Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5855_Библиотеки_им_академика_М_И_Перельмана.pdf
312
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
In 1801, Jenner published his work “On The
Origin Of The Vaccine Inoculation” in The
Medical and Physical Journal and expressed hope
that smallpox, “the most dreadful scourge of
the human species”, would be eradicated from
the face of Planet Earth.
In late 1975, a three-year-old girl from Bangladesh became the last person in the world documented to have smallpox. When she contracted
smallpox, she was isolated at home
with house guards posted 24 hours
a day, until she was no longer infectious. Just over two centuries after
Jenner had expressed his hope that
vaccination will one day eradicate
smallpox, his dreams came true in
1980. On 8 May 1980, the World
Health Organization declared the
world free of smallpox. The eradication of smallpox is one of the
biggest achievements in the history of international public health
management. Although smallpox
https://en.wikipedia.org/wiki/Smallpox#/
media/File:Rahima_Banu.jpg
has been eradicated, the vaccine
can also be used to protect against monkeypox in the same way
that cowpox had protected against smallpox.
Novel and Traditional Vaccines
11.2. Traditional Vaccines Versus Novel Vaccines
What are traditional vaccines and what are novel vaccines? Traditional vaccines are derived from whole organisms such as live-attenuated or inactivated viruses or bacteria. Traditional vaccines
may also be derived from sub-units of the organism, for example,
the toxoids, conjugates and outer membrane vesicles. On the other
hand, novel vaccines are derived from nucleic acids such as mRNA
or DNA, or viral vectors such as adenovirus and lentivirus. Traditional vaccines typically fall into several categories: live attenuated
vaccines, inactivated vaccines, subunit vaccines, toxoid vaccines, and
conjugate vaccines. Here is a breakdown of the dierent categories
of traditional vaccines:
313
• Live attenuated vaccines: These contain a weakened form of the
viruses or bacteria that cause the disease. They closely mimic
the actual infection but are weakened so that they do not cause
illness in most people. Examples of live attenuated vaccines
include the measles, mumps and rubella (MMR) vaccine and
oral polio vaccine.
• Inactivated vaccines: These vaccines use killed versions of the
viruses or bacteria that cause a disease. They are made by killing the disease-causing microorganism using heat or chemicals.
The immune response to these vaccines is typically not as strong
as with live vaccines, so booster doses or adjuvants (substances
added to vaccines to enhance the immune response) might be
needed. Examples of inactivated vaccines include the hepatitis A
vaccine and the inactivated polio vaccine.
• Subunit vaccines: These use only a piece of the virus or bacterium, usually a specific protein or sugars from the pathogen, to
314
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
trigger an immune response. Because they only contain specific
antigens, they tend to produce a targeted immune response and
have fewer side-eects. The hepatitis B vaccine and some flu vaccines fall into this category.
• Toxoid vaccines: These vaccines target diseases caused by bacteria that produce toxins in the body. Toxoids are inactivated
toxins used to generate an immune response. Vaccines against
diphtheria and tetanus are examples of toxoid vaccines.
• Conjugate vaccines: Conjugate vaccines combine a weak antigen, often a polysaccharide (sugar) from the pathogen, with a
carrier protein to enhance the immune response. These vaccines are often used for diseases where the immune system
might not respond well to the weak antigen alone. Conjugate
vaccines have been used for the immunization against certain
types of bacterial infections in infants and young children such
as Hemophilus influenzae type b (Hib) and Streptococcus pneumoniae
infections.
Novel or next-generation vaccines include those that use newer technologies or platforms like mRNA technology or viral vectors.
• mRNA vaccines: These vaccines use a small piece of genetic
material from the virus (mRNA) to instruct cells in the body to
produce a protein that triggers an immune response. COVID-19
vaccines made by Pfizer-BioNTech and Moderna are examples of
mRNA vaccines.
• Viral vector vaccines: These vaccines use a harmless virus (the
vector) to deliver genetic material from the target virus into
cells. The genetic material then instructs cells to produce a
protein that triggers an immune response. The AstraZeneca
Novel and Traditional Vaccines
COVID-19 vaccine and the Johnson & Johnson COVID-19 vaccine are examples of viral vector vaccines.
Novel vaccines are known to oer advantages such as quicker development, potential scalability, and flexibility to adapt to new variants, but they may also require specialized storage or present new
challenges in terms of public acceptance or understanding due to
their innovative nature.
The COVID-19 pandemic has accelerated the pace of research and
development and regulatory approval of vaccines. From a manufacturing perspective, mRNAs can be generated very rapidly using
biotechnology. If the manufacture of mRNA vaccines is so fast and
ecient, will it replace and eclipse other traditional methods of vaccine production? The short answer is no, or not in the near future.
Most large vaccine manufacturers, including the Serum Institute of
India (the largest vaccine manufacturer in the world), have already
been set up with long-standing vaccine formulations, expertise,
equipment and traditional methods of producing vaccines. These
manufacturers are able to produce chickenpox, polio, mumps, measles, rubella, Hepatitis B, flu and many commonly administered vaccines at aordable prices.
315
Furthermore, the success of a new vaccine technology is determined
more by safety and ecacy of vaccines, rather than by manufacturing speed and eciency, per se. The production of mRNA vaccines
involves expensive technology which is currently limited to only
a handful of global innovator companies. Furthermore, mRNA is
fragile, and all mRNA vaccines require ultra-cold chain storage,
which carries enormous costs, putting a financial strain on their
accessibility to low- and middle-income economies. Being novel
316
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
vaccines, long-term pharmacovigilance data and track records are
not quite available yet. In the final analysis, the potential of mRNA
technology to create, at short notice, new vaccines and other novel
medicinal products, is a big plus point. mRNA technology presents
a huge advantage for responding to COVID-19 variants of concern
and other new diseases!
11.3. Published Article on Traditional and Novel
Vaccines
With the rapid development of traditional vaccines over the decades
and the hugely successful introduction of the novel COVID-19 vaccines by Pfizer-BioNTech and Moderna in 2021, the authors decided
to contribute a review article about traditional and novel vaccines.
The article entitled “Challenges in the manufacture, storage, dis-
tribution and regulation of traditional and novel vaccines” was
published in GaBi Journal (Volume 11 | 2022 | Issue 1). Copyright ©
2022 Pro Pharma Communications International. This article has
been reproduced with permission from the publisher of GaBI Journal, and it appears immediately after this introduction.
Novel and Traditional Vaccines
Challenges in the Manufacture,
Storage, Distribution and Regulation
of Traditional and Novel Vaccines
Adjunct Associate Professor Sia Chong Hock, BSc (Pharm), MSc; Adelia
Pheh, BSc (Pharm) (Hon); Vimal Sachdeva, MSc; Associate Professor Chan
Lai Wah, BSc (Pharm) (Hon), PhD
317
Since the onset of the COVID-19 pandemic, there has been a
significant surge in interest of COVID-19 vaccines in particular, and
other traditional vaccines in general. This strong interest is expected
to continue as the industry strives to manufacture safer and more
ecacious vaccines against COVID-19 and other infectious diseases.
Vaccines are a unique class of products, being biologicals that are
administered to healthy individuals to prevent diseases. The equitable distribution and availability of safe, ecacious and good quality vaccines are of utmost importance in preventing and controlling
infections and safeguarding public health. The continued existence
of poor-quality vaccines suggests a lack of control of manufacturing,
storage, distribution, and possibly, their associated regulation. Nonetheless, all these situations — whether positive or negative, present
opportunities for improvements. As regulatory authorities step up
eorts in regulating existing traditional vaccines, advancements
in vaccine research and development churn out novel vaccines that
pose further manufacturing and regulatory challenges. This manuscript provides an overview of vaccines, both traditional and novel,
318
and strives to identify challenges in the manufacture, storage, distribution, handling and their associated regulation. It also evaluates
whether current regulatory frameworks are adequate, and where
applicable, recommends areas for improvements. International harmonization and convergence of national regulatory framework with
the view to facilitate quicker approval of safe, ecacious and good
quality vaccines, that are accessible and aordable to patients worldwide, are also explored.
Keywords: Challenges; COVID-19 vaccines; harmonization;
manufacturing; regulation; traditional vaccines
Introduction
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Each year, millions of people worldwide receive vaccines to protect
themselves from infectious diseases that may otherwise be fatal [1].
Today, a majority of infants are subject to specific vaccines as part
of post-birth care [2]. From the well-known influenza and chickenpox vaccines with a relatively longer history of use [3] to the more
recently developed COVID-19 vaccines [4], there is a myriad of different types of vaccines in use today. Traditionally, vaccines directly
mimic a milder form of the infection to stimulate antibody production in the body of a healthy individual. But, beyond this, there
are now novel vaccines that leverage on dierent technologies to
improve their stability and ecacy [5].
Despite the large number of vaccines available, newer vaccines
are still being introduced to the regional and global markets
[6, 7]. A major reason is the presence of many existing and emerging diseases that still lack a proper preventive vaccine [8] alongside
the ever-evolving variants of such diseases, as in the case of the
Novel and Traditional Vaccines
COVID-19 virus which has evolved from the alpha, beta, delta and
into the omicron variants of concern. Additionally, the formulations of many current vaccines are also being improved to lengthen
their short-lived protection or to expand their coverage of the
disease, including the emerging strains of viruses. The potential
benefits of improved formulations are very promising. However,
there had been an overall drop in the number of vaccines introduced globally in the recent years [2] due largely to challenges
in ensuring the safety of vaccines [9]. Vaccines are of paramount
importance to the control of infections [5] and studies have shown
that they can drastically reduce the rate of infections [10, 11]. They
confer immunity against specific potentially fatal diseases such
as smallpox, diphtheria, tuberculosis, hepatitis, influenza and
COVID-19 [12]. In fact, vaccines are the primary prevention method
against many diseases [13] and are administered to healthy individuals as prophylaxis. While there is overwhelming evidence that
vaccines can prevent diseases and save lives, vaccines are never completely safe [14] and side-eects are inevitable [15].
319
Being biological in nature, the manufacture, storage, distribution
and handling of vaccines require strict temperature control to
maintain their quality [16]. They are considered cold chain products as vaccines have components that are very sensitive to temperature changes [17]. The safety, quality and ecacy of vaccines may
be significantly compromised if they are not handled under appropriate conditions [18] at any stage of their product life cycle, from
manufacture to distribution to their administration to individuals.
Across the world, regulatory authorities adopt specific national and
international standards to assure the safety, quality and ecacy of
vaccines. It is of paramount importance that there is adequate regulatory oversight to ensure that vaccines remain safe and ecacious
when they are administered to individuals at the point of use [19].
320
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Although many studies have identified various challenges in the
formulation of novel vaccines, few have addressed the challenges
in the manufacture and quality assurance of such vaccines, postformulation [20–23], as well as the challenges that are common to
both traditional and novel vaccines.
Hence, this article aims to provide a better understanding of the
evolution of vaccines and identify the challenges in vaccine manufacture, storage, distribution and their regulation. This article also
intends to evaluate whether existing national and international
regulatory frameworks for vaccines are sucient to address these
challenges, and to propose improvements.
Classification of vaccines
There are many dierent types of vaccines, and their key dierences
may form the basis for the need of specific control measures during
manufacturing and regulatory control. Regardless of its classification, a vaccine is scientifically defined as a pharmacological compound for improving immunity to a specific disease [24, 25]. All
vaccines have a general mechanism of action where the body recognizes the vaccine’s components (associated with the disease pathogen) as foreign antigens and thereby stimulates antibody production
against the specific anti-gens. Active immunity is acquired [26] as
future exposure to the same pathogen would trigger memory cells
to begin a chain of signals leading to suppression and removal of the
pathogen [27]. Vaccines may be classified according to the types of
pathogenic component that it contains [28–30]. Vaccines can also be
broadly classified as traditional or novel. Table 1 summarizes some
common vaccines according to class, type and composition.
Vaccine class
type [31] Composition
Traditional Whole Live-
attenuated
Inactivated Killed or
Subunit
Tox oid Inactivated bacte-
[40]
Recombinant Bacterial/viral pro-
Conjugate Bacterial/viral pol-
Vac cine
Table 1: Vaccines: class, type and composition
Vaccine example
Live weakened bac-
teria/ viruses
non-replicating
bacteria/viruses
rial/ viral toxins
tein fragments
ysaccharide antigen conjugated
to toxoids
Priorix®
combined
vaccine
Vari vax®
vaccine
IPOL®
vaccine
Imovax®
vaccine
®
Adacel
(Tdap)
vaccine
Energix B
vaccine
®
ACTHib
vaccine
Prevnar20
vaccine
Measles,
mumps
& rubella
(MMR)
Chickenpox/
Vari cel la
Polio Poliovirus [37] 1896 – Typhoid
Rabies Rabies
Diphtheria Corynebacterium
Tet anu s Clostridium
®
Hepatitis
B [43]
Influenza Influenzae B
®
Pneumococcal
disease and
pneumonia
Rubeola virus,
[32, 33] 1798 – Smallpox
Rubulavirus,
Rubivirus
Varicella virus [35, 36]
[39]
lyssavirus
[41] 1932 – Diphtheria
diphtheriae
tetani
Hepatitis B
[44] 1970 – Anthrax
virus
[46 ] 1987 – Influenzae B
(Hib)
Streptococcus
[48]
pneumoniae
First
licensed in:Name Disease Pathogen Reference
(vaccinia) vaccine [34]
vaccine [38]
vaccine [42]
Novel and Traditional Vaccines
vaccine adsorbed
(AVA) [45]
(Hib) vaccine [47]
(Continued)
321