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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5577_Библиотеки_им_академика_М_И_Перельмана.pdf
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
left at room temperature (2°C to 25°C) for up to 6 hours. No refreezing of such vaccines is allowed after reconstitution. Any remaining
unused vaccine must be discarded after 6 hours [98, 99].
Regulatory controls
The inherent need for scientifically sound vaccine regulation is
acknowledged by regulatory authorities, both globally and nationally [100]. All countries should have an organization that is legally
responsible for vaccine regulatory actions. Vaccines are a distinct
class of biological products which need to be subject to specific
regulations due to their unique characteristics. Since there is currently no single biopharmaceutical products classification system
that clearly defines vaccines and their respective scope of regulation [101], national regulatory authorities (NRAs) across dierent
nations have set their own regulations. Table 3 summarizes some
vaccine-producing countries and the names of their NRAs.
Apart from NRAs, there are other international organizations (IO)
that aid in the harmonization of vaccine regulation. Although not
defined as an RA, these IOs are important in vaccine control as they
act as a benchmark organization for regulation by setting standards
recognized by most countries. These IOs set guidelines which form
the basis of regulations enforced by the NRAs. The World Health
Organization (WHO) is one IO that is a key player in vaccine regulation by its provision of harmonized standards for NRAs. While
dierent NRAs have slightly varying standards, most vaccines are
regulated similarly in accordance with WHO or internationally-standardized guidelines [103].
Novel and Traditional Vaccines
Table 3: Some vaccine producing countries and their NRAs [102]
Country
United States (US) Food and Drug Administration (FDA) — Center for
Biologics Evaluation and Research (CBER)
United Kingdom (UK) Medicines and Healthcare products Regulatory Agency
(MHRA)
European Union (EU) European Medicines Agency (EMA)
Australia
Canada Health Canada
Switzerland Swissmedic — Swiss Agency for Therapeutic Products
Belgium Federal Agency for Medicines and Health Products
France National Agency for the Safety of Medicines and Health
Germany Paul Ehrlich Institute (PEI)
Italy Italian Medicines Agency (AIFA)
Netherlands Medicines Evaluation Board (MEB)
Korea Ministry of Food and Drug Safety
Japan Pharmaceutical and Medical Device Agency (PMDA)/
NRAs: national reg ulatory authorities.
Therapeutic Goods Administration (TGA)
(FAMHP)
Products (ANSM)
Ministry of Health, Labor and Welfare (MHLW)
Regulatory Authority
333
Regulatory control of vaccines begins with the development of
the vaccine where multiple clinical trials are required before it is
eventually licensed for manufacture. This review focuses on postlicensure regulations relating to vaccines’ manufacture and postmanufacture handling.
All procedures involving vaccine handling are bound by specific
regulatory requirements, and details set by the respective NRAs.
Firstly, vaccine manufacturers require a license to operate, regardless of their country of origin [104]. The license is granted under
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
the condition that a set of standard manufacturing procedures is
established and only this approved set of procedures is permitted at
the specific manufacturing facility. In the US, vaccine manufacturers are also required to have a functional department reporting any
proposed changes to the US Food and Drug Administration (FDA),
Centre for Biologics Evaluation and Research (CBER). Strictly no
digression of the standard procedures, raw materials or equipment
will be condoned by FDA until it is approved by CBER [105]. Vaccine
manufacturers are also required to complete and produce all necessary documentations for inspection at all times [105]. FDA stipulates all manufacturing information and documentations required
for the Biologics License Application (BLA) [106].
In general, vaccine manufacture is strictly required to be performed in cleanrooms, that are specifically designed to allow for
sterile manufacture of products in accordance with good manufacturing practices (GMP) guidelines [107]. These GMP guidelines have
been prepared by WHO and other NRAs and IOs (e.g. US FDA, EMA
and PIC/S), and they specify precise measures required to ensure the
manufacture of safe and good-quality vaccines. A specific portion of
the guidelines is used internationally as a reference for individual
countries to set their national GMP requirements in vaccine manufacturing facilities [108]. This means that the cleanrooms have to
maintain a certain GMP grade before they can operate. Figure 4
shows some examples of cleanroom grades for the dierent stages
of vaccine manufacturing.
Additionally, the US Centers for Disease Control and Prevention
(CDC) will assign the biosafety levels (BSLs) to the vaccine-related
facilities after assessment of the level of precautionary measures
required. Dierent vaccine types require dierent BSLs for its
Novel and Traditional Vaccines
Figure 4: Cleanroom grades required for dierent stages of vaccine manufacturing [109]
cleanrooms and related facilities. For example, some cell-culturebased Influenza vaccines are assigned BSL 2 due to its large-scale
open nature, while other Influenza vaccines are assigned BSL 4
due to the virus’ highly virulent nature [110]. According to the BSL
assigned, the amount of safety controls implemented will dier,
such as the compulsory use of dierent personal protective equipment (PPE) or specific training required. Table 4 shows a summary
of the dierent BSL and the respective considerations required.
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Airlocks and airflow hoods are necessary to ensure unidirectional
air flow and to maintain sterility of the environment. The walls
of the facility have to be specially designed and environmental
monitoring is mandatory. The facility also needs to be kept at the
optimal temperature for manufacture by employing heating, ventilation and air conditioning (HVAC) systems [112]. The workers
in the manufacturing facility are also regulated. They need to be
dressed in the appropriate PPE and undergo necessary training.
The complex nature of vaccine processing and handling necessitate
timely inspections of the vaccine facilities and its procedures based
on WHO or other international GMP standards.
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Table 4: Summary of the dierent biosafety levels (BSLs) and the corresponding
controls
Infectious agent
BSL
1 Non-pathogenic – PPE, e.g. laboratory coats, gloves and goggles
2 Moderate risk with
3 Airborne or lethal In addition to BSL 2 controls, other requirements
4 Aerosol transmission
characteristics Specific controls [111]
– Sink
– Separated working space with doors
In addition to BSL 1 controls, other requirements
contact
or lethal with no
therapy available
include:
– Face shields
– Use of biological safety cabinet (BSC) for
specific procedures
– Autoclaving of waste
include:
– Respirators
– Restricted laboratory access
– Medical surveillance and vaccination of workers
– One-directional airflow
In addition to BSL 3 controls, other requirements
include:
– Full-body pressure suit
– Disinfection of all materials and persons
leaving the premise
– Isolated from other parts of the building
Additionally, the International Organization for Standardization
(ISO) has developed a harmonized standard, namely the ISO classification for cleanrooms and controlled areas, as a standardization of
quality assurance across industries, including healthcare. It is widely
used in many countries including the United States and European
Union where vaccine cleanrooms are subjected to ISO classifications [113] according to its particulate content as shown in Table 5.
Novel and Traditional Vaccines
Table 5: ISO classification of cleanrooms [114]
Maximum concentration of particles of sizes:
Class
ISO 5 100,000 23,700 10,200 3,520 832 29 240–480
ISO 6 1,000,000 237,000 102,000 35,200 8,320 293 150–240
ISO 7 Not considered 352,000 83,200 2,930 60–90
ISO 8 3,520,000 832,000 29,300 5–48
Air changes per
hour (ACPH)≥ 0.1μm ≥ 0.2μm ≥ 0.3μm ≥ 0.5μm ≥ 1μm ≥ 5μm
(Unidirectional)
(Turbulent)
(Turbulent)
Each cleanroom used for handling vaccines has a specific ISO class
which determines its respective controls. There are 9 ISO classes
according to the particulate level in the air. In cleanrooms, classes
5 to 8 are the most commonly required and their characteristics
are summarized in Table 5. Lower ISO classes have more stringent
requirements. For example, the areas have a lower maximum concentration of particulates and hence require higher rates of airflow to
maintain the air quality [115].
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Challenges, safety and quality issues and possible solutions
Despite stringent regulation and post-market surveillance of the
vaccine industry, challenges in the manufacture of safe, ecacious,
and good quality vaccines still prevail. Currently, there is no single
harmonized regulatory system that defines the standards for the
manufacture, storage and distribution of vaccines across the world,
resulting in subjectivity of controls [101]. Scientifically, vaccines have
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
been defined to include biological preparations which are administered to confer immunity against specific diseases [24, 25]. Without
a standardized universal definition of vaccines, there are dierences
in how regulatory authorities and manufacturers emphasize control
on vaccines. For instance, RAs tend to focus on safe vaccines and
need for vaccines to contain adjuvants that would ensure its quality
[116–119]. On the other hand, manufacturers may tend to emphasize
on the overall ecacy of vaccines in reducing disease rate or severity
[120]. This variation in emphasis may pose complications and challenges in the regulations and manufacture of vaccines.
The lack of a standardized or internationally harmonized framework can lead to diering frameworks and therefore variations in
terms of regulatory control. For example, currently, the two dominant regulatory frame works are the EU GMP Guidance Annex 1:
Manufacturing of Sterile Medicinal Products [121], and the US
FDA Guidance for Industry: Sterile Drug Products Produced by
Aseptic Processing Current Good Manufacturing Practice [122].
Some key dierences in the US and EU regulations are summarized in Table 6.
Table 6: Key dierences between the US and EU cleanroom regulations [123]
Cleanroom requirements
Size of particulate considered ≥ 0.5mm only Both ≥ 0.5mm and ≥ 5.0mm
Specification of ISO classes
when not in operation
Types of processes considered Aseptic processes
Existing ISO class for aseptic
processes
Existing ISO class for support-
ing clean areas
ISO: International Organization for Standardization.
US FDA EU
Not specified Specified
Aseptic processes terminal
only
ISO 5 ISO 4
Not specified ISO 8
sterilization
Novel and Traditional Vaccines
In comparison with US regulations, the EU GMP Guidance has a
larger and more stringent scope for cleanroom requirements [124].
Additionally, the EU has set dierent requirements for cleanrooms
during and after operation respectively. On the other hand, the US
FDA has no specifications for cleanroom particulate levels when
manufacturing processes are not on-going. While the EU has specified that cleanroom requirements apply to both aseptic processes
and terminal sterilization, the US FDA Guidance specifies only aseptic processes, and does not mention terminal sterilization. Although
Annex 1 of the EU GMP Guidance has recently been revised in 2020
to widen its scope [125], the harmonization of standards between
the two major jurisdictions remains a more desirable solution.
In 2021, a US vaccine manufacturing plant by the name of Emergent BioSolutions (EBS) had its production operations suspended
due to contamination of its vaccine products. The single facility was
used concurrently for the manufacture of two dierent COVID-19
vaccines, one by Johnson & Johnson (JNJ) and the other by AstraZeneca (AZ), leading to a mix-up of distinct starting materials
required for each vaccine [126]. JNJ is a company based in the US
while AZ is a company based in Belgium; however, both vaccines
are manufactured in the same US facility, namely EBS. Although
both vaccines involved are novel vaccines using similar viral vectors,
the respective vectors used were non-identical and incompatible. It
does not help that there are diering cross-jurisdictional regulatory
requirements between the US and Belgium.
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Additionally, it was discovered that the facility at EBS had previously
been found to have a substandard documentation of procedures and
training of sta involved [127]. While existing regulations are in
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
place, subsequent review of these regulations and their enforcement
are equally crucial. This unfortunate event also points to a need for
global convergence and harmonization of international standards
for vaccine manufacture and regulation.
Currently, many developing countries still lack a functioning framework for regulating vaccines. In fact, as of 2020, a significant 73%
of WHO Member States do not have a mature system for optimal
regulation of vaccines [128]. Developing countries also face additional challenges in maintaining the quality of vaccines due to the
lack of funding and resources. To be approved as a functional NRA
by WHO, the regulatory body must be able to perform regulatory
actions such as assuring standards for vaccine licensure and conducting regular inspections of facilities, at least a maturity level of 3
and above [103]. This includes having a national laboratory solely for
testing and evaluating the ecacy of vaccine in the country. This
poses a challenge to developing countries which are already experiencing a strain on their overall regulatory resources.
With the COVID-19 pandemic driving the need for safer and more
ecacious vaccines, new types of vaccines are expected to emerge
in the near future. With this evolution, there are also challenges
that are bound to arise in the manufacture and quality assurance of
both traditional and novel vaccines. The manufacture of traditional
whole vaccines is labor and time intensive, which poses the risk of
pathogenic shift or drift as the vaccines undergo manufacture. Also,
subunit vaccines face the challenge of thorough purification as they
contain antigens of relatively smaller sizes. This can limit the degree
of purification possible and make it harder for the manufacture of
safe vaccines.
Novel and Traditional Vaccines
Likewise, mRNA vaccines face specific challenges to their novelty.
Since most novel vaccines are relatively new, there is still lack of
optimization at many stages of their manufacture, which may compromise the quality of vaccines manufactured. The complexity of
mRNA vaccines also adds to the challenge of requiring more intricate quality assurance systems that are able to assure the vaccine’s
quality at every stage of manufacture [80].
The recent rise in adverse events globally due to the use of poorquality vaccines suggest the possible inadequacy of current regulatory frameworks and presents opportunity for refinement. In 2013,
a batch of Gardasil HPV vaccine was recalled due to contamination
with the vaccine glass shards [129], suggesting poor GMP compliance and inadequate enforcement of regulations.
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WHO has shown much eort in harmonizing regulatory frameworks with regular review of regulatory guidelines. However, international harmonization of vaccine regulations is the way forward as
this would allow cross-border use of all vaccines approved according
to such an internationally-harmonized regulatory framework for
vaccines.
Conclusion
Challenges in the manufacture, storage, distribution and supply chain management, and associated regulation of vaccines are
expected to continue. Vaccines have become a crucial weapon in the
global war against pandemics. Our reliance on vaccines during the
COVID-19 pandemic has clearly illustrated the critical importance