM

10
Ms Puziah bt. Sulaiman National Biotechnology Division
(BIOTEK), Ministry of Science and
Innovation Malaysia (MOSTI)
Mr Paul Devaraj Michael BIOTEK, MOSTI
Mr Jay Padasian Malaysian Biotechnology Corporation
Sdn Bhd (BIOTECHCORP)
Ms Cindy Tai BIOTECHCORP
Ms Haniza Anom Hashim BIOTECHCORP
Ms Hayati Nasir BIOTECHCORP
Dr Lim Teck Onn President, Malaysia Association for Cell
Therapy (MACT)
Mr James Then MACT
Dr Vijayendran Govindasamy MACT
Ms Gan Ching Ching Malaysian Organisation of
Pharmaceutical Industries (MOPI)
Ms Noor Azlina Abdul Rahman MOPI
Ms Vanessa Shalini Daniel MOPI
Ms Alice Chee Pharmaceutical Association of Malaysia
(PhAMA)
Ms Pn Long Siew Mei PhAMA
Ms Janice Tan PhAMA

11
IN APPRECIATION:
FOREWORD BY PRIMARY AUTHOR OF GUIDANCE DOCUMENT

Guidance document is meant to provide assistance to applicants/marketing

authorization holders ( M A H ) on how to comply with the governing acts and
regulations. It also clearly outlines the regulatory framework and registration
requirements and/or process with the necessary guidelines to applicants/marketing
authorization holders

Guidance document also provides assistance to stakeholders on how

National Pharmaceutical Control Bureau’s (NPCB) mandates and objectives
should be implemented in a manner that is fair, consistent and effective. It is
important to note that NPCB reserves the right to request information or material,
or define conditions not specifically described in this document, in order to ensure
the safety, efficacy or quality of a therapeutic biologic product including Cell and
Gene Therapy Products (CGTPs). NPCB is committed to ensure that such
requests are justifiable and that decisions are clearly documented.

For the purpose of this document, t h e t e r m C e l l a n d G e n e T h e r a p y

P r o d u c t s (CGTPs) will be used. These include somatic cell therapy products,
tissue engineered products and gene therapy products as well as combined products.

It is universally agreed that CGTPs have an enormous potential of revolutionizing

therapy. CGTPs show great promise and offer ground-breaking new treatment
opportunities for diseases, for regenerative and replacement medicines, thereby
targeting many unmet medical needs.

The key benefits of regulating CGTPs separately under this framework will:
 safeguard public health and patient protection
 ensure the level of regulation applied matches the level of risk posed by
specific products (tiered risk-based approach)
 provide a more flexible framework to respond to changes in technology
 provide regulatory requirements that are unique to CGTPs which is cross-
boundary in nature. Hence, call for integrated regulatory oversight for quality,
efficacy and safety of the product
 reduce the ambiguity about what should be included or excluded from the
regulation.

12
The purpose of this guidance document is:
 to outline the concept and basic principles of CGTPs;
 to introduce the registration framework and guidelines to be applied;
 to provide applicants with a “user guide” for the relevant scientific data
and information, in order to substantiate the claim quality, safety and efficacy
of the product.

Due to the unique and diverse nature of cell and gene therapy products therefore –
they do not lend themselves to a “one size fits all” concept of product development
and regulation. Each product is unique and merits attention.

It is important to work together with regulatory authority in the course of product

development, but in the case of CGTPs it is imperative. In cognizance, that
stakeholders may have limited capacity to navigate the required regulatory
procedures, approach, compliance and expectations. Our experience demonstrates
that transparent and open dialogue with all relevant stakeholders is key to put in
place a robust and pragmatic regulatory framework in this emerging field whilst
creating and promoting a patient-centred approach.

As such, I hope the information and guidance contained within this document serve
well to assist and harness the complexity as well as future direction to regulators,
product developers and medical practitioners alike in facing the new era of
regenerative medicine.

ARPAH BT. ABAS

Head of Biologics Section, NPCB (until May 2015)
January 2015

13
SOME CONTENTS IN THIS DOCUMENT HAVE BEEN EXTRACTED FROM THE
FOLLOWING REFERENCES:

1. Guidance for industry: Guidance for human somatic cell therapy and gene
therapy (US FDA, March 1998)
2. Guideline on human cell-based medicinal products (EMEA/CHMP/410869/06)
(EMA, January 2007)
3. Reflection paper on classification of ATMPs (EMA, April 2012)
4. Draft Guidance for Industry and FDA Staff: Minimal manipulation of human
cells, tissues, and cellular and tissue-based products (U S FDA, December
2014)
5. Annex 2 Manufacture of biological medicinal substances and products for
human use, PE 009-11 (Annexes) (PIC/S, March 2014)
6. Guidelines for the clinical translation of stem cells (ISSCR, December 2008)
7. Moore WA and Bermel J. Cell therapy manufacturing (Bioprocess
International, March, 2014)
8. Lee MH, Au P, Hyde J, et al. Translation of regenerative medicine products
into the clinic in the United States: FDA perspective (Translational
Regenerative Medicine, 2015)
9. MACT. About Malaysian Cell Therapy Patient Registry (MCTPR). Available at:
https://mact.org.my/reg_about_mctpr.html . Accessed on 17 October 2014

14
ABBREVIATIONS

ACTD ASEAN Common Technical Dossier

BWP Biologics Working Party
CMC Chemistry, Manufacturing and Controls
CHMP Committee for Medicinal Products for Human Use
CDCR Control of Drugs and Cosmetic Regulations
CGTP Cell and Gene Therapy Product
CT Cellular Therapies
CTP Cell Therapy Product
DCA Drug Control Authority
DNA Deoxyribonucleic Acid
ERA Environmental Risk Assessment
ESC Embryonic Stem Cell
EU European Union
EMA European Medicines Agency
GMO Genetically Modified Organism
cGMP current Good Manufacturing Practice
cGTP current Good Tissue Practice
GMTP Gene Modified Therapy Product
GTP Gene Therapy Product
hESCs human embryonic stem cells
HSC Haematopoietic Stem Cells
HTA Health technology assessment
ICH International Conference of Harmonisation
iPSCs induced Pluripotent Stem Cells
IND Investigational New Drug
INN International Non-proprietary Names
MCB Master Cell Bank
MOH Ministry Of Health
MSCs Mesenchymal Stromal/Stem Cells
NCE New Chemical Entity
NRA National Control Authority
NPCB National Pharmaceutical Control Bureau
PK/PD Pharmacokinetic/Pharmacodynamic
Ph. Eur. European Pharmacopeia
PIC/S Pharmaceutical Inspection Convention and Pharmaceutical
Inspection Co-operation Scheme
PSUR Periodic Safety Update Reports
QC Quality Control
QWP Quality Working Party
RM Regenerative Medicines
SC Stem cells
US FDA United States Food and Drug Administration
RMP Risk Management Plan
WCB Working Cell Bank

15
 WHO World Health Organisation
TABLE OF CONTENTS

1.0 INTRODUCTION 18
2.0 REGULATORY FRAMEWORK 19
2.1 Legal basis = INTRODUCTION 19
2.2 About this framework 21
2.3 Guiding principles 22
3.0 SCOPE 22
4.0 DEFINITIONS 24
4 Cell therapy products
4.1 24
4.2 Gene therapy products 26
4.3 Combined products 27
4.4 Cell-based immunotherapy 28
5.0 ORGANISATION OF DATA/DOSSIER = start from here 28
6.0 RISK ANALYSIS OF CELL AND GENE THERAPY PRODUCTS 29
(CGTPs)
7.0 RISK CLASSIFICATION OF CELL THERAPY PRODUCTS 31
7.1 Class I: lower risk cell therapy products 31
7.2 Class II: higher risk cell therapy products 33
7.3 Matrix on regulatory framework of cell therapy products 34
8.0 QUALITY ASSURANCE FOR CGTPS 36
PART I. GENERAL REQUIREMENTS 37
9.0 CHEMISTRY, MANUFACTURING AND CONTROL (CMC) 39
9.1 Starting and raw materials 41
9.2 Cell banking system 44
9.3 Characterisation 46
9.4 Manufacturing process 46
9.5 Manufacturing process validation 48
9.6 Quality control 49
9.7 Stability 52
9.8 Container closure system 53
9.9 Product traceability 53
9.10 Summary on CMC data requirements 54
10 PRE-CLINICAL STUDIES 55
11 CLINICAL STUDIES 57
12 LABELLING REQUIREMENTS 63
13 POST-AUTHORISATION REQUIREMENTS 65

16
PART II. ADDITIONAL REQUIREMENTS ON 68
XENOTRANSPLANTATION
PART III. ADDITIONAL REQUIREMENTS ON GENE THERAPY 73
PRODUCTS
14 ANNEX: ADDITIONAL REFERENCES ON CGTP 78
REGULATION

17
1.0 INTRODUCTION

Intensified research in the field of regenerative medicine (RM) over the last
decades have accelerated our understanding of stem cell biology, and
developmental, morphological and physiological processes that govern tissue
and organ formation, maintenance, regeneration and repair following injuries.
Although there are still gaps in current scientific knowledge, early concepts of cell
therapy have been successfully translated into clinical practice. The utilisation of
bone marrow transplants for haematological malignancies has been practiced for
almost half a century. In addition to stem cells from the embryos, foetal tissues,
amniotic membrane and umbilical cord, some multipotent adult stem cells have
been identified within specific niches in human tissues and organs (e.g. bone
marrow, heart, adipose tissues).

Stem cell-based therapies offer the possibility to restore damaged or lost cells. In
addition, the use of genetically modified stem cells as delivery vehicles also offers
great promise in correcting inherited genetic defects. Nevertheless, the
development of Cell and Gene Therapy Products (CGTPs) present unique
regulatory challenges different from traditional biotechnology and
biopharmaceuticals, some of which are listed as follows:

 Unlike biotechnology products which are mostly purified proteins of cells,

CGTPs contain living and functional cells
 The boundary-crossing nature of CGTPs are subject to a wide variety of
regulatory oversights to encompass product development and
administration in the clinical setting
 The use of CGTPs posts some difficult-to-appraise risks, such as
tumourigenicity, immunogenicity, in vivo migration of transfused cells and
reversibility of administration in the event of an intolerable reaction
 In addition to the requirements of current Good Manufacturing Practice
(cGMP), the principles of current Good Tissue Practice (cGTP) need to be
applied in the quality assurance of a CGTP.

In consideration of the unique challenges of CGTP regulation mentioned above,

the Malaysian CGTP regulation framework has been formulated based on sound
science and international best practices modelled from benchmarked regulatory
authorities. It applies several levels of regulation on products based on the risks
associated with their use. The framework also allows some flexibility in
accommodating emerging RM technologies.

18
This guidance document should be read together with its accompanying Good
Tissue Practice Guideline published by the Centre for Compliance &
Licensing, 2nd Edition, December 2015.

In summary, the guidance document is intended to guide the development and

assessment of CGTPs in Malaysia. As scientific knowledge and technology in RM
are still maturing, this will serve as a living document, evolving further in line with
updates in scientific knowledge and experience. It is hoped that accrued
experience in CGTP registration will allow NPCB to optimally match its guidelines
and policies to the genuine risks and benefits associated with CGTPs. Ultimately,
we aim for a safe and effective translation of novel cellular and gene therapies for
numerous genetic and degenerative disorders in humans.

2.0 REGULATORY FRAMEWORK

2.1 LEGAL BASIS = Laws of Gov.

As Cell and Gene Therapy Products (CGTPs) are presented as having properties
for medical purposes – treating or preventing diseases in human beings, or that
they may be used in or administered to human beings with a view of restoring,
correcting or modifying physiological functions by exerting principally
pharmacological, immunological or metabolic action, they are classified as
medicinal products. CGTPs fit within the meaning of medicinal products under the
Sale of Drugs Act 1952: Control of Drugs And Cosmetic Regulations 1984 [P.U.
(A) 223/84]. And in accordance to the statutory provisions CGTPs would be
classified as biological products. Thus, the essential aim is to safeguard public
health through assurance of products’ quality, efficacy and safety.

This document i s co n s i s t e n t a n d i n t e g r a t e d w i th t h e e xi s t i n g
l e g i s l a t i ve f r a m e w o r k . H e n ce , i t should be read in conjunction with the
relevant sections of the Control of Drugs and Cosmetic Regulations 1984
(CDCR 1984) and the relevant sections of other applicable NPCB guidance
documents and guidelines, as listed below (available at http://www.bpfk.gov.my):

a. Drug Registration Guidance Document (DRGD), First Edition – January

2013, including Guidelines on registration of biologics, DRGD (Appendix 3)
b. Guideline for Submission of Analytical Method Validation Documents
(NPCB)
c. Malaysian Guidelines for the Conduct of Bioavailability and Bioequivalence
Studies (NPCB, September 2000)
d. Malaysian Guidelines for Good Clinical Practice, 3rd Edition (MOH, October

19
 2010)
e. Malaysian Variation Guideline for Pharmaceutical Products (NPCB, 2013)
f. Guidance Document on Foreign GMP Inspection (NPCB, August 2014)
g. Guidance Note for Biological Products Manufacturing Facility Establishment
in Malaysia (NPCB, May 2015)
h. Malaysian Guideline for Application of Clinical Trial Import Licence and
Clinical Trial Exemption, Sixth Edition (NPCB, October 2014)
i. Annex 1, Part 11 – A Guide Manual for Adverse Event Reporting (NPCB)
j. The ASEAN Common Technical Dossier (ACTD) for the Registration of
Pharmaceuticals for Human Use (ASEAN, September 2002)

In addition, the boundary-crossing nature of many of the CGTPs and applications

are subject to a wide variety of regulatory oversights. Thus, the following Ministry of
Health (MOH), Malaysia Acts and Guidelines are also applicable and complement
the CGTP regulatory framework:

a. Private Healthcare Facilities and Services Act 1998 (Act 586)

b. Guidelines For Stem Cell Research And Therapy 2009
MOH/P/PAK/177.08(GU)
c. National Standards For Stem Transplantation 2009
MOH/P/PAK/188.09(BP)
d. National Guidelines For Haemopoietic Stem Cell Therapy 2009
MOH/P/PAK/179.09(GU)
e. National standards For Cord Blood Banking And Transplantation 2008
MOH/P/PAK/131.07(BP)
f. Checklist For Research On Stem Cells and cell-based Therapies (NSCERT
2009)
g. Guidelines On Importation And Exportation Of Human Tissue And/Or Body
parts (CDC 2006)
h. Medical Device Act (2012) (Act 737)

The CGTPs guidance document and guidelines for registration was developed
based on similar fundamental concepts and scientific principles of established
international regulatory framework. Hence, the document should be read in
conjunction with other relevant/applicable international guidelines referenced in this
document. One may refer to 14. ANNEX for other relevant guidelines by World
Health Organization (WHO), International Conference on Harmonisation (ICH),
United States Food and Drug Administration (US FDA), European Medicines
Agency (EMA), Therapeutic Goods Administration (TGA), etc.

20
2.2 ABOUT THIS FRAMEWORK

The regulatory framework aims to provide a clear and predictable pathway for
CGTPs based o n internationally benchmarked regulations. NPCB strives to
emulate the examples set by better established regulatory authorities such as
those cited above, thus it has deemed that it shall not “reinvent the wheel”, rather
adopt and adapt the regulatory guidance and guidelines from these agencies as
appropriate for local use.

This document provides information for manufacturers, applicants, healthcare

professionals and the general public on legal arrangements in Malaysia for the
registration CGTPs.

This framework lays down specific rules on registration and its data requirements
[Chemistry, Manufacturing Control (CMC), nonclinical and clinical], supervision,
risk management plan (RMP) and pharmacovigilance of CGTPs. Included are
some regulatory procedures and guidelines in new areas such as current Good
Tissue Practice (cGTP).

The cross-boundary nature CGTPs involves a multidisciplinary approach;

therefore its full control will also be subject to various other regulations
(authorities), hence an integrated oversight is imperative, as follows:

 The clinical use/medical procedure of the product will be under the ambit
of Medical Development Division and Medical Practice Division of the
Ministry of Health, Malaysia
 The device element of such products must comply with the Medical Device
Act and regulations under the ambit of Medical Device Authority (MDA) of
Malaysia, and
 NPCB will ensure the medicinal product’s quality, efficacy and safety.

Only one agency (NPCB/MDA) will take charge of a product registration at any one
time. There will be no joint evaluation involving both agencies unless due to
extraordinary circumstances. An application for product classification shall be
submitted to NPCB and assignment will depend on the primary mode of action /
principle mechanism of action as claimed. For products not clearly defined as a
drug/cosmetic or a medical device, assignment will be referred to the Medical
Device – Drug-Cosmetic Interface (MDDCI) Product Classification Committee,
jointly held by NPCB and MDA. Please refer to the Guideline for Registration of
Drug-Medical Device and Medical Device-Drug Combination Products, First
21
Edition, November 2015 and Section 1.4 Drug Registration Guidance
Document (DRGD), First Edition – January 2013 for more information.

The framework is based on a risk-management system approach, i.e. different

levels of regulations are applied to CGTPs based on the risks associated with their
use. Applying the risk-based approach throughout all stages of a product’s
lifecycle, from conceptualisation through tissue selection and collection, to its
release and clinical use is essential for ensuring optimum product quality, efficacy
and safety.

2.3 GUIDING PRINCIPLES

The primary objective of CGTP regulation is to safeguard public health and

patient safety. CGTPs should meet the same s t r i n g e n t standards on quality,
safety and efficacy, as o f any other biological products. In regul ating
C GTPs, we und erta ke a cautiou s sci ence-base d ap pro ach bal anced
ag ainst mitiga ti ng unn ece ssary admini stra ti ve co sts to the prod uct
de velo per.

Finally, our experience demonstrates that a transparent and open dialogue with all
relevant stakeholders is t h e key to put in place a robust and p r a g m a t i c
regulatory framework in this emerging field whilst promoting a patient-oriented,
innovative and favourable regulatory environment.

3.0 SCOPE

This multidisciplinary guideline will address development, manufacturing and

quality control as well as nonclinical and clinical development of CGTPs which
include somatic cell therapy, tissue engineering and gene therapy products as
defined in this document. This guideline is intended for products entering the
registration process at NPCB. However, the principles laid down in the guideline
should be considered by applicants entering into clinical trials as well.

Cellular-based medicinal products discussed in this document have the following

characteristics:
 They contain viable human cells of allogeneic or autologous origin
undergoing a manufacturing process
 They may be combined with non-cellular components
 The cells may be genetically modified

22
Although this document does not cover non-viable cells and cellular fragments
originating from human cells, the underlying scientific principles may be applicable
if the manufacturing process of a CGTP involves their use.

The following are included in the framework:

 Human stem cells

 Human tissue therapy products (e.g. skin, cardiovascular, ocular,
musculoskeletal tissues)
 Human cellular therapy products (e.g. cartilage cells, pancreatic islet cells,
cultured skin cells, haematopoietic stem/progenitor cells derived from
peripheral and cord blood)
 Genetically modified cellular products.
 Cell-based cancer vaccines and cell-based immunotherapies
 Dendritic cells, lymphocyte-based therapies, cell-based therapies for cancer,
peptides, proteins.

The following are not included in the framework:

 Fresh viable human organs, or parts of human organs, for direct donor-to-
host transplantation.
 Fresh viable human haematopoietic stem/progenitor cells for direct donor-
to-host transplantation for the purpose of haematopoietic reconstitution.
 Labile (fresh) blood and blood components (e.g. fresh frozen plasma)
 Unprocessed reproductive tissues (e.g. sperm, eggs, embryos for in vitro
fertilization (IVF) and other assisted reproductive technology procedures)
 Secreted or extracted human products (e.g. milk, collagen)
 Samples of human cells or tissues that are solely for diagnostic purposes in
the same individual
 In vitro diagnostic devices

The inclusion and exclusion lists are not self-contained. The lists may be amended
as required.

For other types of stem cell product/therapy not within the scope of this
framework, please refer to:
a. National Standards For Cord Blood Banking And Transplantation January
2008 MOH/P/PAK/131.07(BP)
b. National Guidelines For Haemopoietic Stem Cell Therapy July 2009
MOH/P/PAK/179.09 (GU)
c. National Standards For Stem Cell Transplantation: Collection, Processing,
23
 Storage And Infusion Of Haemopoietic Stem Cells And Therapeutic Stem
Cells, July 2009 [MOH/P/188.09(BP)]

The regulatory framework on CGTPs is broadly divided into three parts: cell
therapy, xenotransplantation, and gene therapy. Cellular therapeutics that
incorporate gene repair or genetic modification must adhere to regulatory
guidelines set forth for both cell therapy and gene therapy products.

In Malaysia, an application to administer an unregistered product may be obtained

from the Director-General of Health / Senior Director of Pharmaceutical Services.
This pathway can apply to CGTPs for compassionate use. For application
procedures, please refer to the website of Pharmaceutical Services Division at
http://www.pharmacy.gov.my/v2/ms/entri/permohonan-memperolehi-
menggunakan-ubat-memerlukan-kelulusan-khas-ketua-pengarah-kesihatan-
malaysia.html .

For CGTPs indicated in rare diseases, an application for Orphan Product status
may be submitted to NPCB. As the establishment of an Orphan Product
registration pathway is underway, NPCB will publish more information on Orphan
Product registration on its website (http://www.bpfk.gov.my) in the near future. At
present, some information is available in Section 5.1.4 Drug Registration
Guidance Document (DRGD), First Edition – January 2013.

4.0 DEFINITIONS = no need heading. For introduction.

4.1 CELL THERAPY PRODUCTS

Somatic cell therapy is the administration to humans of autologous, allogeneic, or

xenogeneic living non-germline cells, other than transfusable blood products for
the purpose of treating, preventing or diagnosing a disease.

Cells can be self-renewing stem cells, more committed progenitor cells or

terminally differentiated cells exerting a specific defined physiological function.

Stem cells (SC) are natural occurring cells in the body that have the ability to
divide and produce a range of different cell types, pertinent to growth and repair
after an injury.

The guideline is relevant to all products using stem cells as starting material. The
final product may consist of terminally differentiated cells derived from stem cells,
or undifferentiated stem cells, or even a mixture of cells with varying differentiation

24
profiles.

For the purpose of this document, stem cells include the following:

a. Embryonic stem cells

b. Adult or somatic stem cells
i. Haematopoietic progenitor/stem cells (HSCs);
ii. Mesenchymal stromal/stem cells (MSCs)
iii. Tissue-specific progenitor/stem cells
c. Induced pluripotent stem cells (iPSCs)

Embryonic stem cells are pluripotent and have the capacity to differentiate to
virtually every cell type found in the human body. Human embryonic stem cells
(hESCs) can be characterised by a distinct set of cell surface markers, as well as
marker genes for pluripotency. hESCs, when transplanted into a permissive host
form teratomas, benign tumours consisting of various cell types derived from all
three germ layers; endoderm, mesoderm and ectoderm. hESCs can be
differentiated in vitro using either external factors in the culture medium, or by
genetic modification. However, in vitro differentiation often generates cell
populations with varying degree of heterogeneity.

Haematopoietic stem cells (HSCs) are a specific class of tissue-specific stem

cells. They can give rise to differentiated cells of all haematopoietic lineages,
myeloid and lymphoid, either in the haematopoietic bone marrow or in the thymus.
These stem cells are also found in the placental and cord blood at birth in
concentrations similar to levels found in adult bone marrow. In the adult body,
HSCs are localised in the red bone marrow and found circulating at a lower
frequency in the peripheral blood. They may also be found at low frequency in
other tissues (liver, spleen and muscle) but their origin and relevance for normal
haematopoiesis remains to be fully determined. HSCs are mobilised to the blood
compartment after treatments with intensive chemotherapy and/or growth factors.

Mesenchymal, stromal/stem cells (MSCs) are primarily derived from bone

marrow stroma or adipose tissue. Additionally, MSCs have been isolated from
numerous other tissues, such as retina, liver, gastric epithelium, tendons, synovial
membrane, placenta, umbilical cord and blood. MSCs are defined by adherence to
plastic, specific surface antigen expression and multipotent differentiation
potential. They are lineage-committed cells as they can differentiate towards
mesenchymal lineages, mainly adipogenic, osteogenic and chondrogenic cell
lineages. Under appropriate culture conditions in vitro differentiation to tenocytes,
skeletal myocytes, astrocytes and neurons has been described.

25
Tissue-specific progenitor/stem cells have a limited differentiation capacity and
normally produce a single cell type or a few cell types that are specific to that
tissue (e.g. tenocytes, myocytes, astrocytes).

Induced pluripotent stem cells (iPSCs) are artificially generated stem cells.
They are reprogrammed from somatic adult cells such as skin fibroblasts to re-
acquire both the stemness and differentiation capacity of self-renewing embryonic
stem cells. iPSCs share many features of hESCs; they have self renewing
capacity, are pluripotent and form teratomas. Increasingly iPSCs are being
produced from different adult cell types. Their differentiation capacity seems to be
dependent on the cell type and age of the cells from which the iPSCs were
reprogrammed. There is a current knowledge gap with respect to alterations of
cell-specific regulatory pathways, differences in gene expression and in epigenetic
control. These characteristics may result in tissues chimerism or malfunctioning of
the cells.

NOTE:
Product containing or consisting exclusively of non-viable human or animal cells
and/or tissues, which do not contain any viable cells or tissues and which do not
act principally by pharmacological, immunological or metabolic action, shall be
excluded from this definition.

4.2 GENE THERAPY PRODUCTS

A gene therapy medicinal product means a biological medicinal product:

a. which 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; and
b. its therapeutic, prophylactic or diagnostic effect relates directly to the
recombinant nucleic acid sequence it contains, or to the product of gene
expression of this sequence.

Gene therapy products shall not include:

 vaccines against infectious diseases

 *chemically synthesised nucleic acids (e.g. RNA, DNA, oligonucleotides)

The final medicinal product may contain as an integral part a medical device or an
active implantable medical device.

26
When the genetic manipulation is ex vivo on cells that are then administered to the
patient, this is also a type of cell therapy or also known as gene-modified cellular
products and must adhere to regulatory guidelines set forth for both gene therapy
and cell therapy products.

NOTE:
i) A chemically synthesised nucleic acid is synthesised from relatively short
fragments (building blocks) of nucleic acids with defined chemical structure.
The fragments are sequentially coupled to the growing oligonucleotide chain
in the order required by the desired sequence of the product. Synthetic
nucleic acids are typically single-stranded DNA or RNA molecules around
15–25 bases in length.
ii) A recombinant nucleic acid contains a sequence usually consisting of
combination between original nucleic acids with foreign nucleic acids; where
foreign nucleic acids are usually synthesised and amplified through
polymerase chain reactions (PCR).

4.3 COMBINED PRODUCTS

A combined product means 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
non-viable cells that act upon the human body with an action that can be
considered as primary to that of the devices referred to.

A product can be composed of different categories of regulated articles: Device-

biologic, biologic-drug-device (not biologic-biologic, etc). They can be physically or
chemically combined, co-packaged or packaged separately but cross-labelled.

Products containing both a somatic cell component and another drug or device
component in the final product will be considered and managed as combination
products.

Please refer to the Guideline for Registration of Drug-Medical Device and

Medical Device-Drug Combination Products, First Edition, November 2015
and Section 1.4 Drug Registration Guidance Document (DRGD), First Edition
– January 2013 for more information.

27
4.4 CELL-BASED IMMUNOTHERAPY

Cell-based immunotherapy aims at treating patients by stimulating their immune

system using autologous or allogeneic cells. Immunotherapy of cancer is based on
an immune response targeted against tumour-specific/tumour associated
antigen(s), leading to destruction of malignant cells. The targeting of interactions
between the immune system and the tumour constitute a complex approach of
which the precise mechanisms of action are often not fully understood.

In the scientific literature, cell-based immunotherapy products for the treatment of

cancer are sometimes called cell-based tumour vaccines or cell-based cancer
vaccines.

This guidance document covers viable cell products for cancer-immunotherapy

from autologous or allogeneic origin, consisting of e.g. whole tumour cells or
autologous dendritic cells loaded with tumour antigens, all intended to induce
tumour-specific cytotoxicity although the immunological pathway may differ
between products. Tumour-specific cells intended for adoptive transfer (i.e. passive
immunisation strategies) are also included, for example ex-vivo primed T-cells.
Some principles outlined in this document may also be applicable to tumour cell
lysates.

The cells may be chemically treated or genetically modified in vitro to immortalise

them or to express certain gene products like growth factors or tumour antigens. If
the medicinal product is to be considered as a gene therapy medicinal product,
further guidance can be found in the Note for Guidance on the Quality,
Preclinical and Clinical Aspects of Gene Transfer Medicinal Products
(CPMP/BWP/3088/99, EMA, April 2001).

5.0 ORGANISATION OF DATA/DOSSIER = important.

As the majority of cell therapy products are unique, the manufacturer must
understand both the science behind the specific cell product and the regulations in
order to successfully communicate with the authorities. Though the regulations are
written in general terms to be applied to all cell therapy products, they can be
tailored to an individual product with good communication and sound, data-driven
scientific justification.

As regards to the amount/kind of data requirements for a CGTPs application,

the “one size fits all” approach cannot be applied. This is due to the wide
spectrum of molecular complexity among the various products concerned.

28
Although stem cells share the same principle characteristics of cell-renewal
potential and differentiation, stem cell-based products are extremely diverse, i.e.
do not constitute a homogenous class. Thus, the requirements to demonstrate
safety and efficacy of C G T P s are essentially product class-specific or even
product specific.

To investigate the use of CGTPs in a local clinical trial, an application that reports
data from pre-clinical studies on the likely safety and efficacy of the investigational
product must be filed at NPCB. An approval for a Clinical Trial Import Licence
(CTIL) or a Clinical Trial Exemption (CTX) is mandatory before an unregistered
CGTP is administered to human trial subjects in Malaysia.

To register a CGTP, an application for product registration must be filed at NPCB.

Such approvals require sufficient data that the investigational product is of
acceptable quality, and is safe and effective to humans.

The data for submission are organised according to the ASEAN Common
Technical Dossier (ACTD) format. Most CGTPs will require conduct of clinical
trials prior to its marketing authorisation. Exceptions to this rule may include lower
risk haematological products that qualify as being minimally manipulated, perform
the same basic function in the donor as the recipient (homologous use), not to be
combined with other agents and not have a systemic effect. Such products will be
regulated clinically under the Medical Practice/Development Divisions, Ministry Of
Health Malaysia. They do not require pre-market approval and are regulated by
site registration including establishment of cGTP.

6.0 RISK ANALYSIS OF CELL AND GENE THERAPY PRODUCTS (CGTPs) =

important

“Risk” is defined as “a potential unfavourable effect that can be attributed to the

clinical use of CGTPs and is of concern to the patient and/or to other populations
(e.g. caregivers and offsprings)”.

“Risk factors” are defined as “qualitative or quantitative” characteristics that

contribute to a specific risk following handling and/or administration of CGTPs”.
Aspects that should be taken into account when identifying risk factors include, but
are not limited to: origin of cells or tissues (autologous vs. allogeneic), ability of
cells to proliferate and differentiate, ability to initiate an immune response (as
target or as effector), level of cell manipulation (in vitro vs. ex vivo expansion,
activation, genetic manipulation), aspects of manufacturing process, non-cellular
components, mode of administration (ex vivo perfusion, local, systemic) and

29
duration of exposure (short-term or permanent). In addition, the use of products
that are “banked, transported, or processed in facilities with other cellular or tissue-
based products” increases the risk of contamination or damage and may affect the
infectivity, virulence, or other biologic characteristics of adventitious agents in the
tissue. Furthermore, the clinical use of the CGTPs should be considered when
identifying risk factors. Patient-, disease-, and medical procedure-related risk
factors may contribute to the specific risks associated with a CGTP.

The risk-based approach is defined as a strategy aiming to determine the extent of

quality, nonclinical and clinical data to be included in the registration dossier, in
accordance with the scientific guidelines relating to the quality, safety and efficacy
of the products.

For the purpose of classification and control of cell therapy products in this
framework, processing is defined as any activity performed other than recovery,
donor screening, donor testing, storage, labelling, packaging, or distribution, such
as testing for microorganisms, preparation, sterilisation, steps to inactivate or
remove adventitious agents, preservation for storage, and removal from storage.

With regards to processing, the terms “minimal manipulation” is defined as follows:

Minimal manipulation means:

a. For structural tissue: processing that does not alter the original relevant
characteristics of the tissue relating to the tissue’s utility for reconstruction,
repair or replacement
b. For cells or nonstructural tissue: processing that does not alter the
relevant biological characteristics of cells or tissues.

The following processes are generally considered as minimal manipulation: cutting,

grinding, shaping, centrifugation (including the addition of an appropriate
anticoagulant), soaking in antibiotic or antimicrobial solutions, sterilisation,
irradiation (depending on dose), cell separation/concentration/purification, filtering,
lyophilisation, freezing, cryopreservation, vitrification. It should be pointed out that
this list is non-exhaustive, and any other manipulations can be considered as
minimal manipulation, based on scientific considerations.

Examples of substantial manipulation are cell expansion (culture), genetic

modification of cells, and differentiation with growth factors. If information does not
exist to show that the processing meets the definition of minimal manipulation, the
processing will be considered to be “more than minimal manipulation”.

30
Typically, minimally manipulated products (commonly defined as cells maintained
in culture under non-proliferating conditions for short periods of time, normally less
than 48 hours) require less burdensome characterisation and control than cell
products subjected to extensive manipulations ex vivo.

Cells and tissues are considered ‘engineered’ if they have been subjected to
substantial manipulation, so that their biological characteristics, physiological
functions or structural properties relevant for the intended regeneration, repair or
replacement are achieved.

For examples of structural tissue and cells or nonstructural tissues, and examples
of minimal/ more than minimal manipulations for each tissue type, refer Draft
Guidance for Industry and FDA Staff: Minimal manipulation of human cells,
tissues, and cellular and tissue-based products (December 2014).

In essence, for a cell/tissue to be considered as minimally manipulated, data will

need to be provided to support that the manufactured tissue/cell fulfils the definition
of minimal manipulation (as stated in the earlier part of this section).

7.0 RISK CLASSIFICATION OF CELL THERAPY PRODUCTS = no need much

info.

The risk-based approach to CTPs regulation means products that present greater
risk of adverse clinical outcome require more and better control, and hence more
stringent regulation and oversight. Thus, two classes/categories of products have
been identified:

7.1 CLASS I: LOWER RISK CELL THERAPY PRODUCTS = what is it, what
does it mean. Can put on table.

For lower risk products, the regulatory framework focuses on minimising the risk of
transmission of infectious diseases. A product eligible for regulation as Class I is
not subjected to premarket review requirements or approval. However, the product
must be listed at the practitioner’s premises. The product is further regulated by: (i)
site/facility licensure and listing by the Medical Practice Division under the purview
of the Private Healthcare Facilities and Services Act 1998 (Act 586) (ii) donor
screening and testing (iii) Good Tissue Practices (please refer to National
Pharmaceutical Control Bureau, Ministry of Health: Good Tissue Practice
Guideline, 2nd Ed., December 2015) (iv) labelling (v) adverse event reporting and;
(vi) inspection and enforcement.

31
To be a Class I CTP, the product must meet all four of the following criteria:

a. It is minimally manipulated (not activated, encapsulated, expanded ex vivo,

or genetically modified)
b. It is intended for homologous use* only as determined by
labelling/intended use and advertising
c. Its manufacture does not involve combination with another
drug/article/device, except for water, crystalloids, or a sterilising, preserving,
or storage agent (not raising new clinical safety concerns for the CTP)
d. It does not have a systemic effect and is not dependent upon the metabolic
activity of living cells for its primary function; or if it has such an effect, it is
intended for autologous use

*Homologous use means the replacement or supplementation of a recipient’s

cells or tissues with a CTP that performs the same basic function(s) in the recipient
as the donor. A CTP is generally considered to be for homologous use when it is
used to repair, construct, replace, or supplement:
 Recipient cells or tissues that are identical (e.g. skin for skin) to the donor
cells or tissues, and perform one or more of the same basic functions in the
recipient as the cells or tissues performed in the donor; or
 Recipient cells that may not be identical to the donor’s cells, or recipient
tissues that may not be identical to the donor’s tissues, but that perform one
or more of the same basic functions in the recipient as the cells or tissues
performed in the donor.

This basically means cells or tissues are used clinically in a manner that is
essentially the same as the natural endogenous function that it performed.

Some e.g. of homologous use:

 A heart valve is transplanted to replace a dysfunctional heart valve. This is
homologous because the donor heart valve performs the same basic
function in the donor as in the recipient of ensuring unidirectional blood flow
within the heart.
 Pericardium is intended to be used as a wound covering for dura mater
defects. This is homologous use because the pericardium is intended to
repair or reconstruct the dura mater and serve as a covering in the recipient,
which is one of the basic functions it performs in the donor.

32
Some e.g. of non-homologous use:
 using CD34+ HSCs in repairing heart function
 using adipose or bone marrow MSCs to treat neurological conditions
 using an adipose-derived MSC product as a bone graft substitute for the
repair, replacement, or reconstruction of musculoskeletal defects 
 using a human amniotic membrane product for bone tissue replacement to
support bone regeneration following surgery to repair or replace bone
defects or other orthopaedic indications.

The document entitled Draft Guidance for Industry and FDA Staff: Homologous
use of human cells, tissues, and cellular and tissue-based products (October
2015) may be referred.

7.2 CLASS II: HIGHER RISK CELL THERAPY PRODUCTS

If a cell therapy product does not meet all the four criteria in Class I, then the
product will fall under Class II. A Class II product is “highly processed”, used for
other than normal function, is combined with non-tissue components, or is used for
metabolic purposes”. It is regulated as a biologic product. The evaluation for
CTIL/CTX approval and product registration requires sufficient data demonstrating
that the product is safe and effective in humans. Both cGTP and cGMP are
required. The product dossier should follow the ACTD format. Please refer to
NPCB’s Drug Registration Guidance Document – Appendix 3: Guidelines on
Registration of Biologics, First Edition, January 2013 for general information
and requirements for registration of biologic products in Malaysia. For CTIL/CTX
requirements, please refer to Malaysian Guideline for Application of CTIL/CTX, 6 th
Edition (NPCB, 2015).

In the clinical development of a Class II product, the quality and scientific

evaluation must be adequate to permit an evaluation of the product’s effectiveness
and safety. Prior to clinical development phase, manufacturing description and
pre-clinical pharmacology/toxicology data must sufficiently characterise product
quality and safety.

For a combination cell therapy product, proof must also be provided on the drugs
and devices used having met the requirements of the relevant legislations. As
currently envisioned – most, if not all, stem cell based therapies will be considered
as medicinal product and would be subject to this framework.

Note:
NPCB reserves its full jurisdiction on assignment of product classes – this means
33
that all classification activities must be conducted with the agreement of NPCB. In
addition, a risk-based classification approach should be adopted, i.e. product
presumed to present the highest level of risk until demonstrated otherwise.
7.3 MATRIX ON REGULATORY FRAMEWORK OF CELL THERAPY
PRODUCTS = no need.

The following figures summarise the regulatory framework of CGTPs, and include
information on relevant local authorities other than NPCB and their processing
timelines.

Figure 1: Clinical trial approval pathway for CGTPs

* CTIL/CTX shall only be issued once ethical and DCA approval has been
obtained
CTIL = Clinical Trial Import Licence
CTX = Clinical trial Exemption
MOH = Ministry of Health
MREC = Medical Research and Ethics Committee
IRB = Institutional Review Board
IEC = Institutional Ethics Committee
NSCERT = National Stem Cell Research and Ethics Subcommittee
34
Figure 2: Cell therapy registration pathway for Class II products = no need.

PIC/S cGMP = Pharmaceutical Inspection Co-operation Scheme

HTA = Health Technology Assessment
BPF = Bahagian Perkhidmatan Farmasi
CKAPS = Cawangan Kawalan Amalan Perubatan Swasta
MDA = Medical Device Authority

Figure 3: Cell therapy registration pathway for Class I products

35
8.0 QUALITY ASSURANCE FOR CGTPs = important

Cell based therapies are inherently challenging to current Good Manufacturing

Practice (cGMP) compliance due to their human origin and associated problems in
providing a mechanistic dose-related mode of action for their intended clinical use.
The quality of a cell based product depends heavily on its manufacturing process.
Therefore, standardised procedures to be followed strictly for all steps are
absolutely necessary. The processing environment is a common source of
microbiological contamination and should be controlled to minimise this risk and to
prevent growth of contaminants. Poor control of production processes can lead to
the introduction of adventitious agents or other contaminants, or to inadvertent
changes in the properties or stability of the biological product that may not be
detectable in final product testing.

Therefore, the manufacture of cellular therapy products should be in compliance

with the principles of current Good Manufacturing Practices (cGMP). The
Pharmaceutical Inspection Convention/Scheme (PIC/S) cGMP regulations
comprise basic requirements applying to all products as well as annexes with
detailed requirements for special types of products. Of particular relevance to
CGTPs are:

 Annex 1: Manufacture of Sterile Medicinal Products

 Annex 2: Manufacture of Biological Medicinal Products for Human Use
 Annex 11: Computerised System
36
  Annex 13: Manufacture of Investigational Medicinal Products
 Annex 14: Human Blood and Plasma Products
 Annex 15: Qualification and Validation

In addition to the requirements of current Good Manufacturing Practices (cGMP),

the principles of current Good Tissue Practices (cGTP) need to be applied in the
quality assurance of a CGTP. For cGTP requirements, refer to Good Tissue
Practice Guideline published by the Centre for Compliance & Licensing, 2 nd
Edition, December 2015.

PART I. GENERAL REQUIREMENTS

A risk-based approach will be taken in determining the extent of the quality, non-
clinical and clinical data to be included in the dossier. The risk analysis should
cover the whole development and risk factors considerations including:

a. The origin of the cells

b. Their ability to proliferate, differentiate or initiate an immune response
c. The level of cell manipulation
d. The combination of cells with bioactive molecules or structural materials
e. The level of integration of nucleic acid sequences or genes into the genome
f. Long term functionality
g. The risk of oncogenicity
h. The mode of administration or use
i. The nature of gene therapy product
j. The extent of replication competence of viruses or microorganisms used in
vivo

The general requirements of a CGTP dossier are as shown in the following table:

37
Table 1: CGTP registration requirements

General Requirements of cGTP, cGMP, GCP

Class I II

Novel Cell and Gene Therapies

Pre-Market Cell Products Exempted from Complete CMC, Pre-Clinical &
Review/Approval Marketing Authorisation Clinical Data

Compliance with GMP Only products with current

Statement on compliance/
for human and blood manufacturing licence will be
GTP (listing of manufacturer)
tissue standards accepted

CMC & Pre-Clinical evaluation

Investigational Product

GCP Clinical Trials

38
 Marketing Monograph/product
New Biologic Product
Authorisation profiling

Active surveillance
Post Marketing Routine Pharmacovigilance
(Patient Registry)

9.0 CHEMISTRY, MANUFACTURING AND CONTROL (CMC) = important

It is imperative to develop appropriate quality management systems for the entire

“needle-to-needle” process from collection to transplant, including donation,
procurement testing, coding, processing, preservation, storage and distribution of
the cells.

All manufacturing steps need to be conducted in a controlled aseptic environment,

in accordance with the requirements of Annex 2 Manufacture of biological
medicinal substances and products for human use, PIC/S March 2014.
Sterility is a fundamental test requirement for cellular products. Since the product
relies on the biological activity of living cells, none of the common sterilisation or
virus elimination/inactivation steps can be performed. In addition, tight
specifications regarding freedom from adventitious agents in the source cells, all
materials used in the process, as well as in the final bulk and end products need to
be applied.

As biological processes may display inherent variability, quality risk management

(QRM) principles are particularly important to develop a control strategy across all
stages of manufacture to minimise variability and reduce contamination.

Also, sufficient information is required to assure the proper identification, safety,

quality and purity of the cell product. In general, the cGMP requirements for
CGTPs are illustrated in the following table.
39
Table 2: Illustrative guide to manufacturing activities for CGTPs
Type and Example Application of cGMP to manufacturing steps shown in grey
source of product
material
Human and/or Gene therapy: Manufacture Ex vivo Formulation,
animal sources genetically vector and cell genetic filling
modified cells purification and modification of
processing cells,
Establish
MCB, WCB or
primary cell lot
Somatic cell Establish MCB, Cell isolation, Formulation,
therapy Donation, WCB or culture combination, fill
procurement primary cell lot purification,
and testing of combination
starting tissue / with non-
cells cellular
components
Tissue Initial Cell isolation, Formulation,
engineered processing, culture combination, fill
products isolation and purification,
purification combination
Establish MCB, with non-
WCB or cellular
primary cell lot components
Animal source: CGTPs Collection of Cutting, mixing, Isolation and Formulation,
non-transgenic immunosera plant, organ, and /or initial purification filling
tissue or fluid processing
Virus or bacteria/ Viral or Establishment Cell culture Inactivation Formulation,
40
fermentation/ bacterial and and/or when filling
cell culture vaccines maintenance of fermentation applicable,
MCB, WCB, isolation and
MVS, WVS purification
Biotechnology Gene therapy Establishment Cell culture Isolation, Formulation,
fermentation/ vaccines (viral and and/or purification, filling
cell culture and non-viral maintenance of fermentation modification
vectors, MCB, WCB,
plasmids) MSL, WSL

Increasing GMP requirements

MCB = Master Cell Bank
WCB = Working Cell Bank
MVS = Master Virus Seed
WVS = Working Virus Seed

Once a cell or tissue product has been manufactured, a controlled process must
be in place for review and release preferably before distribution of the product.
However, a conditional release for shipping and transplant may be permitted where
required to achieve desired clinical effect, as accompanied by additional controls
are in place based on detailed risk assessment, including for e.g. statistical
analysis, trending information and in-process microbial contamination data.

The adage that quality cannot be tested into a product is particularly true for
CGTP. It is expected that as a product transitions from one developmental phase
to the next (pre-clinical, clinical, licensure) the control of the manufacturing and
testing process will become more stringent. Likewise, the release process must
become more robust.

The following information should be included in the CMC section of a CGTP

product dossier, to be organised in accordance with the ACTD – Part II
format.

9.1 STARTING AND RAW MATERIALS = important.

As CGTPs are complex products, the source, origin and suitability of biological
starting and raw materials (e.g. cryoprotectants, feeder cells, reagents, culture
media, buffers, serum, enzymes, cytokines, growth factors) should be clearly
defined. The identification of all starting materials should be in compliance with the
requirements appropriate to its stage of manufacture.

In all aspects of sourcing, banking and preparation of cell cultures, the principles of
41
Good Cell Culture Practice should be observed, the fundamentals of which are
summarised below:

 All raw materials of human and animal origin must be stringently sourced
and qualified based on product and process-related requirements and
acceptance criteria
 All raw materials derived from humans and animals must be assessed and
tested based on risk of adventitious agent introduction (e.g. microbial
contamination, other cell line contamination) in the manufacturing process of
CGTPs
 The authenticity, provenance and genotypic/phenotypic characteristics of
the source cells must be demonstrated
 The stability and functional integrity of the cells in extended in vitro passage
must be monitored
 Variation in physical culture parameters (e.g. pH, temperature, humidity, gas
composition) which can significantly influence the performance and viability
of cells and should be specified with established tolerances, and relevant
equipment calibrated and monitored
 Any culture reagents prepared in the laboratory should be documented,
controlled for quality and released against an established specification
 Care should be taken to minimise manipulations in the in vitro processing of
cells to improve process consistency.

Qualification of source cells = summarise

The sources of donor cells:

a. Patient’s own cells (autologous cell products)

b. Cells from another human being (allogeneic cell products)
c. Cells derived from animals (xenogeneic cell products)

Regardless of the source, the following principles generally apply:

 The initial procurement of cell should always be conducted using sterile

techniques and universal precautions to minimise the risks of contamination,
infection and pathogen transmission
 The transport of human tissues and cells to the manufacturing site must be
controlled, with documentary evidence of adherence to the specified storage
and transport conditions at the manufacturing site
 For products where production batches are frequently small the risk of
cross-contamination where cell preparations from different donors with
42
 various health statuses should be controlled under defined procedures and
requirements
 The risk of infectious disease transmission from starting materials to the
product recipient during their passage along the supply chain must be
assessed, with particular emphasis on TSE, mycoplasma, endotoxin, donor-
specific viruses, and appropriate microbiological screening profile based on
the country of donor origin
Please refer Requirements for Registration of Blood Products in
Appendix 3: Drug Registration Guidance Document, First
Edition, January 2013 for relevant checklists to be filled
 The quality management system must allow all raw materials including
tissues and cells to be traced from donor to recipient, and vice versa.

In the case of an allogeneic donor, these additional principles apply:

 Medical history and health status of the donor should be investigated for
potential further risks to the recipient
 The importance of matching for histocompatibility antigens (HLA Class I
and/or II and perhaps minor antigens in some cases) between donor and
recipient should be addressed and typing procedures and acceptance
criteria to be provided
 As characterisation of multiple donor mixtures may be challenging, the
establishment of a single master cell source may mitigate variability.
Nevertheless, all cell lots must be appropriately characterised.

Organ/tissue dissociation

The procedure to obtain the cells from the organ/tissue must be described (with
respect to the type of enzyme, media, etc.). A procedure performed repeatedly
must be validated. Considerations should be given to the degree of disruption
applied to the tissue in order to preserve its functional integrity and to minimise
cell-derived impurities (e.g. cell debris, cross contamination with other cell types)
in the product.

Cells cultured in or on a matrix/device/scaffold

If cells are grown directly inside or on a matrix/device/scaffold, the quality of the

combined product relies predominantly on properly controlled manufacturing
process. For such products, the cell culture process has to be thoroughly validated
43
with the effect of the device on the cell growth, function and integrity taken into
account. In addition, the effect that the cells may exert on the device (e.g. on rate
of degradation) need to be considered.

Raw materials, excipients and adjuvants

All raw materials, excipients and adjuvants must be qualified, i.e. characterisation
of identity, purity, functionality, and demonstration of freedom from adventitious
agents and suitability.

Other materials and reagents

Other materials and reagents to which the product is exposed to during

manufacturing should be clearly specified and evaluated for its suitability of use. All
materials and reagents should be sterile, unless otherwise justified. It is
recommended to keep the use of such materials to a minimum and to avoid the
use of reagents with sensitisation potential e.g. β-lactam antibiotics.

Transmissible Spongiform Encephalopathies (TSEs)

As with other biologics, the use of animal-derived material is unavoidable for

production of some CGTPs. Therefore, measures taken to minimise the risk of
TSEs need to be documented by filling in Checklist A/B in Requirements for
Registration of Blood Products in Appendix 3: Drug Registration Guidance
Document, First Edition, January 2013.

When manufacturers have a choice, the use of materials from non TSE-relevant
animal species is preferred. The rationale for using materials derived from TSE-
relevant animal species instead of materials from non-TSE relevant species or of
non-animal origin should be given. If materials from TSE-relevant animal species
have to be used, consideration should be given to all the necessary measures to
minimise the risk of transmission of TSE.

Viral safety

For products manufactured using human or animal materials, the risk of viral
contamination and transmission must be mitigated using these complementary
measures, as described in the ICH Q5A: Guideline on quality of
biotechnological products: Viral safety evaluation of biotechnology product
derived from cell lines in of human or animal origin (September 1999):

44
  Selection of source of materials and testing for viral contaminants
 Testing the capacity of the production process to remove and/inactivate
viruses
 Testing of viral contamination at appropriate stages of production.

Where appropriate, one or more validated procedures for removal or inactivation of

viruses should be applied.

9.2 CELL BANKING SYSTEM

The overall quality of the cell bank is a critical parameter that impacts the safety
and efficacy of the final product. Sufficient knowledge of the properties of the
original cell source is an important aspect of ensuring product quality. Generally,
the establishment of a cell banking system should comply with the following
principles:
 The cell bank system used should be adequately described, including: origin
and history of cells, procedures such as freezing and thawing,
characterisations, testing for contaminating organisms, and stability
monitoring for expiration dating
 The number of passages between seed lot or cell bank, the active
substance and the finished product should be consistent with specifications
and across product batches. As part of product lifecycle management, the
establishment of seed lots and cell banks should be performed under
circumstances which are demonstrably appropriate in accordance to cGMP.
Their on-going stability and suitability for use should be further
demonstrated by trend evaluation and the consistency of the characteristics
and quality of the successive batches of product.
 Some specific elements to consider and document when developing an
appropriate panel of tests to assess cell bank safety include: source material
from which the bank is derived, cell line history, procedures used to
establish the cell bank, materials and reagents used during manufacture,
critical cell intermediate, final product characteristics, microbiological testing
for bacteria/fungus/mycoplasma/virus, and expiration dating.
 Generally, the panel of tests is more extensive for the MCB than the WCB.
At the very minimum, the cell bank should be tested for identity (phenotypic
characterisation, genotypic marker, isoenzyme testing), purity, viability,
stability, oncogenicity, tumorigenicity, and safety (sterility, free from
contaminating agents including adventitious agents, exo/endogenic viruses,
mycoplasma).
 If the need arises to introduce genetic materials into the cells, the
expression construct has to be described and characterised, including:
45
 origin, identification, isolation and sequence. The cell banks as well as the
final product have to be tested for gene expression, integrity, copy numbers
and stability of the inserts.

In the clinical development stage of a CGTP, the MCB or WCB possibly becomes
the source of cells for every batch produced for human trials. In this case,
appropriately tested and qualified primary cells may be used in lieu of creation of
cell banks.

Further guidance on cell banking and characterisation can be obtained from the
following documents:

a. ICH Q5A: Guideline on quality of biotechnological products: Viral

safety evaluation of biotechnological product derived from cell lines
on of human or animal origin (September 1999)
b. ICH Q5D: Derivation and characterisation of cell substrates used for
production of biotechnological/biological products (July 1997)
c. Recommendations for the evaluation of animal cell cultures as
substrates for the manufacture of biological medicinal products and
for the characterisation of cell banks, Annex 3: WHO TRS 978, 61 st
Report (2010)

9.3 CHARACTERISATION

The characterisation of a CGTP should encompass all the components present in

the finished product, including matrices, scaffolds and devices. An extensive
characterisation of the cellular component should be established in terms of
identity, purity, potency and suitability for the intended use, unless justified. when
considering the extent of characterisation, the following issues should be taken into
account: (i) autologous cells vs. allogeneic cells (ii) extensively or minimally
manipulated in vitro (iii) immunologically active or neutral (iv) proliferative capacity
of the cells (v) cell-like or tissue-like organisation and dynamic interactions
amongst cells and with the structural component; and (vi) intended use.

The characterisation should be designed to allow setting up the routine controls

that will be applied for release of the active substance and finished product as well
as those to be performed at several steps of the process to guarantee batch
consistency. If biologically active molecules are present as components of the cell
based products, these have to be described fully and their interaction with the
other components of the product and the surrounding tissues after administration
should be characterised. In the course of product development, it is imperative to

46
validate surrogate markers of the identity and potency of cell products. This should
involve an appropriate range of in vitro and where necessary in vivo methods. For
an extensive guidance on CGTP characterisation, please refer to Guideline on
human cell-based medicinal products (EMEA/CHMP/410869/06) (EMA,
January 2007).

47
9.4 MANUFACTURING PROCESS

The variety of distinct cell types, tissue sources, and modes of manufacture and
use necessitate individualised approaches to cell processing and manufacture.
The success of a CGTP highly depends on the robustness of its manufacturing
process. Quality must be built into the product, rather than achieved by testing
during batch release. Since the quality of CGTPs is determined by the production
process, the use of standardised procedures and ensuring high quality
documentation for all steps of production from sourcing to final product are
absolute prerequisites.

The manufacture of CGTPs should be carefully designed and validated to ensure

product consistency. The consistency specifications should be defined and
justified.

The manufacturing area should be physically separated from the area where
biological fluids, tissues or organs are collected. If diverse tissues and cellular
products are collected, processed and stored in the same manufacturing area
there is an increased risk of cross contamination during each step of the
procedure, e.g. via processing equipment or in storage containers such a liquid
nitrogen tanks, and therefore, adequate control measures to prevent cross-
contamination should be put in place.

The manufacturing processes of CGTPs require a number of operations and

manipulations by individuals who are well trained in aseptic processing techniques.
Equipment and premises used for manufacturing should be suitable and validated
for aseptic production. It is recommended that dedicated, product-specific or
single-use equipment are used in the production, whenever possible. If the same
equipment is used for production of e.g. multiple autologous products, sanitation
and sterilisation procedures should be described and validated.

A detailed description of the manufacture of the active substance and of the

finished product should be provided. The type of manipulation(s) required for cell
processing and the physiological function of the cells shall be described. A flow
diagram of the entire process starting from biological fluid/tissue/organ or from cell
banks should be prepared indicating critical steps and intermediate products (e.g.
intermediate cell batches), as well as operating parameters, in-process controls
and acceptance criteria. Manufacture of combined medicinal products consisting of
cells and matrices/devices/scaffolds, require additional consideration regarding the
cell-matrix/scaffold interactions and quality issues raised there from. Attention
should be paid on biodegradable materials which may possess the potential for

48
environmental changes (e.g. raising pH) for the cells during the manufacture or
after administration.

Where possible, components of animal origin used in the culture or preservation of

cells should be replaced with human components or with chemically defined
components to reduce the risk of accidental transfer to patients of unwanted
chemical or biological material or pathogens.

Information on procedures used to transport material during the manufacturing

process of the product, including transportation and storage conditions and holding
times, should be provided.

For the purpose of consistency and traceability, batch definition, i.e. a clear
definition of a production batch from cell sourcing to labelling of final container
should be provided (i.e. size, number of cell passages, pooling strategies, batch
numbering system). In the autologous setting, the manufactured product should be
viewed as a batch on its own.

49
9.5 MANUFACTURING PROCESS VALIDATION

As with all biological processes, manufacturing should be designed with validation

in mind. The entire manufacturing process, including cell harvesting, cell
manipulation processes, maximum number of cell passages, combination with
other components of the product, filling, packaging, transport, storage etc., should
be validated. Validation of the production process of a combined product should
encompass all steps from separate components up to the final combination to
ensure consistent production.

It should be demonstrated that each step of the manufacturing process of the

active substance, supportive components and final product is well controlled. The
selection and acceptance criteria of the operational parameters and the in-process
controls should be justified. Putative variability, related to starting materials and
biological processes, should be taken into account in the validation. Furthermore,
the critical points of the manufacturing process should be defined and validated,
especially the aseptic processing.

S17

In case of limited sample sizes (e.g. autologous preparation for a 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. It is recommended that validation of such a
manufacturing process is performed (depending on the product characteristics) for
adventitious agents, identity, potency, viability, purity and other product-specific
parameters.

50
9.6 QUALITY CONTROL

Specific tests and quality control (QC) paradigms are required for implementing in-
process and product lot release for CGTPs. An array of unique QC tests is used
for stem cells products: e.g. tests to determine extent of differentiation using gene
expression, evaluation of cell morphology, etc.

Analytical methods

The complexity and scope of cell based therapies are reflected in the wide range of
analytical methods that are used to establish in-process controls and final product
release criteria. Quality specifications for CGTPs should be chosen to confirm the
product’s quality, safety and potency.

The development and setting of specifications for cell and tissue products should
follow the principles outlined in ICH Q6B: Specifications: Test procedures and
acceptance criteria for biotechnological/biological products (March 1999). All
release testing should be performed using methods validated at the latest at the
time of submission of an application.

The following table provides some basic analytical tests for CGTPs.

Table 3: Basic Analytical Tests for Cell and Gene Therapy Products = no
need.
Test Cell Therapy Gene Therapy Products
Products (not limited to the listed tests)
(not limited to the Viral Nonviral and
listed tests) Antisense-
Oligonucleotide
Identity of Surface marker Restriction enzyme map Restriction enzyme map
biological determination PCR PCR
substance Species Immunoassay for Immunoassay for
Morphology expressed gene expressed gene
Genotypic/phenotypic Sequencing and Sequencing and
markers integrity of transgene integrity of transgene
Bioassay
Biochemical marker
Dose Viable cell number Particle number Plasmid-DNA weight
Enumeration of Transducing units (DNA Formulated-complex
specific cell hybridization assay) weight HPLC or
population Total protein capillary electrophoresis
Total DNA HPLC assay using assay using
Total protein authenticated reference authenticated reference
standard standard

51
Potency Viable cell number Function of expressed Function of expressed
(cells intended for gene (induction of gene (induction of
structural repair) secondary effect and secondary effect and
Bioassays: other bioassays) other bioassays)
Colony-formation
assay
Function of
expressed gene
Induction of
secondary effect
(e.g., human
leukocyte antigen
(HLA) induction,
secretion of
cytokines, and up-
regulation of surface
marker)

Purity Percentage of viable Residual host-cell DNA Percentage of specific

cells Process contaminants physical form (e.g.,
Percentage of (e.g., serum and cesium percentage supercoiled)
transduced cells chloride) Residual host-cell DNA
Percentage of cells Residual helper virus Residual RNA
with specific surface Optical density ratio Residual host-cell
marker Residual host-cell proteins
Percentage of proteins Residual solvents
differentiated cells Viral protein profile Optical density ratio
Process (HPLC assay for Process contaminants
contaminants (e.g., defective or immature (e.g., cesium chloride
serum) particles) and synthetic
Residual RNA oligonucleotide by-
products)

Safety Mycoplasma General safety Mycoplasma

Sterility Mycoplasma Sterility
Pyrogen and Sterility Pyrogen and
endotoxins Pyrogen and endotoxins endotoxins
Adventitious viruses Adventitious viruses
Residual virus (for RCV
transplanted cells)
Replication-
competent vector
virus, RCV
(transfected cells)

Table adapted from the United States Pharmacopeia, USP 31-NF26

HPLC = high performance liquid chromatography
RCV = respiratory syncytial virus

52
In-process controls

In-process control tests enable manufacturer to gather process and product

characterisation data, useful in assessing the impact of process changes or
excursions. Cells in culture age and may accumulate both genetic and epigenetic
changes, as well as changes in behaviour. Unfortunately, scientific understanding
of genomic stability during cell culture is primitive at best and assays of genetic
and epigenetic status of cultured cells are still evolving. Defining optimal quality
control for cultured cell products remains a key goal.

Examples of in-process controls:

 Enumeration and viability

 Expression of phenotypic or genotypic markers
 Verification of morphology against visual reference standards
 Determination of population doublings, passage number, age of culture
 Assays of product- and process-related process impurities
 Monitoring of culture system parameters (e.g. % relative humidity, pH,
glucose, etc.)
 Functional tests such as colony forming units (CFU) and expression of cell
specific proteins
 Microbiological (sterility, endotoxin, mycoplasma) contaminants should be
tested periodically to cells or spent media to ensure that aseptic conditions
are maintained throughout processing.

Quality control of active substance/final product

The release specifications of the active substance and finished product should be
selected on the basis of parameters defined during the characterisation studies
(see Section 9.3 CHARACTERISATION). Selection of tests is product-specific
and has to be defined by the manufacturer.

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:

 Some release tests might not be feasible on the combined components of

the active substance/ finished product for technical reasons
53
  A complete release testing cannot be finalised before the product is
administered to the recipient due to time restrictions. 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. Integration of specialised test methods
within a manufacturing facility can be of particular value for stem cell
products with short shelf lives.
 Sometimes, rapid microbiological methods (RMM) are used. Alternatively,
the United States Pharmacopeia (USP) and the European Pharmacopeia
(EP) have recently published relevant chapters as follows:
- USP <1223> “Validation of Alternative Microbiological Methods”
- Ph. Eur. 5.1.6 “Alternative Methods for Control of Microbiological
Quality”
- Ph. Eur. 2.6.27 “Microbiological Control of Cellular Products”
 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.

Product release testing

All CGTPs will undergo some form of release testing prior to issuance for clinical
use. Product release is often handled through a Certificate of Analysis (CoA)
system. The CoA summarises the characteristics of the product and the tests
performed. Specifications for release testing should include identity, purity, dose,
potency and safety evaluation.

54
10. PRE-CLINICAL STUDIES

The recommendations of the ICH S6(R1): Preclinical safety evaluation of

biotechnology-derived pharmaceuticals (Revision 1) (June 2011) should be
considered.

However, traditional, standardised approaches to preclinical safety testing may not

be appropriate for CGTPs. In addition, the diversity and complexity of CGTPs call
for individualised pre-clinical testing programmes.

Some specific considerations pertaining to CGTPs are as follows:

Proof-of-concept (POC)
 The desired outcomes in the pre-clinical POC studies include identification
of (i) a pharmacologically active effective dose range and dosing regimen
(ii) an optimal route of administration; and (iii) a viable window for product
administration relative to the onset of disease/injury
 Information on the mechanism of action should be provided as detailed as
possible to facilitate an informed development of a potency assay with
potential biomarkers for activity and toxicity for clinical monitoring.

Inherent risks of some CGTPs

 The fate of infused cells and tissue distribution profile of gene therapy
products need to be determined.
 Uncontrolled proliferation of the administered cells and insertional
mutagenesis following administration of integral viral vectors are risks
unique to CGTPs. Thus, tumorigenicity and genotoxicity studies may be
necessary.

Translation from bench to bedside use

 A critical step in the translational process is a thorough pre-clinical
assessment of product safety, including local and systemic toxicities, dose-
toxicity response, and onset and reversibility of any toxicity findings. In
addition, the feasibility and safety of the delivery device and procedure
need to be sufficiently evaluated.
 The use of multiple species (small and large animals – depending on aim of
study) or animal models may be necessary to adequately model the
functional aspects and potential toxicities of the investigational CGTP. The
need for animal models is especially strong in the case of extensive

55
 manipulation of cells and/or when cells have been derived from pluripotent
stem cells
 A hybrid pharmacology-toxicology study in a model of disease/injury that
more adequately reflect the clinical profile is recommended
 Cells grown in culture, particularly for long periods or under stressful
conditions, may become aneuploid or have DNA rearrangements,
deletions, and other genetic or epigenetic abnormalities that could
predispose them to cause serious pathologies such as cancer. Risks for
tumorigenicity in stem cell products must be assessed especially when
extensively manipulated in culture or when genetically modified.

Combined CGTP
 For products intended to provide some mechanical support, biomechanical
performance should be comprehensively assessed at multiple time points
following product administration.
 In addition, the safety and suitability of all structural components for their
intended function must be demonstrated, taking into account their physical,
mechanical, chemical and biological properties.

Other safety considerations

 The need for reproductive studies is dependent on the CGTP and should
be considered on a case-by-case basis
 The induction of an immune response against the cells themselves and/or
towards cell-derived pharmacological active substances might modulate
the efficacy of the CGTP. Therefore, the possible immunogenicity of a
CGTP should be considered
 Cell cultures and animal models should be used to test the interaction of
cells with drugs (e.g. immunosuppressants and drugs to treat underlying
disease process) to which recipients will be exposed.

Responsible animal research should adhere to the principles of the three R’s –
Reduce numbers, Refine protocols, and Replace animals with in vitro or non-
animal platforms wherever possible. Further, animal models may not replicate the
full range of human toxicities. Therefore, particular vigilance must be applied in
pre-clinical analysis of the toxicities of cell based interventions. In any case,
comparability of the product used in pre-clinical experiments to that intended to be
used as clinical material should be ensured.

For details on non-clinical studies, kindly refer to EMA Guideline on human

cell-based medicinal products/ US FDA Preclinical Assessment of
Investigational Cellular and Gene Therapy Products.
56
11. CLINICAL STUDIES = very important. In humans. Safe and effective.

General aspects

In general, when a CGTP enters the clinical development phase, the same
requirements as for other biologics apply. The necessity and extent of clinical
studies will be considered on a product-specific basis.

The clinical development plan should be designed in accordance to the existing

general guidance’s and specific guidance’s for the condition evaluated. Due to the
diverse biology and scientific issues associated with CGTPs, it is important to
conduct a careful risk-benefit analysis, performed in the context of the particular
clinical indication under study.

Any deviation from Phase I to Phase III clinical trials progression needs to be
justified by the specificity of the CGTP, the pre-clinical studies, previous clinical
experience and the treated pathology.

57
The clinical development plan should consider the following trial design
considerations:
 Delivery of CGTPs to the target place may necessitate surgery or other
invasive procedures. Moreover, a concomitant treatment may be necessary
to get the desired therapeutic effect. The biological effects of CGTPs are
largely dependent on the in vivo environment and may be impacted by the
replacement process or the patient's or cell-based product's immune
response. For the final application of these goods, several needs derived
from clinical development should be considered. Their standardisation and
optimization should be a fundamental component of clinical development
investigations. The entire therapeutic procedure, including delivery
technique and essential concomitant medication such as
immunosuppressive regimens, must be examined and detailed in the
product information.

 Certain CGTPs can survive in humans for an extended period following a

single dose or have an extended duration of impact even after the
substance itself has been eliminated. The product's effects may evolve over
time (e.g., stem cells that proliferate and differentiate to form tumours).
Thus, evaluation of safety may necessitate prolonged observation of people
to comprehend the safety profile.

 CGTPs have the potential to provoke an immune response in the body of

the recipient. Immunogenicity can be significant in either of the two ways
listed below.

 First, pre-existing antibodies or antibodies that develop after administration

of the product could diminish or eliminate a beneficial effect, cause an
adverse reaction (such as an autoimmune syndrome), or affect the safety or
efficacy of subsequent administrations. The development of antibodies to an
allogeneic CGTP may jeopardise the likelihood of a successful
transplantation in patients with a condition that could be treated with a
cellular, tissue, or organ transplant in the future.

58
Early phase trials

The pre-clinical data generated may not always be as informative as other

pharmaceuticals since it is usually not feasible to conduct traditional PK/PD
studies. Due to various issues, such as species specificity and immunogenicity,
extrapolation from a CGTP dose administered in animals to a clinical dose can be
less reliable than the customary allometric scaling typically used for
pharmaceuticals. These issues can limit the ability of the pre-clinical data to guide
various aspects of the design of the early phase clinical trial.

Thus, the design of early-phase clinical trials of CGTPs often involves

consideration of clinical safety issues, pre-clinical issues, and CMC issues that are
encountered less commonly or not at all in the development of other
pharmaceuticals. For CGTPs, these early phase trials often assess not only safety
of specific dose levels, but also other issues, such as feasibility of administration
and pharmacologic activity.

CGTPs sometimes require specialised devices or novel procedures for

administration, customised preparation of products, special handling of products
(e.g., very short expiration time), or adjunctive therapy. In these cases, sponsors
should consider designing early phase trials to identify and characterise any
technical or logistic issues with manufacturing and administering the product.

A common secondary objective of early phase trials is to obtain preliminary

assessments of product activity, using either short-term responses or longer-term
outcomes that could suggest potential for efficacy. For CGTPs, these outcomes
might include specialised measures such as gene expression, cell engraftment, or
morphologic alterations, as well as more common measures such as changes in
immune function, tumour shrinkage, or physiologic responses of various types.

Product development rationale

The information presented in this section should address the following:

a. Compare product to current treatment options

b. Rationale for product development as an unmet medical need
c. Important questions to clarify in clinical trials
d. Most suitable cell types
59
 e. Optimal timing/dose/delivery/site
f. Survival/distribution/engraftment/integration of CGTPs
g. (Ideal) mechanism that CGTP promotes recovery/structural reorganisation,
e.g.: (i) secretion of growth factors (ii) cell-to-cell interactions
h. Association of inflammation/injury response to implant procedure
i. Potential adverse events

In addition, the applicant should attempt the following unresolved questions:

a. Long-term fate of transplanted cells in the recipient tissue

b. Ability of transplanted cells to find their optimum ‘niche’
c. Potency of cells to transdifferentiate
d. Optimal angiogenic milieu needed for transplanted cells in hypoperfused
tissue
e. Capability of recipient tissue to enable an enhanced environment to offer
optimum, milieu-dependent differentiation of engrafted cells
f. Specific detection of engrafted cells/cell populations by labelling techniques
g. Optimal time course of availability and application for SC replacement
therapy
h. Arrhythmogenic potential of implanted myocardial cells
i. Specific characterisation of the progenitor cells that should be measured to
predict therapeutic effect of transplanted cells
j. Development of safe and reproducible catheter-based delivery systems for
depositing SCs to recipient muscle/organ

In this section, a provision to refer to findings of previous studies (e.g. published

literature, clinical practice guidelines, abstracts from conference – stratified by
levels of evidence) can be considered.

Pharmacodynamics / Biodynamics

There is a relative lack of clinical experience with some CGTPs and the risk-benefit
assessment will be especially difficult. Even if the mechanism of action is not
understood in detail, the main effects of the product should be known.

When the purpose of the product is to correct the function of deficient or destroyed
tissue, then functional tests should be implemented. If the intended use of the
product is to restore/replace tissues, with an expected lifelong functionality,
structural/histological assays may be potential pharmacodynamic markers.
Suitable pharmacodynamic markers, such as defined by microscopic, histological,
imaging techniques or enzymatic activities, could be used.

60
When the product includes a non-cellular component, the combination should be
assessed clinically for compatibility, degradation rate and functionality.

Pharmacokinetics / Biokinetics

Due to the unique nature of CT products, the conventional absorption, distribution,

metabolism and elimination (ADME) studies are usually not relevant.

Methodologies to assess and monitor viability, proliferation/differentiation, body

distribution/migration and functionality during the period of use of the product
should be conducted.

If multiple administrations are proposed, the test schedule should address the
expected in vivo life span of the product.

Dose finding studies

The selection of dose should be based on findings from quality determination, non-
clinical development, and linked with the potency of the product.

For individualised dosage (e.g. cell mass density per body weight, volume of
missing tissue, missing surface area), the dose to be tested should be supported
by the evidence provided in earlier phases (Phase I/II) of studies.

An attempt should also be made to quantify the Safe Maximal Dose (the maximal
dose which could be administered on the basis of clinical safety studies without
unacceptable adverse effects), taking into account the possibility of repeated
administration. The dose of cells administered to humans should be below the
minimum number of cells observed to form tumours in animal models.

Phase I/II studies should be conducted to identify Minimal Effective Dose (the
lowest dose to obtain the intended effect) or an Optimal Dose Range (the largest
dose range required to obtain the intended effect based on the clinical results for
efficacy and tolerability).

Clinical efficacy

Clinical efficacy studies should demonstrate efficacy in the target patient

population using clinically meaningful endpoints, to demonstrate an appropriate
dose-schedule that results in the optimal therapeutic effect, to evaluate the
duration of therapeutic effect of the administered product and to allow a benefit-risk

61
assessment taking into account the existing therapeutic alternatives for the target
population. Confirmatory studies should be conducted in accordance to the
existing general and specific guidelines for the condition being evaluated.

Deviations from established recommendations will need a justification. For

example, the fact that the nature and the mechanism of action of the CGTP may
be entirely novel does not mean necessarily that the therapeutic benefit should be
measured by different endpoints from those recommended in the current disease-
specific guidelines (e.g. medicines vs. cell implants for Parkinson’s disease).

For new therapeutic applications of CGTPs where limited guidance exists,

consultation with ethics committee and regulatory authorities on the clinical
development plan, including the confirmatory studies, is highly recommended.

The use of previously validated or generally accepted surrogate endpoints is

possible provided that a correlation-between clinical meaningfully endpoints and
efficacy can be established. In the case where the desired clinical endpoint, such
as prevention of arthrosis, can be observed only after a long follow up, the
marketing authorisation can be based on surrogate markers. If the efficacy is
dependent on the long-term persistence of the product, marketing authorisation
may be granted with commitment by marketing authorisation holder to conduct
long-term follow up / investigation plans post-marketing approval.

Clinical safety

The risks associated with CGTP can be of a different nature from those typically
associated with other pharmaceuticals. The main safety concern is to prevent
transmissible diseases. The safety database should be able to detect common
adverse events. The size of the database might be decided also in the light of
previous clinical experience with similar products.

The risk of the therapeutic procedure as a whole, e.g. the required surgical
procedures to administer the product or the use of immunosuppressive therapy,
shall be evaluated and used to justify the clinical studies and the choice of the
target patient population.

All safety issues arising from the pre-clinical development should be addressed,
especially in the absence of an animal model of the treated disease or in the
presence of physiologic differences limiting the predictive value of homologous
animal model.

62
Particular attention should be paid to the biological processes including immune
response, infections, malignant transformation and concomitant treatment during
development and post-marketing phase.

For products with expected long term viability, patient follow-up is required in order
to confirm long term efficacy and safety issue related to the product.

Clinical safety studies on repeated administrations should be performed as

required by the risk analysis. The definition of Maximal Safe Dose should also take
repeated administration into account.

Extensive patient monitoring and long term follow up

Extensive patient monitoring and long term follow up will be necessary to address
the safety concerns and look for instances of release of endogenous viruses or
clinical effects as a result of prolonged expression of foreign protein.

For pre-clinical development, besides the strong proof-of-concept, the focus should
be on safety, especially tumourigenicity, cell persistence and trafficking in vivo. In
this area, establishment of appropriate models, analytical methods and non-
invasive imaging techniques will have to be developed.

The need for long term (maybe lifelong) follow up may interfere with the decision of
the patient to withdraw from the trial. This has to be taken into consideration and
addressed early in the clinical development programme. If possible, mechanisms
with genetically induced potential to selectively kill the transplanted cells or use of
devices for easy retrieval of cells in case of malfunction should be devised.

For details on clinical studies, kindly refer to EMA’s Guideline on human cell-
based medicinal products.

63
12. LABELLING REQUIREMENTS FOR IMMEDIATE AND OUTER PACKAGING
= very good for pharmacist & doctors. Proper usage.

In addition to labelling requirements of biologic products in the Drug Registration

Guidance Document (DRGD), First Edition – January 2013, the following
requirements apply:

a. The name of the product and, if appropriate, an indication of whether it is

intended for babies, children or adults

b. The international non-proprietary name (INN) shall be included, or, if the

product has no INN, the common name

c. A description of the active substance(s) expressed qualitatively and

quantitatively including, where the product contains cells or tissues, the
statement “This product contains cells of human/animal [as appropriate]
origin” together with a short description of these cells or tissues and of their
specific origin, including the species of animal in cases of non-human origin

d. The pharmaceutical form and, if applicable, the contents by weight, by

volume or by number of doses of the product

e. A list of excipients, including preservative systems

f. The method of use, application, administration or implantation and, if

necessary, the route of administration. If applicable, space shall be provided
for the prescribed dose to be indicated

g. Any special warning necessary for the particular medicinal product

h. The manufacturing and expiry dates in clear terms (month and year; and
day if applicable)

i. Special storage precautions (if required)

j. Specific precautions relating to the disposal of unused medicinal products or

waste derived from medicinal products, where appropriate, as well as
reference to any appropriate collection system in place

k. The manufacturer’s batch number and the unique donation and product
codes
64
l. In the case of CGTPs for autologous use, the unique patient identifier and
the statement “For autologous use only”

NOTE:
Some of the information required can also be included in the local pa ckage
insert.

65
13. POST- AUTHORISATION REQUIREMENTS

Pharmacovigilance and Risk Management Plan (RMP)

 While CGTPs provide new possibilities for restoring, correcting or modifying

physiological functions, or making a diagnosis, their novelty, complexity and
technical specificity may bring along new, unexplored risks to public health
and to individual patients. Thus, specific risk management requirements are
called for. When preparing a risk management plan (RMP) for a particular
CGTP comprehensive scientific consideration should be given to the
important identified or potential risks, and to the important missing
information.

 Generally, routine pharmacovigilance and traceability of the CGTPs should

be described in RMP and the product may need special long-term studies to
monitor specific safety issues, including loss of efficacy.

 Traceability in the donor-product-recipient axis, or product-recipient axis for

autologous products, is required in all circumstances.

 The long-term safety issues, such as infections,

immunogenicity/immunosuppression and malignant transformation as well
as the in vivo durability of the associated medical device/biomaterial
component should be addressed in the RMP.

 As many of the CGTPs incorporate living organisms, the efficacy of these

CGTPs is subject to their changing characteristics after their administration
to patient over long periods of time. This may result in an increase (e.g.
overexpression of a gene of interest) or decrease of efficacy, and the
consequences for the patient may not be fully established during pre-
registration clinical trials.

 The efficacy follow-up systems should use the same infrastructure for safety
follow-up whenever feasible in order to ensure that safety and efficacy data
are comparable and consistent. Safety follow-up alone might be appropriate
for ‘loss of efficacy’ or ‘less than expected efficacy’ of CGTPs. However,
further study of the product’s efficacy profile in the post-authorisation phase
may be considered on a case-to-case basis when it is inappropriate to use
the safety follow-up alone for this purpose.

66
  Periodic Safety Update Reports (PSURs) and their assessment reports
should discuss on-going cumulative efficacy and safety data as well as
safety data relating to donors and close contacts. Assessment of the
effectiveness of the risk management system and the results of any newly
finished studies should be regularly included in the PSUR and regular
updates of the RMP. For CGTP-specific concerns in the RMP, please refer
Section 6.1 Safety Concerns in Guideline on safety & efficacy follow-
up – Risk management of advanced therapy medicinal products (EMA,
December 2008).

 The product registration holder (PRH) should inform the Drug Control
Authority (DCA) of any steps which are to be taken with regards to safety
concerns raised in the PSUR. A copy of the most updated relevant package
insert/s should be submitted together with the PSUR. Any consequential
variations (e.g. package insert changes) simultaneously with the PSUR at
the time of its submission should also be submitted.

 The PRH must also inform the DCA within 3 calendar days of first
knowledge by the registration holder, whether new evidence becomes
available which may significantly impact on the benefit/risk assessment of a
product or which would be sufficient to consider changes in the conditions of
registration of the product.

 Additional pharmacovigilance data such as actual case reports, drug usage

figures, the regulatory status of the product in other countries, independent
pharmacoepidemiology studies, pre-clinical studies or significant product
quality data may be requested by the Authority as the situation warrants.
This must be submitted within a time period specified by the Authority.

Adverse drug reaction reporting and Safety updates

 In accordance with Regulation 28 : Reporting adverse reaction under

Control of Drugs and Cosmetics Regulations 1984, Sale of Drugs Act
1952 (amendment 2006), the product registration holders or any person
who possesses any registered product shall inform immediately the Director
of Pharmaceutical Services of any adverse reaction arising from the use of
the registered product.

 The adverse drug reaction reporting should be in accordance with the

Malaysian Guidelines for the Reporting & Monitoring (MOH Malaysia,
March 2002).
67
  Product registration holders are required to monitor and report any product
safety issues that arises locally or internationally to the NPCB and comply
with all safety-related directives issued by the DCA.

 Regulatory action/s may be imposed if the PRH fails to inform the DCA of
any serious adverse reactions upon receipt of such reports and safety
updates.

Patient Registry for Class II Products

Safety signals can also be investigated through observational studies. For this
purpose, the safety outcome of a CGTP can be tracked via a carefully designed
non-randomised observatory trial. A relevant example of such a trial is a patient
registry.

A registry may serve any or all of the following functions:

a. determination of effectiveness
b. surveillance on safety
c. evaluate access to and quality of healthcare

For regulatory expectations on the design and conduct of a registry, the ICH Topic
E2E: Pharmacovigilance Planning. Note for guidance on planning
pharmacovigilance activities (ICH, June 2005) and the document entitled
Guidance for Industry: Good Pharmacovigilance Practices and
Pharmacoepidemiologic Assessment. US FDA, March 2005 may be referred
and NPCB consulted.

68
 PART II. ADDITIONAL REQUIREMENTS ON XENOTRANSPLANTATION = no
need. Last.

Xenotransplantation refers to procedure that uses living, non-human animal cells,

tissues or organs for human therapeutic purposes. Non-viable animal tissue such
as porcine heart valves and bone has been used for many years, offsetting limited
supply of human equivalents. One example is pancreatic islets intended to treat
diabetes.

Xenotransplantation involves the transplantation, implantation, or infusion into a

human recipient of either:

a. live cells, tissues, or organs from a non-human animal source; or

b. human body fluids, cells, tissues, or organs that have had ex vivo contact
with live non-human animal cells, tissues, or organs (e.g. extracorporeal
perfusion)

[US FDA (2001) definition]

Examples of xenotransplantion products:

 The use of mouse cells as feeder layer fits part (b) of this definition. Even if
the feeder layer cells are irradiated to render them non-proliferative, they
are still regarded as living cells and within the definition of
xenotransplantation.
 Xenotransplantation products must be alive, and circulation and return of
patients’ blood must occur through live non-human cells. For example,
human skin cells grown outside the body on a layer of non-human cells and
then used in humans for skin reconstruction can also be considered a
xenotransplantation product.
 Xenotransplantation products include those from transgenic or non-
transgenic non-human animals and composite products that contain
xenotransplantation products in combination with drugs or devices. These
include but are not limited to, porcine fetal neuronal cells, encapsulated
porcine islet cells, encapsulated bovine adrenal chromaffin cells.

Xenotransplantation products are considered to be biologics, or combination

products that contain a biological component. Accordingly, xenotransplantation
products are subject to evaluation, regulations governing clinical investigations and
product approval as of any CGTP.

The use of animal cells and tissue in the manufacture of cell therapy products
69
requires that the tissue be sourced in a controlled and documented manner from
designated-free animals bred and raised in captivity in countries or geographic
regions that have appropriate disease prevention and control systems.

The concept of cellular xenotransplantation faces many challenges, including the

potential for zoonotic disease transmission to human, and the fact that most
animals have shorter lifespan than humans, so their tissues age at a different rate.
In addition, a risk of recombination or reassortment of source-animal infectious
agents, such as viruses, with non-pathogenic or endogenous human infectious
agents to form new pathogenic entities exists.

It is obvious that for the use of xenogeneic cells much more stringent requirements
have to be fulfilled according to the increased risk profile. In the EU, the applicable
guidelines exclude the use of primary xenogeneic cells; only well-defined and
characterised cell lines can be taken into considerations. Hence, a tiered approach
to regulation of xenotransplantation products based on degrees of risk and levels
of surveillance appropriate to that risk.

The main scientific and technical issues identified so far concern the sourcing and
testing of animals, manufacture, quality control, as well as the non-clinical and
clinical development of xenogeneic cell-based products. Relevant public health
aspects are discussed and measures to ensure a proper surveillance for infections,
including zoonosis are required.

Overall, the general principles of CGTP regulation may apply to of products using
animal tissues as the starting material, as the key objective is to ensure that the
product to be administered is of acceptable quality and standard, and free from
contamination.

70
Table 5: Overview on risks associated with xenotransplantation
Area Risk

Patient Recipients/patients immunocompromised

Direct chronic contact

Normal first line of defence against infection, such as skin

and mucosal surfaces, circumvented.

Infection Zoonotic infections of humans e.g Toxoplasma spp.,

Salmonella spp.

Experience with human allografts; transmission of

HIV,CJD,HBV,HCV

Aggravating Varying incubation periods and possible clinical latency of

factors virus

Transmission of organisms pathogenic in humans that may

not be pathogenic or even detectable in the source animal

Recombination of viruses with non-pathogenic human

infectious agents to form new pathogens

Public/ Infections originating in animals known to infect and be

community transmitted between humans e.g. HIV

Transmission of infections from patients to close contact and

eventually to general public

HIV = human immunodeficiency virus

CJD = Creutzfeldt-Jakob disease
HBV = hepatitis B virus
HCV = hepatitis C virus

The principal concern is the potential for the transmission of infectious disease
from non-human animals to humans. This concern relates not only to the recipient
of the xenotransplantation, but also extends to the general public because of the
potential for subsequent transmission. Accordingly, during the development and
approval of xenotransplantation products much stricter requirements have to be
met to safeguard against these increased safety concerns. These specific
regulatory requirements apply for xenotransplantation products:

71
  Appropriate clinical and scientific expertise of the xenotransplant research
team and facility
 Stringent requirements regarding animal facilities, animal procurement and
pre-transplantation animal source screening
 Risk minimisation precautions during all steps of production
 Thorough health surveillance program
 Very comprehensive informed consent and patient education process
 Long term or even life-long surveillance of xenotransplant recipients
regardless of outcome of the clinical trial or the status of the graft or other
xenotransplantation products
 Xenotransplantation recipients to refrain from blood donation
 Biological specimens archived for public health investigations and for use by
sponsor in conduct of surveillance of source animals and
xenotransplantation recipients
 Archiving of health records and biologic specimens to be maintained for 30
years

International efforts to harmonise xenotransplantation should be aimed at the

development of reasonable and appropriate methods in recognition of a growing
body of evidence and experience regarding the safety of this therapy, and be
framed within existing public health monitoring and surveillance systems.

As this guideline is not meant to cover in sufficient details of the requirements for
xenotransplantation product, please refer to the following guidelines:

1. US Department of Health and Human Services, Food and Drug

administration, Centre of Biologics Evaluation and research. Guidance for
Industry : Source Animal, Product, Pre-clinical, and Clinical issues
Concerning the Use of Xenotransplantation Products in Humans (April,
2003)
2. US Public Health Services Guideline on Infectious Disease Issues in
Xenotransplantation (January, 2001)
3. EMEA/CHMP/CPWP/83508/2009: Guideline on Xenogeneic Cell-Based
Medicinal Products (December, 2009)

NOTE:

The focus of the regulation currently is on human cells and tissues. It is

acknowledged that more recently, additional efforts and developments have been
directed towards xenotransplantation. However, the potential risk for cross-species
72
transmission of infectious agents continues to be debated. We are still cautious of
its clinical impact. As such, the relevant party is urged to refer to the specific
comprehensive xenotransplantation guidances by US FDA and EMA and approval
of products from these agencies may be a prerequisite for an application for
registration of such products in Malaysia.

73
 PART III. ADDITIONAL REQUIREMENTS ON GENE THERAPY PRODUCTS

Gene therapy involves introducing genetic materials into cells to help prevent or
treat a range of diseases such as cancer, degenerative diseases and haemophilia.
Cells may be modified ex vivo for subsequent administration to humans, or may be
altered in vivo by gene therapy given directly to the subject. When the genetic
manipulation is performed ex vivo on cells which are then administered to the
patient, this is also a form of somatic cell therapy. The genetic manipulation may
be intended to have a therapeutic or prophylactic effect, or may provide a way of
marking cells for later identification. Recombinant DNA materials used to transfer
genetic material for such therapy are considered components of gene therapy and
as such are subject to regulatory oversight.

Gene Therapy Products (GTPs) include recombinant nucleic acid sequence(s) of

biological origin, genetically modified virus(es), genetically modified
microorganism(s) and cells genetically modified by one or more of these
substances.

Gene therapy products can be broadly classified based on the approach to delivery
and include the following: (i) viral vectors [viruses that harbor the gene(s) of
interest but usually without the mechanism to self-replicate in vivo]; (ii) nucleic
acids in a simple formulation (naked DNA); and (iii) nucleic acids formulated with
agents such as liposomes that enhance their ability to penetrate the cell. Where
introduction of nucleic acids to cell takes place ex vivo, the cell population that is
administered becomes the gene therapy product.

The scope of GTP regulation includes:

 The addition and expression of a gene for therapeutic purposes

 The inoculation of nucleic acids for the purpose of developing therapeutic
vaccines
 The transfer of nucleic acids with the aim of modifying the function or the
expression of an endogenous gene

As GTPs contain genetic and other material of biological origin, many of the quality
guidelines for biotechnological products also apply. Information on all starting
materials used for manufacturing of the active substance could be provided. This
will include the products necessary for the genetic modification of human or animal
cells as well as materials used in culture and preservation of the cells.

74
As many GTPs consist of, or contain, genetically modified organisms (GMOs), the
potential risk of the GMO to the environment also need to be evaluated. An
environmental risk assessment (ERA) must be provided. For GTPs consisting of a
GMO, and in particular a viral vector, investigations of sheddings and the risk of
transmission to third parties should be provided within the ERA.

A major concern with gene therapy is that it can result in permanent changes that
are passed from one generation to the next.

NOTE:

There are still many technical and ethical issues to be addressed and numerous
guidelines in development as knowledge and experience evolve in this field.
Because gene therapy products are being developed around the world, the
International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) via the ICH Gene Therapy
Discussion Group are actively engaged in development of new guidelines. Three of
these guidelines are available on the ICH website
(http://www.ich.org/consideration-documents.html ) - on Risk of Inadvertent Germ-
line Integration of Gene Therapy vectors, Oncolytic Viruses, and Virus and Vector
Shedding.

The general chapter on Gene Transfer Medicinal Products (GTMPs) For Human
Use in European Pharmacopoeia provide a framework of requirements
applicable to the production and control of GTMPs. Guidance specific to
manufacturing, processing, purification, characterisation, formulation, and
administration of gene therapy products is provided in Gene Therapy Products, in
United States Pharmacopoeias (USP) <1047>. The European Medicines Agency
(EMA) provides multidisciplinary gene therapy guidelines, concept papers and
reflection papers on various aspects of gene therapy products including guidelines
on follow-up patients, virus and gene therapy vector shedding and transmission,
environmental risk assessment, etc.

The evaluation require special disciplines, expertise and skills and as such
Malaysian regulatory authority decided to adopt the guidelines published by the
European Medicines Agency (EMA) and United States Food and Drug
Administration (US FDA). Subsequently, an application for registration for gene
therapy products will only be accepted if the product had already been approved
by any of our reference regulatory agencies [US FDA, EMA, Health Canada,
Swissmedic, TGA (Australia) and PMDA (Japan)].

75
Pre-clinical requirements

As GTPs differ in their complexity and heterogeneity, the extent of non-clinical

package varies and will depend on the risk profile of each product. Some
requirements are listed below:

 Pharmacodynamic proof-of-concept (POC) studies should involve

appropriate models and relevant animal species, taking target selectivity
into account
 Pharmacokinetics should provide detail analysis of the biodistribution of the
GTPs including investigations on its persistence, clearance, mobilisation,
shedding and germ line transmission
 Toxicology should address unintended effects on physiological function,
repeated toxicity and immunogenicity
 Evaluation of safety of the GTPs is required by extensive toxicological
testing including analyses on genotoxicity, tumorigenicity, and reproductive
and developmental toxicity

Clinical requirements

Human pharmacokinetic studies should include:

 Shedding studies to address excretion of the GTPs

 Biodistribution studies
 Pharmacokinetic studies of the product and the gene expression moieties
(e.g. expressed proteins or genomic signatures)

Human pharmacodynamic studies should address the expression and function of

the nucleic acid sequence following administration of the product.

Efficacy

The “proof-of-concept” might be desirable and sometimes necessary. Where the

mechanism of action is established and the condition to be treated is common, it is
sensible to establish efficacy in small studies before undertaking a large
confirmatory trial. Dose finding is one of the most important aspects.

Safety studies should address the following aspects:

 Emergence of replication-competent vector

76
  Emergence of new strains
 Re-assortment of existing genomic sequences
 Neoplastic proliferation due to insertional mutagenicity

Follow-up of efficacy and safety

As treatment of gene therapy could be curative, maintenance of efficacy is

important. Follow-up of safety post-marketing is important. As for efficacy, the
duration and nature of the follow-up will depend on the disease and its prognosis.

To help applicants developing gene therapy products EMA has issued a Note for
guidance on the quality, non-clinical and clinical aspects on gene therapy
transfer medicinal products (April, 2001). Generally, the Note of Guidance
provides general and specific considerations on:

 Development of genetics (also refer ICH Q5B)

- suitability of the vector and delivery system
- description and documentation of each element of the expression
construct; scientific rationale based on their function and their inclusion
in the expression vector
- control and stability of gene expression
- selection markers, etc.
 Manufacturing issues (ICH Q5A-5B-5D-5E)
- the vector
- cells (bacteria, cell lines, primary cells)
- cell bank system (MCB/WCB)
- viral seed lot system (MVS/WVS)
- reagents (serum, growth factors, monoclonal antibodies)
- TSE and viral safety
 Purification
- suitability of the purification process to remove impurities (both process-
and product-related impurities)
- validation for the absence of extraneous viruses
 Characterisation and consistency (ICH Q6B)
- identity, purity, potency
- suitable tests: biological, immunological, biochemical
- justification of the specifications
- batch analysis on at least three consecutive batches
 Safety testing
- sterility
- pyrogens / endotoxins
77
- mycoplasma
- freedom from adventitious agents
- in vitro and in vivo viral testing and species-specific viruses

78
14. ANNEX: ADDITIONAL REFERENCES ON CGTP REGULATION

Malaysia

Sale of Drugs Act and its Regulations. In Bahagian Perkhidmatan Farmasi,

Kementerian Kesihatan Malaysia. Document in Malay language. Retrieved June 5
2014, from
http://www.pharmacy.gov.my/v2/en/documents/akta-jualan-dadah-1952-peraturan-
peraturannya.html

Private healthcare facilities and services act 1998 (Act 586) (May 2006). In
Malaysian Medical Association. Retrieved June 5 2014, from
http://www.mma.org.my/Portals/0/private%20healthcare%20facilities%20and
%20services%20act%201998.pdf

Drug registration guidance document (DRGD), First Edition (April 2014). In

National Pharmaceutical Control Bureau, Ministry of Health, Malaysia. Retrieved
June 5 2014, from http://portal.bpfk.gov.my/newsmaster.cfm?
&menuid=52&action=news&search=yes&searchcategory=Drug%20Registration
%20Guidance%20Document%20Updates

National guidelines for haemopoietic stem cell therapy (July 2009). In Medical
Development Division, Ministry of Health, Malaysia. Retrieved June 5 2014, from
http://www.moh.gov.my/images/gallery/Garispanduan/Stem_Cell/haemopoietic.pdf

National standards for stem cell transplantation: Collecting, processing, storage

and infusion of haemopoietic stem cells and therapeutic cells (July 2009). Clinical
Support Services Unit, Medical Development Division, Ministry of Health, Malaysia.
Retrieved June 5 2014, from http://www.moh.gov.my/images/gallery/orga/National
%20Standards%20for%20Stem%20Cell%20Transplantation%20-%20Collection,
%20Processing%20and%20Infusion%20of%20HSC%20and%20Therapeutis
%20Cell.pdf

Guidelines for stem cell research and therapy (July 2009). In Medical Development
Division, Ministry of Health, Malaysia. Retrieved June 5 2014, from
http://www.moh.gov.my/images/gallery/Garispanduan/Stem_Cell/stem_cell_therap
y.pdf

National standards for cord blood banking and transplantation (January 2008). In
Medical Development Division, Ministry of Health, Malaysia. Retrieved June 5
2014, from
http://www.moh.gov.my/images/gallery/Garispanduan/Stem_Cell/guideline_nationa
l_cord_blood_banking.pdf

Guideline on importation and exportation of human tissue and parts. 1 st Ed.

(August 2006). In Disease Control Division, Department of Public Health, Ministry
of Health, Malaysia. Document in Malay language. Retrieved June 5 2014, from
http://www.moh.gov.my/images/gallery/Garispanduan/PubHea/GP_Tisu.pdf

79
Medical Device Authority. Combination products – List of reference documents. In
Medical Device Authority, Ministry of Health, Malaysia. Retrieved August 28 2014,
from
http://www.mdb.gov.my/mdb/index.php?
option=com_content&task=view&id=87&Itemid=129
http://www.mdb.gov.my/mdb/index.php?option=com_docman&Itemid=30

WHO (Quality, Clinical & Combined Guidelines)

WHO guidelines on tissue infectivity distribution in transmissible spongiform

encephalopathies
(2010). In World Health Organization. Retrieved June 5 2014, from
http://www.who.int/bloodproducts/tse/WHO%20TSE%20Guidelines%20FINAL-
22%20JuneupdatedNL.pdf

First WHO Global Consultation on Regulatory Requirements for

Xenotransplantation Clinical Trials, Changsha, China, 19-21 November 2008 - The
Changsha Communiqué. In World Health Organization. Retrieved August 26 2014,
from
http://www.who.int/transplantation/xeno/en/
Second WHO global consultation on regulatory requirements for
xenotransplantation clinical trials, Geneva 17-19 October 2011. In World Health
Organization. Retrieved August 26 2014, from
http://www.who.int/transplantation/xeno/report2nd_global_consultation_xtx.pdf
Statement from the xenotransplantation advisory consultation, Geneva 18-20 April
2005. In World Health Organization. Retrieved August 26 2014, from
http://www.who.int/transplantation/XenoEnglish.pdf
WHO guiding principles on human cell, tissue and organ transplantation (n.d.). In
World Health Organization. Retrieved June 5 2014, from
http://www.who.int/transplantation/Guiding_PrinciplesTransplantation_WHA63.22e
n.pdf

WHO Expert Committee on Biological Standardization: Recommendations for the

evaluation of animal cell cultures as substrates for the manufacture of biological
medicinal products and for the characterisation of cell banks, WHO TRS No. 978
(61st Report) - Annex 3 (2000). In World Health Organization. Retrieved August 26
2014, from
http://apps.who.int/medicinedocs/documents/s21092en/s21092en.pdf

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ICH (Quality, Nonclinical & Clinical)

In International Conference on Harmonisation. Retrieved June 5 2014, from

http://www.ich.org/products/guidelines.html

Q2(R1) Validation of analytical procedures: Text and methodology (Revision 1)

(November 2005)

Q5A: Guideline on quality of biotechnological products: viral safety evaluation of

biotechnology product derived from cell lines in of human or animal origin
(September 1999)

Q 5 B: Analysis of the expression construct in cells used for production of r-DNA

derived protein products (November 1995)

Q5C: Stability testing of biotechnological/biological products (July 1996)

Q5D: Derivation and characterisation of cell substrates used for production of

biotechnological/ biological products (July 1997)

Q5E: Comparability of biotechnological/biological products subject to changes in

their manufacturing process (November 2004)

Q6B: Specifications: test procedures and acceptance criteria for

biotechnological/biological products (March 1999)

Q9: Quality risk management (November 2005)

M6: Virus and gene therapy vector shedding and transmission (September 2009)

S6(R1): Preclinical safety evaluation of biotechnology-derived pharmaceuticals

(Revision 1) (June 2011)

S9: Nonclinical evaluation for anticancer pharmaceuticals (October 2009)

E2C(R2): Periodic benefit-risk evaluation report (Revision 2) (November 2012)

E2E: Pharmacovigilance planning (November 2004)

E6(R1): Good Clinical Practice (May 1996)

E8: General Considerations for Clinical Trials (July 1997)

E9: Statistical Principles for Clinical Trials (September 1998)

E10: Choice of control group and related issues in clinical trials (July 2000)

81
E11: Clinical investigation of medicinal products in the pediatric population (July
2000)

U.S. FDA (Quality, Nonclinical, Clinical & Combined)

In U.S. Food and Drugs Administration. Retrieved June 5 2014, from

http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInform
ation/Guidances/CellularandGeneTherapy/default.htm and
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInform
ation/Guidances/Tissue/default.htm

Draft guidance for industry: Use of donor screening tests to test donors of human
cells, tissues and cellular and tissue-based products (HCT/Ps) for Infection with
Treponema pallidum (Syphilis) (October 2013)

Draft guidance for industry: Use of nucleic acid tests to reduce the risk of
transmission of West Nile Virus from donors of human cells, tissues, and cellular
and tissue-based products (HCT/Ps) (October 2013)

Guidance for industry: Current good tissue practice (cGTP) and additional
requirements for manufacturers of human cells, tissues, and cellular and tissue-
based products (HCT/Ps) (December 2011)

Guidance for industry: Class II special controls guidance document: cord blood
processing system and storage container (March 2011)
Guidance for industry: Potency tests for cellular and gene therapy
products (January 2011)
Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry,
Manufacturing, and Control (CMC) Information for Human Gene Therapy
Investigational New Drug Applications (INDs) (April 2008)

Draft guidance for industry: Use of serological tests to reduce the risk of
transmission of trypanosoma cruzi infection in whole blood and blood components
for transfusion and human cells, tissues, and cellular and tissue-based products
(March 2009)

Draft guidance for industry: Use of nucleic acid tests to reduce the risk of
transmission of west nile virus from donors of whole blood and blood components
intended for transfusion and donors of human cells, tissues, and cellular and
tissue-based products (HCT/Ps) (April 2008)

Guidance for FDA reviewers and sponsors: content and review of chemistry,
manufacturing, and control (CMC) information for human somatic cell therapy
investigational new drug applications (INDs) (April 2008)

82
Guidance for industry: Certain human cells, tissues, and cellular and tissue-based
products (HCT/Ps) recovered from donors who were tested for communicable
diseases using pooled specimens or diagnostic tests (April 2008)

Draft guidance for industry: Validation of growth-based rapid microbiological

methods for sterility testing of cellular and gene therapy products (February 2008)

Guidance for industry: Regulation of human cells, tissues, and cellular and tissue-
based products (HCT/Ps) small entity compliance guide (August 2007)

Guidance for industry: Eligibility determination for donors of human cells, tissues,
and cellular and tissue-based products (August 2007)

Guidance for industry: Screening and testing of donors of human tissue intended
for transplantation (July 1997)

Guidance for the submission of chemistry, manufacturing, and controls information

and establishment description for autologous somatic cell therapy
products (January 1997) 

Points to consider in the characterisation of cell lines used to produce biologicals

(July 1993)
Guidance of industry: Preclinical assessment of investigational cellular and gene
therapy products (November 2013)

Draft guidance for industry: Assay development for immunogenicity testing of

therapeutic proteins (December 2009)

Draft guidance for industry: Considerations for the design of early-phase clinical
trials of cellular and gene therapy products (July 2013)

Guidance for Industry: Gene Therapy Clinical Trials - Observing Subjects for
Delayed Adverse Events 
(November 2006)

Guidance for industry: Clinical considerations for therapeutic cancer

vaccines (October 2011)

Draft guidance for industry: Non-inferiority clinical trials (March 2010)

Draft guidance for industry: Adaptive design clinical trials for drugs and biologics
(February 2010)

Guidance for industry: Patient-reported outcome measures: Use in medical product

development to support labeling claims (December 2009)

Guidance for industry: cGMP for phase 1 investigational drugs (July 2008)

83
Guidance for industry: Clinical trial endpoints for the approval of cancer drugs and
biologics (May 2007)

Guidance for industry: Gene therapy clinical trials - observing subjects for delayed
adverse events 
(November 2006)

Guidance for industry: Providing clinical evidence of effectiveness for human drug
and biological products (May 1998)

Guidance for industry: Content and format of investigational new drug applications
(INDs) for phase 1 studies of drugs, including well-characterised, therapeutic,
biotechnology-derived products (November 1995)

Guidance for industry and FDA staff: Investigational new drug applications for
minimally manipulated, unrelated allogeneic placental/umbilical cord blood
intended for hematopoietic and immunologic reconstitution in patients with
disorders affecting the hematopoietic system (March 2014)

Biologics license applications for minimally manipulated, unrelated allogeneic

placental/umbilical cord blood intended for hematopoietic and immunologic
reconstitution in patients with disorders affecting the hematopoietic system  (March
2014)

CFR – 21 – Part 1271: Human cells, tissues, and cellular and tissue-based
products (1 April 2012)

Guidance for industry: Preparation of IDEs (Investigational Devices Exemption)

and INDs for products intended to repair or replace knee cartilage  (December
2011)

Guidance for industry and FDA staff: Investigational new drug applications for
minimally manipulated, unrelated allogeneic placental/umbilical cord blood
intended for hematopoietic reconstitution for specified indications (June 2011)

Guidance for industry: Cellular therapy for cardiac disease (October 2010)

Guidance for industry - minimally manipulated, unrelated allogeneic

placental/umbilical cord blood intended for hematopoietic reconstitution for
specified indications (October 2009)

Guidance for industry: Considerations for allogeneic pancreatic islet cell

products (September 2009)

Guidance for industry and FDA staff: Early development considerations for
innovative combination products (September 2006)

NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH

Guidelines) (April 2002)
84
Guidance for industry: Guidance for human somatic cell therapy and gene
therapy (March 1998)

A proposed approach to the regulation of cellular and tissue-based products (62

FR 9721) (February 1997)

Guidance on applications for products comprised of living autologous cells

manipulated ex vivo and intended for structural repair or reconstruction (61 FR
26523) (May 1996)

FDA guidance concerning demonstration of comparability of human biological

product, including therapeutic biotechnology-derived products (April 1996)

PHS guideline on infectious disease issues in xenotransplantation (January 2011)

Guidance for Industry: Source, Animal, Product, Preclinical, and Clinical Issues
Concerning the Use of Xenotransplantation Products in Humans (April 2003)

Draft Guidance for Industry and FDA Staff: Minimal manipulation of human cells,
tissues, and cellular and tissue-based products (December 2014)

EMA (Quality, Clinical & Combined)

In European Medicines Agency. Retrieved June 5 2014, from
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/
general_content_000405.jsp&mid=WC0b01ac058002958a and
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/
general_content_000298.jsp&mid=WC0b01ac05800862bd

Guideline on the use of bovine serum in the manufacture of human biological

medicinal product (Revision 1) (EMA/CPMP/BWP/457920/2012 rev 1) (December
2013)

CHMP/CAT position statement on Creutzfeldt-Jakob disease and advanced

therapy medicinal products (adopted guideline & overview of comments)
(CHMP/CAT/BWP/353632/2010) (June 2011)

Note for guidance on minimising the risk of transmitting animal spongiform

encephalopathy agents via human and veterinary medicinal products (EMA/410/01
rev.3) (March 2011)

Development pharmaceutics for biotechnological and biological products

(CPMP/BWP/328/99) – Annex to note for guidance on development pharmaceutics
(CPMP/QWP/155/96) (April 2000)

85
Potency testing of cell-based immunotherapy medicinal products for the treatment
of cancer (CHMP/BWP/271475/06) (May 2008)

Position statement on the use of tumourigenic cells of human origin for the
production of biological and biotechnological medicinal products
(CPMP/BWP/1143/00) (February 2001)

Note for guidance on virus validation studies: The design, contribution and
interpretation of studies validating the inactivation and removal of viruses
(CPMP/BWP/268/95) (Revision 1) (August 1996)

Clinical aspects related to tissue engineered products (draft reflection paper)

(CAT/CPWP/573420/2009) (April 2012)

Guideline on safety and efficacy follow-up and risk management of advanced

therapy medicinal products (EMEA/149995/2008) (November 2008)

Guideline on strategies to identify and mitigate risks for first-in-human clinical trials
with investigational medicinal products (EMEA/CHMP/SWP/28367/07) (September
2007)

Points to consider on application with 1. Metaanalysis; 2. One pivotal study

(CPMP/EWP/2330/99) (May 2001)

Risk-based approach according to Annex I, part IV of directive 2001/83/EC applied

to advance therapy medicinal products (CAT/CPWP/686637/2011) (February
2013)

Guideline on quality, non-clinical and clinical aspects of medicinal products

containing genetically modified cells (EMA/CAT/GTWP/67636/2008) (November
2012)

Reflection paper on stem cell-based medicinal products (CAT/571134/09) (January

2011)

Reflection paper on in-vitro cultured chondrocyte containing products for cartilage

repair of the knee (CAT/CPWP/568181/2009) (April 2010)

Guideline on human cell-based medicinal products (CHMP/410869/06) (January

2007)

Guideline on xenogeneic cell-based medicinal products (adopted guideline &

overview of comments) (adopted guideline & concept paper)
(CHMP/CPWP/83508/09) (December 2009)

86
Points to consider on xenogeneic cell therapy medicinal products (CPMP/1199/02)
(December 2003)

Xenotransplantation guidance, Department of Health UK (December 2006)

Guideline on risk management systems for medicinal products for human use
(CHMP/96268/2005) (November 2005)

Guideline on scientific requirements for the environmental risk assessment of gene

therapy medicinal products (EMEA/CHMP/GTWP/125491/2006) (February 2007)

Guideline on potency testing of cell-based immunotherapy medicinal products for

the treatment of cancer (EMEA/CHMP/BWP/271475/2006) (October 2007)

Draft guideline on the quality, non-clinical and clinical aspects of gene therapy
medicinal products (EMA/CAT/80183/2014) (May 2015)

TGA

Australian regulatory guidelines for biologicals (ARGB) (February 2014). In

Therapeutic Goods Administration. Retrieved June 5 2014, from
http://www.tga.gov.au/industry/biologicals-argb.htm

Others

Gee A, ed. Cell therapy cGMP facilities and manufacturing. New York: Springer
Science + Business Media, 2009. Print.

Moore WA and Bermel J. Cell therapy manufacturing. Bioprocess International,

March 1, 2014. Retrieved January 2 2015, from
http://www.bioprocessintl.com/manufacturing/cell-therapies/cell-therapy-
manufacturing-350564/

Schletter J. Regulatory requirements of stem cell-based therapies (Part I). The

Regulatory Affairs Journal (Pharma). 2003: 185-193.

Schletter J, Ruedinger M and Esser S. Regulatory requirements of stem cell-based

therapies (Part II). The Regulatory Affairs Journal (Pharma). 2003: 277-285.

Schletter J. Regulatory requirements of stem cell-based therapies (Part III). The

Regulatory Affairs Journal (Pharma). 2003: 277-285.

International Society for Cellular Therapy (ISCT). (n.d.). Retrieved January 27

2015, from http://www.celltherapysociety.org/

International Society for Stem Cell Research (ISSCR). (n.d.) Retrieved January 27
2015, from http://www.isscr.org/

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