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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
during the manufacture of the product, thus increasing the complexity of the manufacturing process. In addition, there is much
uncertainty in terms of whether signaling molecules can bring
about the desired cellular dierentiation, whether the scaold supports cellular growth and vascularization or whether the product
has the desired structural properties [7].
Quality control
Due to the limited amount and variability of the material, the traditional approach of process validation can be dicult to perform,
especially for autologous products, as it requires multiple successful production batches to be evaluated and potential changes to be
made to critical processes, equipment and materials subsequently.
Additionally, as the mechanism of actions for cells are not well recognized, the critical quality attributes (CQAs) associated with measurable product attributes for assuring functional quality and reproducibility cannot be determined [54].
The intrinsic variability of cells also contributes to the variability of
critical process parameters (CPPs). In the use of cells in tissue engineering, purity is assured since characterization has been achieved
for dierentiated cells. However, pluripotent cells would require
100% purity to avoid tumorigenicity, thus creating ambiguity in the
assessment of their safety and ecacy [55]. Each component, such
as the production of scaolds, would require the maintenance of
their quality attributes before seeding them with cells, raising the
complexity of tissue-engineered products [45].
The monitoring of CPPs, such as culture conditions, which are
elements of the production process that aect CQAs such as cell
Cells, Tissues, and Gene Therapy Products
quality and reproducibility across multiple batches and manufacturing sites have not been established. Extensive data analytics
and models would thus have to be used to identify sets of markers
(as CQAs) from animal studies and clinical trials to establish product safety [54]. Currently, there is a shortage of robust process analytical technologies (PATs) to examine CPPs for cell-expansion and
other processes. Although PAT devices that monitor pH, dissolved
oxygen (DO), and other biopharmaceutical CPPs have improved
significantly in terms of miniaturization and integration, the
manufacture and quality control of CTGTPs are still using monitoring or detection devices that can damage the sample [56]. Overall, CTGTP manufacturing does not currently incorporate quality-by-design principles that allow for high quality and extensive
production of therapeutic cells [54].
373
Cryopreservation
Cell function starts to deteriorate after the collection of the sample and continues up to cryopreservation [25]. In cryopreservation,
cells are commonly stored in liquid nitrogen at −196 C. To recover
cryopreserved cells, slow freezing and fast thawing are usually performed [57]. The construction of a cryo-chain for extended storage
and delivery is pertinent to preventing the decrease in metabolic
activity and cell viability as cells go through dierent stages in the
manufacturing process, which may take up to more than 4 weeks
due to quality assessments, release controls and shipment in the
case of a centralized process [58]. In contrast, a decentralized process takes up to only 2 weeks as there is no need for cryopreservation nor the shipment of T cells, which protects the cells from
injury during freezing and thawing [59]. A shortened duration
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
between leukapheresis and infusion also reduces the need for the
patient to receive bridging chemotherapy, which is important in
controlling disease progression and averting infections from low
blood cell count [58]. A patient would need to receive bridging therapy to control disease progression and prevent potential infections
due to low blood cell counts while waiting for the infusion [58],
thus a shortened duration between leukapheresis and infusion in
decentralized processes would also cut down on costs of chemotherapy and extended hospital stay [59].
Human resource and accreditation
Due to the novelty of technology involved in the manufacturing
process, human resources would have to be trained, requiring
expertise from biology, engineering and computer science [54].
A survey conducted has shown that human resources in multiple fields such as business expansion and product development,
together with researchers possessing a comprehensive scope of
qualifications, were much sought after. Personnel with GMP manufacturing experiences were also needed by a large portion of
respondents [60]. In the context of centralized processing, the ecient allocation of manpower and equipment can be realized [27],
if professionals have a thorough under- standing of cryopreservation protocols [25], treatment guidelines and possible complications of CTGTP administration, such as cytokine release syndrome
and neurotoxicity [8]. Additionally, physicians tend to be clinically
conservative and are unwilling to utilize novel treatments especially if they require atypical methods of delivery, thus necessitating evidence in safety assurance and the ability for processes to
integrate into existing clinical practice [61, 62].
Cells, Tissues, and Gene Therapy Products
Potential solutions to the challenges encountered in manufacturing
Outsourcing
Due to the substantial cost of manufacturing CTGTPs, it is important to decide which manufacturing strategy is suitable to cater to
a specific product and to design a strong supply chain that can withstand disruptions, such as in a global pandemic where a shortage of
materials can result in delayed shipments of cell therapies [63]. One
strategy where pharmaceutical start-ups and small developers who
lack the resources to manage in-house manufacturing may choose
to outsource to contract development and manufacturing companies (CDMO), which are larger and better able to utilize economies of
scale [64]. In the absence of trained personnel, it may be prudent to
outsource aseptic procedures to avoid potential sterility and contamination issues. If companies struggle to meet guidance standards, they
should be strongly encouraged to increase the extent of outsourcing to
help in the compliance of GMP standards. It is of critical importance
that the CTGTP manufacturing setup complies with GMP standards.
375
Qualifications
Current GMP guidelines for CTGTPs only require healthcare professionals to have appropriate training in terms of aseptic handling
and gowning with no specific qualifications or minimum years of
training [1]. While these guidelines cannot be too specific due to the
wide range of CTGTPs, higher standards are expected for products
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
that have undergone substantial manipulation as opposed to minimally manipulated products, which are allowed to comply with
less stringent standards. Going forward it is recommended that a
minimum length of relevant working experience be stipulated for
personnel handling CTGTPs. It should also be made mandatory
for personnel who are directly engaged in CTGTP processing to
undergo training and be certified in basic aseptic techniques. Professionals may also be encouraged to participate in further education programmes to increase their scientific knowledge of CTGTPs.
This is particularly important as a lack of skills and knowledge can
impact the quality of the product significantly. This can be seen
from the trends in biologicals manufacturing where mishandling in
production and administration has led to substandard and unsafe
protein products [65]. As more products undergo clinical trials,
more scientific knowledge will be generated, some of which can
then be incorporated into regulations. The requirements for personnel qualifications and training may then be more clearly stipulated based on the types of CTGTP products manufactured.
Technology
A changing mindset is also necessary in terms of embracing emerging trends of Industry 4.0, including disruptive technologies to
improve the comparability of products and to reduce contamination. Technologies can be used to model available data in the calculation of operational feasibility and cost implications to avoid
unnecessary cost, as shown in a study by Lam C et al. [66], and to
improve the quality of products through robust and non-destructive monitoring techniques.
Cells, Tissues, and Gene Therapy Products
Control of CTGTPs
Current regulatory framework
Table 5 summarizes the regulatory frameworks governing CTGTPs
across several jurisdictions. Some are more comprehensive than
others in providing for the dierent types of pathways. Many countries have expedited pathways to cater to the need for CTGTPs to
reach patients quickly.
Gaps identified in regulatory control and potential
solutions
377
Risk-based approach
The risk-based approach is contingent upon identifying risks associated
with the use of a CTGTP in the clinical setting and its inherent risks
concerning quality, safety and ecacy. This process starts at the beginning of product development and matures over time, as the knowledge of the product and its characteristics increases [31]. Expedited
pathways shorten this process, allowing therapies to reach patients
quickly and increase options available, which is important especially
in life- threatening diseases. However, this means that less evidence of
safety and ecacy is collected, which may impact product quality [74].
Furthermore, manufacturers have no incentive to perform postmarketing promptly due to potential adverse eects leading
Table 5: An overview of regulatory frameworks by Regulatory Authorities (RAs) and International Organisations (IOs)
US FDA Europe EMA
Act/regulation Food, Drug and Cosmetic Act (FDCA), Code of
Federal Regulations (CFR) Title 21, Public Health
Service (PHS) Act.
Expedited
pathways
Exempted from
licensing
Authorization
procedure/
comments
• Fast-track
• Priority review
• Breakthrough designation
• Accelerated approval
• Rare pediatric disease designation
• Regenerative Medicine Advanced Therapy (RMAT)
designation
Minimally manipulated: Section 361 HCT/Ps. Hospital exemption if the following conditions are satisfied:
An investigational new drug (IND) application is
needed to start clinical trials for CTGTPs. This is
then used to support a Biologics License Applica-
tion (BLA) for the marketing of the product.
The license demonstrates safety and ecacy of the
drug for a clinical indication. The review time for a
standard BLA is 10 months, and 6 months for
Regulation (EC) No 1394/2007 (2007)
• Conditional approval
• Accelerated assessment
• Approval under exceptional circumstance
• Adaptive pathway
• PRIME
1) be constituted on a non-routine basis under quality
standards; 2) be used within the same Member State in
a hospital under the sole responsibility of a healthcare
professional; and 3) follow a medical prescription for a
personalized product for a single patient.
A centralized procedure where the evaluation for marketing
authorization (MA) is done by the appropriate European
Medicines Agency (EMA) committee instead of a national
regulatory agency, allowing product to be marketed
throughout the European Economic Area (EEA) with
a single Marketing Authorization. The Committee for
Advanced Therapies (CAT) reviews the data submitted
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
priority review. All CTGTPs are mostly regulated as
biologicals/combination products.
An IND that is intended to treat a serious condition
where nonclinical or clinical data can demonstrate
the possibility of addressing unmet medical needs
is eligible for fast-track designation.
Breakthrough therapy designation requires prelim-
inary clinical evidence proving that the product
may be better than existing therapies on clinically
significant endpoints. For RMAT designation, the
IND must also meet the definition of regenerative
medicine therapy in addition to the requirements
for breakthrough therapy. Priority review, fast
track and breakthrough designation applicants will
receive a response within 60 calendar days, while
the response timing for accelerated approval is not
specified.
Ref. [30], [67] [68]
Australia TGA Japan PMDA China NMPA
Act/regulation Therapeutic Goods Order 88,
Australian Code of Good Man-
ufacturing Practice, Australian
Gene Technology Act 2000.
Pharmaceuticals and Medical Devices (PMD)
Act.
The accelerated assessment pathway is for medicinal
No response timeframe is stipulated for the pathways.
and makes recommendations. Clinical trial authoriza-
tion (CTA) approvals occur within each Member State
advanced therapy medicinal products (ATMPs) are regu-
lated as drugs.
products of major interest to public health and targets
an unmet medical need, whereas the approval under
exceptional circumstance requires products to target
rare indications which applicants are unable to provide
comprehensive evidence for. Conditional approval covers
products that are used in emergency situations. PRIME
covers products that fulfil unmet clinical needs.
Cells, Tissues, and Gene Therapy Products
No specific legislation
Drug Administration Law (1984).
(Continued)
379
Expedited
pathways
Exempted from
licensing
Authorization
procedure/
comments
US FDA Europe EMA
Therapeutic Goods Order 88,
Australian Code of Good Man-
ufacturing Practice, Australian
Gene Technology Act 2000.
1) Must be manufactured and
administered by healthcare
professionals responsible for
clinical care.
2) For a single indication, in a
single clinical Procedure.
Clinical trials are conducted
under the clinical trial notifica-
tion (CTN) or clinical trial
exemption (CTX) scheme and is
dependent on the risk level and
newness of the therapy. The
CTN requires scientific and
ethical reviews by the relevant
human research ethics commit-
tees (HRECs) with only central
trial documents
Table 5: (Continued)
• Conditional market authorization
• SAKIGAKE Designation
• Priority review
• Orphan designation
Minimally manipulated, for homologous use. —
A special regulatory pathway is used,
whereby a conditional, time-restricted
marketing authorisation pathway is estab-
lished specifically for CTGTPs under the
PMD Act CTGTPs which can demonstrate
safety and ecacy in preliminary clinical
trials are eligible for conditional market-
ing authorisation for 7 years, following
which conditional MA holders reapply to
check if the product is eligible for standard
MA through post-market corroboration.
• Conditional approval
• Priority review
• Designation for breakthrough
therapeutics
• Designation for foreign new
drugs
A clinical trial application (CTA)
is to be submitted for biologi-
cal products and reviewed by
the Centre for Drug Evalua-
tion (CDE). After approval by
the CDE, clinical trials can be
conducted for the preparation
of New Drug Application
(NDA) submission, to be
approved by the NMPA Drug
Registry Department.
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
required for submission to
them, while the CTX scheme
requires dossier submission in
the Common Technical Doc-
ument (CTD) format, which
requires a longer evaluation
process than the CTN.
Genetically modified human
cells (Class 4 biologicals) must
be submitted under the CTX
scheme unless a trial with the
same product for the same indi-
cation has been approved in a
comparable jurisdiction.
Ref. [36], [69], [70] [33] [71 , 72]
India CDSCO Singapore HSA Malaysia NPRA
Act/regulation No specific legislation.
The Drug and Cosmetic Act
(1940).
The priority review takes nine months,
catered for products with no standard
existing therapy and is applicable to
serious diseases. The SAKIGAKE, meaning
pioneer, oers a prioritised consultation
with reduced waiting time for medical
products targeting diseases with unmet
medical need.
Health Products (Cell, Tissue and Gene Ther-
apy Products) Regulations 2021.
Since 1 January 2021, 23 new
guidelines have been issued
by the CDE, such as the
Guidelines for Clinical Trials
of Antimicrobial Drugs for
Complex Abdominal Infec-
tions (No. 10 of 2021)
Fast track approvals take up to
16 months. Drugs for rare and
life-threatening diseases with
no existing treatment which
have already been approved
in the US, EU or Japan in the
past decade and unapproved
in China may go through for
breakthrough, priority, fast-
track or special designation for
approval.
Regulated as biological product.
Sale of Drugs Act 1952, Control
of Drugs and Cosmetic Regu-
lation 1984.
Cells, Tissues, and Gene Therapy Products
381
(Continued)