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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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- •About the Authors
- •Preface
- •Acknowledgements
- •Contents
- •1.1. Singapore as a British Colony
- •1.5.1. Levelling Up the Pharmaceutical Inspection System of Singapore
- •1.5.2. Advantages of PIC/S Membership to Singapore and Other Participating Authorities
- •1.6. Emergence of MNC Pharmaceutical Manufacturing Industry in Singapore
- •1.6.1. Why do MNC Pharmaceutical Manufacturers Set Up Facilities in Singapore?
- •2.2. Geographical Background of ASEAN vis-à-vis Asia and the Rest of the World
- •2.4. Formation of an ASEAN MRA Taskforce on GMP Inspection
- •2.5. Signing of ASEAN Sectoral MRA on GMP Inspection
- •2.6. Formation of ASEAN JSC on GMP Inspection and Establishing Register of ASEAN LIS
- •2.8. Assessment of FDA Philippines by ASEAN PoE
- •2.9. Register of ASEAN Listed Inspection Services (LIS)
- •3.1. Introduction: Urgency of Training ASEAN Inspectors
- •3.3. Collaboration with Korea Ministry of Food and Drug Safety (MFDS)
- •3.4. Collaboration with the Generics and Biosimilars Initiative (GaBI)
- •3.5. Pre-employment Training in Pharmacy and Pharmaceutical Science Schools
- •4.1. Introduction
- •4.2. Historical Context to WHO Reliance Initiative
- •4.3. The First NRAs to Achieve ML4 and WLA Status
- •4.5. Other International Reliance and Harmonization Initiatives
- •4.5.1. Access Consortium
- •4.5.2. Association of Southeast Asian Nations (ASEAN)
- •4.5.3. East African Community (EAC)
- •4.5.4. European Medicines Agency (EMA)
- •4.5.6. International Council for Harmonization (ICH)
- •4.5.6.1. Introduction
- •4.5.6.2. ICH Members and Observers
- •4.5.6.3. Future Direction
- •4.5.7.1. Introduction
- •4.5.7.2. Addressing Common Regulatory Issues
- •4.5.7.3. ICMRA Pilot Program for Collaborative Hybrid Inspection
- •4.5.8. International Pharmaceutical Regulators Program (IPRP)
- •4.5.9. Latin America
- •4.5.10. Pharmaceutical Inspection Co-operation Scheme (PIC/S)
- •4.5.10.1. Introduction
- •4.5.10.2. PIC/S Participating Authorities
- •4.5.11. WHO Collaborative Registration Procedure for Medical Products (CRP)
- •4.5.12.1. Introduction
- •4.5.12.3. WHO Inspection Report
- •4.5.13. ZaZiBoNa
- •4.6. Conclusion
- •5.1. Introduction to GMP
- •5.2. Overview of the PIC/S GMP Standard
- •5.3. How is an On-site GMP Inspection Conducted?
- •5.3.1. Why is the Warehouse Inspected?
- •5.3.3. Why are the Production Areas Inspected?
- •5.3.4. Why are the Packaging Areas Inspected?
- •5.3.5. Why are the QC Laboratories Inspected?
- •5.3.6. Why do GMP Inspectors Visit Other Miscellaneous Areas?
- •5.3.8. Why is there a Need to Conduct Documentation Audit/Review?
- •5.3.8.1. Assessing Product Quality Review
- •5.3.8.3. Assessing Self-Inspection Program
- •5.4. The 20 Annexes of PIC/S GMP Standard
- •5.5. PIC/S Inspection System: A Risk-based Approach
- •5.5.1. Whom can the GMP Inspector Interview?
- •5.5.2.1. Inspector’s Expectations of a Manufacturer
- •5.5.2.2. Manufacturer’s Expectations of an Inspector
- •5.6. Who Inspects the Inspectors?
- •6.1. Historical Development of Pharmaceutical Quality
- •6.2. What is a High-Quality Medicinal Product?
- •6.3. Purity of a Medicinal Product: Elimination of Impurities and Contaminants
- •6.3.1. What is a Contaminated Medicinal Product?
- •6.3.2. Why is There a Need to Control Impurities?
- •6.3.2.1. Types of Impurities from APIs
- •6.3.2.2. Types of Impurities from Container-Closure System
- •6.3.3. Control of Intrinsic Contaminants
- •6.3.4. Control of Extrinsic Contaminants
- •6.3.5. General Assessment of Cross-Contamination Risks
- •6.4. Stability and Shelf-Life Testing of a Medicinal Product
- •6.4.1. Why is Proper Storage, Distribution and Handling of a Medicinal Product Important?
- •6.6. Summary of High-Quality Medicinal Products
- •7.1. Introduction to Stability and Quality
- •7.3.1. Why is Proper Storage Important?
- •7.3.2. Why is Proper Transportation of a Medicinal Product Important?
- •7.3.3. Why is Proper Handling of a Medicinal Product during Use Important?
- •7.4.1. Number and Size of Batches
- •7.4.2. Testing Frequency
- •7.4.3. Storage Conditions
- •7.4.4. Test Methods
- •7.4.5. Container-Closure Systems
- •7.5. Stability Study Schedule and Report
- •7.6. Temperature Excursions and Product Stability
- •7.8. Cold Chain Products and Temperature Excursions
- •7.11. Conclusion
- •8.1. Christopher Columbus versus the Vikings
- •8.4. Pharmaceutical Data Integrity and ALCOA
- •8.5. Article(s) on Pharmaceutical Data Integrity
- •Introduction
- •Current trends
- •Reasons for Data Integrity violations (inadvertent and intentional)
- •Assuring and promoting Data Integrity via legislation and guidance documents
- •Legislation
- •Guidance documents
- •Proposed Solutions to Better Promote and Assure Data Integrity
- •Culture of integrity
- •Database management systems
- •Robust quality agreements
- •Collaboration between countries
- •Computerized systems validation
- •List of abbreviations
- •Conclusion
- •Authors
- •References
- •9.1. Pharmaceuticals versus Biopharmaceuticals
- •9.2. Transcription and Translation: Central Dogma of Genetics
- •9.3. Biotechnology-derived Medicinal Products: Microbial versus Mammalian Substrates
- •9.4. Manufacture of Biotechnology-derived Medicinal Products: Key Processes
- •Introduction
- •Manufacture of biopharmaceuticals — an overview
- •Procurement and testing of biological starting materials
- •Generation and characterization of cell banks/seed lots
- •Cell culturing
- •Challenges concerning manufacture of biopharmaceuticals
- •Extensive process and product understanding required
- •Inherent variability of host cells
- •Downstream processing remains a key bottleneck
- •Review of current GMP frameworks for biopharmaceuticals
- •Challenges in the regulation of biopharmaceuticals
- •Resource-intensive evaluation of biosimilarity
- •Growing number of data integrity lapses
- •Proposed solutions to challenges of biopharmaceuticals
- •Optimizing biopharmaceutical manufacturing with Industry 4.0
- •Enhancing data integrity with a culture of quality (quality culture)
- •Conclusion
- •List of abbreviations
- •Authors
- •References
- •10.1. Introduction
- •10.2. Advantages of Nanomedicines
- •10.3. Types of Nanomedicines
- •10.3.1. Nanocarrier Systems
- •10.3.2. Nanosuspensions
- •10.4. Future of Nanomedicines
- •10.5. GMP Requirements Governing Nanomedicines and Challenges
- •10.5.1. Lack of Trained Personnel to Operate Manufacturing Processes
- •10.5.2. Lack of Safety Protocol for Manufacturing Personnel
- •10.5.3. Challenges in Controlling for Nanoparticle Contamination
- •10.6. Conclusion
- •11. Novel and Traditional Vaccines
- •11.1. Historical Development and Evolution of Traditional and Novel Vaccines
- •11.2. Traditional Vaccines Versus Novel Vaccines
- •Introduction
- •Traditional vaccines
- •Novel vaccines
- •Vaccine manufacture
- •Vaccine storage, transport and distribution
- •Regulatory controls
- •Challenges, safety and quality issues and possible solutions
- •Conclusion
- •Authors
- •References
- •12.1. Cells and Tissues
- •12.2. Gene Therapy Products
- •12.3. Published Article on CTGTPs
- •Introduction
- •CTGTPs and their principles of action
- •Manufacturing of CTGTPs
- •Premises and equipment
- •Materials and processing
- •Starting material
- •Quality control
- •Cryopreservation
- •Human resource and accreditation
- •Potential solutions to the challenges encountered in manufacturing
- •Outsourcing
- •Technology
- •Control of CTGTPs
- •Current regulatory framework
- •Risk-based approach
- •Conclusion
- •Authors
- •References
- •13. Hand Sanitizers
- •13.1. What are Hand Sanitizers?
- •13.4. Published Article and Commentary on Hand Sanitizers
- •Introduction
- •The microbiology of bacteria, fungi and viruses
- •Antimicrobial compounds and their applications in hand sanitizers
- •FDA policy for testing of alcohol and USP limits for methanol
- •Common myths about hand sanitizers
- •A lack of regulatory framework
- •Proposed solutions
- •Tightening the regulatory framework
- •Training pharmacists on hand sanitizer vigilance
- •Public Education
- •Conclusion
- •Authors
- •References
- •14. Pharmaceutical Dosage Forms
- •14.1. Introduction
- •14.2. What Are Pharmaceutical Dosage Forms?
- •14.4.1. Routes of Administration
- •14.4.1.1. Oral Dosage Forms — Solids
- •14.4.1.2. Oral Dosage Forms — Liquids
- •14.4.1.3. Topical Dosage Forms
- •14.4.1.5. Inhaled Dosage Forms
- •14.4.1.6. Ophthalmic Dosage Forms
- •14.4.1.7. Nasal Dosage Forms
- •14.4.1.8. Otic Dosage Forms
- •14.4.1.9. Rectal Dosage Forms
- •14.4.1.10. Vaginal Dosage Forms
- •14.4.1.11. Transdermal Patch
- •14.4.2. Physical Forms
- •14.4.2.1. Solid Dosage Forms
- •14.4.2.2. Liquid Dosage Forms
- •14.4.2.3. Semi-solid Dosage Forms
- •14.4.2.4. Gaseous or Aerosol Dosage Forms
- •14.5. Manufacture and Important Characteristics of Common Pharmaceutical Dosage Forms
- •14.5.1. Tablets
- •14.5.2. Capsules
- •14.5.3. Solutions
- •14.5.4. Suspensions
- •14.5.5. Emulsions
- •14.5.6. Creams
- •14.5.7. Ointments
- •14.5.8. Metered Dose Inhalers
- •14.6. Overall Summary of the Manufacture of a Pharmaceutical Dosage Form
- •15.1. Introduction

Safety in
manufacturing
process
Cryopreservation,
storage, trans-
port
Starting
materials
Table 2: (Continued )
Biologicals Autologous CTGTP Allogeneic CTGTP Comments Ref.
Central high-through-
put manufacturing;
integrated biobank
and cryopreservation
protocols
Typically, able to
withstand higher
temperatures (–20°C
to –40°C) with larger
time windows
Low heterogeneity High heterogeneity Low heterogeneity,
Decentralized with
multiple manu-
facturing facil-
ities; reg ional
manufacturing
sites recom-
mended
Sensitivity to cryopreservation w ithin
cell subsets dier. Cryopreservation
temperatures range from –196°C to
approximately –170°C with a limited
time window
Central
high-throughput
manufacturing; inte-
grated biobank
and cryopreserva-
tion protocols
however thera-
peutic ecacy
compromised
(immunity)
Financial cost of CTGTPs is a concern in markets
with changing sale volumes for autologous
therapies
Batch-to-batch variation is minimized while
maintaining quality for allogeneic therapies
Products need to arrive at clinical provider sites
unchanged with proven sterility, safety and
potency standard
Cryopreservation of CTGTPs can lead to cellular
injuries, potential deleterious changes in cell
morphology, metabolic activity, function, and
cell death
Low temperature can trigger specific stress
response pathways, such as necrotic and apop-
totic pathways a fter defrosting; substantial
cell injury can occur due to the changes in the
frozen sa mple, such as ice crystal formation
Depending on source of CTGTPs, isolation
methods and criteria may vary. In the case of
scale-up/changes in manufacturing methods/
facilities, comparability
studies may be compromised due to incomplete
product characterization
Cell culture platform must be flexible to
accommodate heterogeneity in type and
number of cells
362
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
[28]
[24] ,
[25]
[18],
[24] ,
[29]

Biomarkers Characterized by
pharmacogenomic
information
(e.g. enzymatic
pathways)
Transduction
(vector)
Bioreactor design Bioreactor design chosen
Cell harvesting Cells may have to be
Potency assay
development
CTGTPs: cel l, tissue and gene therapy product s; QC: qu ality control.
Established: chemical
transformation/
electroporation into
host cells
according to host cell
used
lysed/ destroyed to har-
vest the intracellular
therapeutic proteins
Characterized by pha rma-
cogenomic informa-
tion (e.g. enzymatic
pathways)
Unknown Biomarkers indicative of safety and ecacy
Transduction ecacy limited, reduces
usable cell numbers.
Transduction process eect on cell
properties unknown
Cell culture conditions must be modified
for each cell type.
Viruses are larger and heavier than
proteins, thus tend to shear even at low
velocities
Requires design for detachment (adherent
cell types), isolation and purification
that do not destroy cells
Depends on indication of product and
patient’s cell quality Limited by amount
of materia l available for testing, lack of
appropriate reference standards
in vivo are of particular interest for CTGTPs
For biologicals, eect on protein is of concern,
whereas eect on whole cell must be consid-
ered for CTGTPs
Cell culture conditions include nutrient and oxy-
gen supply, mechanical stress and strain
Shear forces generated may cause shedding of the
viral envelope, thus aecting infectivity
Stirring speed, circulation and shearing dynamics
are crucial parameters
Desired critical quality attributes of CTGTPs must
not be hampered
Test methods must be able to measure relevant
biologica l function that aects clinical indi-
cation
[26 ]
[24]
[24]
Cells, Tissues, and Gene Therapy Products
[24]
[24] ,
[27]
363

Table 3: An overview of classifications of CTGTPs by Regulatory Authorities (RAs) and International Organizations (IOs)
CTGTP Not CTGTP Ref.
US Classified based on manipulation extent and use [30]
More-than-minimal manipulation, non-homologous use Minimal manipulation
Product-based classification Human cells, tissues, and cellular
Gene therapy Somatic-cell therapy Combination products
EU, PIC/S Classified based on manipulation extent and use [31],
Substantial manipulation or non-homologous use Products for infectious disease
Product-based classification
Gene therapy Somatic-cell therapy Tissue-engineered
Japan Medical care/academic research technol-
ogies
Classified based on manipulation and extent of
use
Class I Class II Class III
medicines
Commercial product:
processed (more than min-
imal manipulation) live
human/animal cells
Combined
ATMPs
and tissue-based products
(HCT/ Ps), products for
infectious disease treatment
(vaccines)
treatment (vaccines)
Based on PIC/S GMP Guide,
Annex 2A, vaccines may be
controlled under CTGTP
regulations if beneficial and
appropriate to do so (e.g.
mRNA vaccines) as deter-
mined by the Competent
Authority
Technologies excluded by
Cabinet Order
[32]
[33]
364
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products

Singapore Classified based on manipulation extent and use
Class 1 (minimally manipulated, homolo-
gous use)
China Classification based on types of CTGTPs Blood components used for blood
Cell therapy products Gene therapy products
India A biological that introduces ‘alterations’ in the genome to achieve a
therapeutic outcome. No subcategories. Only gene therapy product is
regulated. Includes DNA vaccines
Australia Classification based on types of CTGTPs [36 ]
Human cell/tissue-based products; contain live animal cells, tissues, combi-
nation products. Gene therapy is mentioned but has no ocial definition
available
Classified based on manipulation extent and use
Class 1 Class 2 Class 3 Class 4
Indonesia Human cell-based drugs are drugs derived from somatic cells and/or engi-
neered human tissue products
Class 2 (not Class 1) Bone marrow, peripheral blood,
umbilical/placental cord blood
transfusion, tissue and organ
products composed of cells.
Oncolytic virus products,
CAR-T cells, in vitro genetically
modified cell therapy products
— [35]
Vaccines, recombinant products;
eligible autologous human
cells and tissues products
Derivative products produced
by these cells, autologous and
embryonic stem cell products,
or blood products
[1]
[34]
[37]
(Continued )
Cells, Tissues, and Gene Therapy Products
365

Table 3: (Continued )
CTGTP Not CTGTP Ref.
Thailand Product-based classification [38]
Cell therapy
medicinal
product
Malaysia Classified based on manipulation extent and use Fresh viable human organs/
Class I (low
risk)
S Korea Classified based on manipulation extent and use [39]
Manufactured via physical, chemical or biological manipulation Minimal manipulation such as
Product-based classification
Cell therapy
products
World Health
Organization
(WHO)
ATMPS: advanced therapy medicinal products; CAR-T: chimeric antigen receptor T; CTGTP: cell, tissue and gene therapy prod-
uct; GMP: good manufacturing practice; MRNA: messenger ribonucleic acid; PIC/S: Pharmaceutical Inspection Co-operation
Scheme.
No classification available; only International Nonproprietary Names (INN) for cell therapies is available [40]
Gene therapy
products
Class II
(regulated
as biolog-
ical)
Gene therapy
products
Tissue engi-
neered
product
Combination products
Classified & regulated based on primary
mode of action
Drug Medical device
Tissue engi-
neered
products
Combined ATMP Cell or tissue products that do
Combination products
not contain viable cells
[84]
haematopoietic stem/progen-
itor cells, blood and blood
components; vaccines against
infectious diseases
where a medical doctor con-
ducts minimum manipulation
which does not aect the qual-
ity of autologous/allogeneic
cells at a medical institution
366
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products

Cells, Tissues, and Gene Therapy Products
Figure2: Stepwise process of manufacturing CAR-T cells [18]
CAR-T: chimeric receptor T; MRNA: messenger ribonucleic acid.
367
physiological tissues to a high degree [6]. Other components may
include signaling molecules or medical devices [45].
Premises and equipment
Since CTGTPs cannot be terminally sterilized, they must be aseptically processed as stipulated under national and international
CTGTP guidelines, including those of Singapore HSA. This means
that a Grade A environment with a Grade B background for open
systems, or a Grade D background for closed systems, including
isolators, are used to reduce the number of contaminants in an
aseptic environment [1]. The relevant cleanroom requirements are

368
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Manufacturing Workflow for Scaffolds Used in TERM Therapies
Tissue/Organ Acquisition Decelluarisation Cell Seeding (if required)
Allogeneic
Autologous
Data (e.g. CT Scan/MRI) Prototyping 3D Model
Allogeneic
Autologous
Shipping & Distribution Release Testing Storage
Manufacturing Workflow for Bioprinted TERM Therapies
3D Bioprinting (e.g. organ, skin,
cartilage and bone)
Shipping & Distribution
Release Testing Storage
Figure 3: Manufacturing workflows for scaolds and bio-printed materials used
in tissue engineering and regenerative medicine (TERM) products [45]
CT: computed tomography; MRI: magnetic resonance imaging.
listed in Table 4, together with an example of a cleanroom in Figure 4. To reduce the risk of contamination, a closed system is typically preferred, as an open processing system allows for materials
to be exposed to the room’s environment. A closed processing system consists of closed tubing pathways and connections, incorporating pre-sterilized, single-use components [46], thus eliminating
the introduction of adventitious agents. This allows for flexibility
and space in process design for regulatory compliance since materials of closed systems are pre-assembled [47], with closed automated
systems such as the CliniMACS Prodigy from Miltenyi which can
perform cell preparation, enrichment and activation, transduction,
expansion and purification, allowing for easy integration into manufacturing strategies [48]. A Grade D cleanroom environment also

Cleanroom
classification
Airborne
particle
concentration
Microbial load
in operation
Non-viable
particle
monitoring
Viable
particle
monitoring
Table 4: Cleanroom requirements for Classes A, B and D [1]
Max. permitted no. of particles
equal/greater than 0.5 µm
Grade AGrade
B
At rest (per m3) 3,520 2,520 3,520,000
In operation
3,520 352,000 Not defined
Grade
D
(per m3)
Air sample cfu/m
Settle plates (diameter 90 mm) cfu/4 hours 5 100
3
No
10 200
growth
Contact plates (diameter 55 mm) cfu/plate 5 50
Max. limits for particles
^ 0.5 µm/m
3
Max. limits for particles
^ 5 µm/m
Air sample cfu/m
3
3
Settle plates (diameter 90 mm) cfu/4 hours 5 100
At rest 3,520 3,520 3,520,000
In operation 3,520 352000 Not defined
At rest 29 29 29,000
In operation 29 2,900 Not defined
No
10 200
growth
Contact plates (diameter 55 mm cfu/plate) 5 50
Glove print (5 fingers) cfu/glove 5 —
Cells, Tissues, and Gene Therapy Products
369

370
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Figure 4: An example of a cleanroom for CTGTP processing [50]
CTGTP: cell, tissue and gene therapy product.
equates to less strict ventilation, cleaning, and gowning requirements [20] which can reduce financial costs. However, due to the
novelty of closed process technology, many personnel are still unfamiliar with using the technology, thus preferring the traditional
process of biomanufacturing [47]. Additionally, the healthcare technology that is available at hospitals is often not enough to meet all
GMP requirements, such as installation, operation and maintenance
which require suitably qualified technicians to implement them,
often leading to the outsourcing of these activities [48]. Currently, a
small number of cell-processing facilities in CTGTP manufacturing
are closed systems; however, they are anticipated to increase in the
years to come [49].

Cells, Tissues, and Gene Therapy Products
Materials and processing
Starting material
Since the initial cell populations are obtained from the patients
themselves in autologous cell therapies, they can be highly heterogeneous as the quality of the cells depends on the patient’s health.
This can reduce the reproducibility and definition of the final product [24]. With a limited amount of starting material available from
the patient, the amount of material available for quality control test
methods may be correspondingly limited. Thus, the sampling strategies to ensure a sucient final product dose for patients may in turn
aect the accuracy of the test results which reflects the properties of
a batch of CTGTP [48]. Several cell types are also adherent in nature,
requiring detachment from cultures in their intact form before being
processed down- stream, thus potentially aecting cell quality [3].
Furthermore, cells are highly sensitive to their environment and display changing behaviours in response, further contributing to their
variability [51]. Patients receiving the therapy are also cancer patients
who undergo aggressive therapies which can aect T-cell fitness negatively, leading to failure in product generation altogether [52].
371
Next, as the biophysical properties of full and empty viral capsids
are similar, it is a challenge to separate them. This can result in
them being processed together, causing the final product to contain
both kinds of vectors during the delivery of genetic materials into
the cells. If many empty vectors are present, a larger therapeutic
dose may be needed, which may lead to adverse immune reactions
in patients [53].
For tissue-engineered products, additional materials such as cells,
scaolds and signaling molecules are required to be combined
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