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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5335_Библиотеки_им_академика_М_И_Перельмана.pdf
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
of vaccines in the war against this elusive infection. The COVID-19
pandemic has also highlighted the importance of both the industry and the authority to work closely together to assure that safe,
good quality, and ecacious products are available at vaccination
centers and points of use that are located at each and every nook
and corner of the world. In a more positive light, the COVID-19
pandemic has presented opportunities for collaboration amongst
NRAs, IOs and the industry in vaccine manufacture, storage, distribution, handling, regulation, and international convergence of
standards. Globally, NRAs should strive towards an internationallyharmonized regulatory framework that will facilitate the approval
and use of vaccines, whether traditional or novel, across national
borders.
Competing interests: None
Provenance and peer review: Not commissioned; externally peer
reviewed.
Authors
Adjunct Associate Professor Sia Chong Hock1, BSc (Pharm), MSc
Adelia Pheh
Vimal Sachdeva
Associate Professor Chan Lai Wah
1
Department of Pharmacy, National University of Singapore, 18 Sci-
ence Drive 4, Singapore 117543
1
, BSc (Pharm) (Hons)
2
, MSc
1
, BSc (Pharm) (Hons), PhD
Novel and Traditional Vaccines
2
Technical Ocer (Senior GMP Inspector), WHO/HQ/MHP/RPQ/
PQT/INS, 20 Avenue Appia, Geneva CH-1211, Switzerland
References
This article has 129 references which can be found at https://gabijournal.net/challenges-in-the-manufacture-storage-distributionand-regulation-of-traditional-and-novel-vaccines.html.
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Chapter 12
Cells, Tissues, and Gene Therapy
Products
rom the apothecary of yore that mixed and compounded
extemporaneous traditional medicines, to the innovator
Big Pharma that manufactures drug substances, recombi-
F
large batch sizes, we are now into the era of tailor-made personalized medicines. Cells, tissues, and gene therapy products (CTGTPs)
are personalized medicines. These therapies often involve customization to an individual’s specific genetic makeup, health condition,
or disease state. Like a meticulous tailor who takes detailed measurements to come out with the best-fit suit for his customer, the
same goes for someone who is making a CTGTP. His goal is also
to produce a personalized and targeted medicine for his patient,
taking into consideration his serious medical condition and overall
well-being.
nant therapeutic proteins and monoclonal antibodies in
Cells, Tissues, and Gene Therapy Products
Welcome to the brave new world of CTGTPs. Here is a breakdown
of the dierent categories of CTGTPs.
12.1. Cells and Tissues
Some medical treatments involve using a patient’s own cells or
tissues (autologous) or those from a donor (allogeneic) to repair,
replace, or regenerate damaged tissues or organs. These therapies
can be tailored to the individual’s needs and thus fall within the
realm of personalized medicine.
Cells are the fundamental units of life. In the context of CTGTPs,
cells play a crucial role in regenerative medicine and cell-based therapies. Dierent types of cells can be used. They are:
345
• Stem Cells: These possess the remarkable ability to develop
into various cell types in the body. They can be sourced from
embryos, adult tissues (like bone marrow), or induced pluripotent stem cells (reprogrammed adult cells).
• Immune Cells: Certain therapies involve modifying a patient’s
immune cells, such as Chimeric Antigen Receptor T-cell therapy,
to target and destroy cancer cells more eectively.
• Progenitor Cells: These are more specialized than stem cells but
can still dierentiate into specific cell types. Progenitor cells
may be used in tissue repair or regeneration.
Tissues are groups of cells working together, each with a specific
function. In CTGTPs, tissues can be used for various purposes:
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
• Organ Transplants: During organ transplantation, tissues from
donors may be used to replace damaged organs.
• Tissue Engineering: During tissue engineering, scientists can
create artificial tissues for transplantation or research purposes.
For instance, engineered skin grafts can aid burn victims or
those with skin conditions.
• Regenerative Medicine: In regenerative medicine, tissues may
be used to stimulate the body’s natural healing processes, thus
aiding in tissue repair or regeneration.
12.2. Gene Therapy Products
Gene therapy involves modifying or manipulating a person’s genes
to treat or prevent disease. This can involve adding a gene, replacing
a faulty gene, or turning o a gene causing issues. Gene therapies
can be highly specific to an individual’s genetic profile and are often
considered a form of personalized medicine. Gene therapy products
involve the modification or introduction of genetic material into a
person’s cells to treat or prevent diseases caused by genetic mutations or deficiencies. They include:
• Viral Vectors: Certain viruses are modified to carry therapeutic
genes into the body’s cells. They act as delivery vehicles for introducing genetic material to correct or replace faulty genes.
• Naked DNA/RNA: Direct introduction of genetic material into
cells without using a viral carrier. This method is being explored
for various applications.
Both cell-based and gene-based therapies aim to provide targeted and
tailored treatments that address specific aspects of an individual’s
Cells, Tissues, and Gene Therapy Products
health or genetic makeup, making them part of the broader landscape of personalized medicine. Cell therapies include the use of
stem cells for regenerative purposes or via the insertion of gene into
T-cells for the production of special receptors such as the chimeric
antigen receptor as gene therapies for the treatment of cancers and
rare diseases. Gene therapies oer a more permanent solution to
genetic diseases, when compared to conventional treatments such
as chemotherapy, through the introduction of genetic material
which produces therapeutic proteins. Typically, this circumvents
the restrictions related to the therapeutic use of recombinant peptides, including low bioavailability, clearance rates, and exorbitant
production cost.
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Today, it is known that CTGTPs are medicinal products with
immense potential for the treatment of diseases with no existing
cure, e.g., Friedreich’s ataxia, or rare diseases with high treatment
burdens, e.g., hemophilia. CTGTPs also hold enormous promise for
treating certain medical conditions arising from genetic disorders,
as in some childhood cancers and more. They are also used in regenerative medicine to restore previously compromised or deteriorated
tissues such as those of the knees and joints and other neurodegenerative diseases, as well as those of the heart, brain, spine and
eyes.However, their development and application require thorough
research, clinical trials, and regulatory approval to ensure safety,
ecacy, and ethical considerations are met.
CTGTPs have also been referred to as Advanced Therapy Medicinal
Products (ATMPs). This is because they emphasize the innovative
and sophisticated nature of these therapies compared to conventional medicinal products. They often require complex manufacturing processes, personalized or tailored therapeutic approaches, for
medical conditions which cannot be eectively treated by conventional medicinal products. Also, regulatory authorities such as the
European Medicines Agency and the US FDA categorize CTGTPs
under the broader umbrella of ATMPs to subject them to specialized and more stringent regulatory oversight. ATMPs require more
stringent evaluation to ensure their safety, ecacy, and quality due
to their complex nature and potential risks associated with manipulating genetic material or cellular components.
12.3. Published Article on CTGTPs
The landscape of CTGTPs is dynamic, with ongoing research
and development leading to the emergence of new therapies and
Cells, Tissues, and Gene Therapy Products
expanded applications which are still evolving. This led the authors
to work on a review paper about this group of novel therapies. The
review paper entitled “Manufacture and regulation of cell, tissue
and gene therapy products: global perspectives, challenges and
next steps” has been published in GaBI Journal (Volume 11 / 2022 /
Issue 2). Copyright © 2022 Pro Pharma Communications International. The article has been reproduced with permission from the
publisher of GaBI Journal, and it appears immediately after this
introduction.
In 2023, this article had been given the recognition by GaBI Journal
for being the “Most Viewed Biosimilar Article of 2022”. The certif-
icate from GaBI Journal is exhibited below.
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Manufacture and regulation of cell,
tissue and gene therapy products:
global perspectives, challenges and
next steps
Adjunct Associate Professor Sia Chong Hock, BSc (Pharm), MSc; Christine
Koh, BSc (Pharm) (Hon); Associate Professor Chan Lai Wah, BSc (Pharm)
(Hon), PhD
Cell, tissue and gene therapy products (CTGTPs) are therapeutic
products intended for use in humans for prophylactic, diagnostic,
curative, palliative or diagnostic purposes. Generally, they are breakthrough therapies with immense potential in treating diseases with
no cure or rare diseases with high treatment burdens. Thus far, the
number of approved cell, tissue and gene therapies globally are few
and far between, with some approved products being recalled due
to safety and ecacy issues. This situation highlights the need to
rectify the challenges that are present in the manufacturing and regulation of these medicines. This article presents an overview of how
CTGTPs work using examples of existing approved products across
dierent product categories, as their mechanisms of action and characteristics contribute to manufacturing challenges. The dierences
between CTGTPs and conventional biologicals will be highlighted
to understand the need for dierent regulatory frameworks to be
designed. Additionally, these frameworks by the major regulatory
authorities and international organizations will be analysed to
Cells, Tissues, and Gene Therapy Products
elucidate whether CTGTPs are regulated to dierent extents across
countries. Challenges faced in the manufacturing and regulation of
CTGTPs include quality assurance issues, lack of expertise and limitations in technology. Potential solutions include implementing a
tighter regulatory framework, fostering the international harmonization of regulations, increasing outsourcing to meet good manufacturing practice (GMP) guidelines, and incorporating automation
into manufacturing processes to improve quality con- trol to address
the challenges encountered.
Keywords: Cell, tissue and gene therapy products; good manufacturing practice; manufacturing; quality control; regulatory authorities;
regulatory framework
Introduction
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Cell, tissue and gene therapy products (CTGTPs) are distinct categories of therapeutic products intended for use in humans for curative, prophylactic, palliative or diagnostic purposes [1]. Currently,
these revolutionary products target diseases that are managed by
therapies with high treatment burdens such as the use of recombinant factor IX protein therapy in lieu of repeated intravenous blood
infusions for hemophilia B, or rare genetic diseases where no therapies exist for patients, as in Friedreich’s ataxia (FRDA) [2].
Cell therapies include the use of stem cells for regenerative purposes
[3], or via the insertion of gene for special receptors such as the chimeric antigen receptor (CAR) onto T-cells, as gene therapies for the
treatment of cancers and rare diseases. Gene therapies oer a more
permanent solution to genetic diseases, when compared to conventional treatments such as chemotherapy through the introduction