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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Table 4: The 5Vs of leader influence
Vision • Keep the vision consistent
• Be determined in driving the cultural change
• Communicate the vision frequently
• Make the vision readily available to all levels of organization
Visibility • Conduct Gemba walks (i.e. on-site walkthroughs) to interact with
employees and observe routine operations
• Conducting informal and formal quality-based discussion with
employees to identify quality concerns, or new ideas to improve
organizational culture
Voi ce
Values
Vigilance • Identifying and consistently monitoring measurable quality met-
• Believe in the organizational values to influence the desired
behaviour eectively
• Messages on the importance of quality should be easily
understood
• Routine operations should be consistent with organizational
values
• “Soft skills”, i.e. humility, empathy, active listening promotes a
positive culture
• Empower employees to voice out their concerns
rics to ensure accountability for continuous quality improvement
• Consistently monitoring employee engagement and encourage
feedback for assessing current organizational culture
integrity as it provides practical recommendations on building a
quality culture [138].
In facilitating a behavioural change, employers may consider the
ABC (antecedent, behaviour, consequence) model: where an antecedent encourages a behaviour and leads to a consequence, which
in turn influences the recurrence of behaviours [141], see Figure 3.
While antecedents are essential in triggering a behaviour, it is the
consequence that significantly motivates or demotivates the latter
Manufacture and Supply, Science and Reg ulation of Biopha rmaceutical Products
Antecedent
Behaviour
Consequence
Figure 3: ABC model of behavioural change
SOPs: standard operating procedures.
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Examples:
Employees’ attitudes and skillset
SOPs
Available resources (i.e. time,
equipment)
Examples:
Promotion
Employers’ approval or
disapproval
Developing a sense of pride
[142]. As such, in the implementation measures to eectively correct a behaviour, consequences should be emphasized over antecedents. In addition, a ratio of positive to negative consequences
at 4:1 is recommended to sustain performance outcomes [141].
Employees are also crucial in transforming the organizational culture [143]. Training for employees should help them understand the
organization’s quality objectives, SOPs and their individual role in
achieving said objectives [144]. In addition, they should leverage on
the “speak up” culture to provide feedback on how the senior management can customize the quality culture messages to be more
relevant to their work [145].
Developing a culture of quality excellence is not an instantaneous
process as it requires a change of mindsets: senior management must
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
drive the change while employees must be motivated to change. An
eective collaboration at all organizational levels will ensure that
the change can be expedited, and the culture remains sustainable
in the long term.
Conclusion
With the patent expiry of innovator biopharmaceuticals, more biosimilars will be developed for use. In general, this paper has shown
that most biopharmaceuticals share similar manufacturing processes and considerations, providing useful insights for manufacturers who are interested to include biosimilars in their pipeline.
However, it is still highly advisable for manufacturers to demonstrate an extensive product and process understanding as there may
be certain methods that are not suitable or relevant for their product. Due to their inherent complexity, biopharmaceuticals present
challenges in assuring product quality. This can be addressed with
real-time monitoring and better predictive modelling, as well as
other solutions that are not discussed in this paper.
For the RAs and IOs, the outlook on GMP harmonization for biopharmaceuticals is highly promising. As countries improve and harmonize their GMP standards, there will be a greater assurance of
quality and safety of biopharmaceuticals. However, more eort is
needed in providing guidelines on the interchangeability of biosimilars to encourage their use. With greater collaboration among RAs
and IOs, practical experience can be shared, and this can facilitate
improvement of existing guidelines. The challenges presented by
biopharmaceuticals, although daunting, are not insurmountable.
With technological advances and better collaboration between key
stakeholders, these challenges can be eectively managed.
Manufacture and Supply, Science and Reg ulation of Biopha rmaceutical Products
List of abbreviations
ABC Antecedent, Behaviour, Consequence
ALCOA
AMS
API
ASEAN
ATMP
CAPA
CAR
CDSCO
CBER
cGMP
CHO
CPP
CQA
EMA
EU European Union
GMP
HEK-293 Human Embryonic Kidney 293
HPLC
ICH
IoT Internet of Things
mAb
MRA
NMPA
PAT
PIC/S
PRCA Pure Red Cell Aplasia
QbD
QRM
RA
rDNA
Attributable, Legible, Contemporaneous, Original and
Accurate
ASEAN Member States
Active Pharmaceutical Ingredient
Association of Southeast Asian Nations
Advanced Therapy Medicinal Product
Corrective Action and Preventive Action
Chimeric Antigen Receptor
Center for Biologics Evaluation and Research
Current Good Manufacturing Practice
Chinese Hamster Ovary
Critical Process Parameters
Critical Quality Attributes
European Medicines Agency
Good Manufacturing Practice
High-Performance Liquid Chromatography
International Council for Harmonisation
Monoclonal Antibody
Mutual Recognition Arrangement
National Medical Products Administration
Process Analytical Technologies
Pharmaceutical Inspection Co-operation Scheme
Quality-by-Design
Quality Risk Management
Regulatory Authority
Recombinant Deoxyribonucleic Acid
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
RIPP Recovery, Intermediate Purification And Polishing
RT-PCR
SMRT
SOP
TRS
Reverse Transcriptase Polymerase Chain Reaction
Single Molecule Real Time
Standard Operating Procedure
Tech nical Report Series
US United States
WHO
World Health Organisation
Competing interests: None.
Provenance and peer review: Not commissioned; externally peer
reviewed.
Authors
Adjunct Associate Professor Sia Chong Hock1, BSc (Pharm), MSc
Sia Ming Kian
Chan Lai Wah
1
National University of Singapore
1
, BSc (Pharm) (Hons), Graduate Associate Professor
1
, BSc (Pharm) (Hons), PhD
Department of Pharmacy, 18 Science Drive 4, Singapore 117543
References
This article has 145 references which can be found at https://gabijournal.net/global-challenges-in-the-manufacture-regulation-andinternational-harmonization-of-gmp-and-quality-standards-forbiopharmaceuticals.html.
Chapter 10
Manufacture and Supply, Science and
Regulation of Nanomedicines
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10.1. Introduction
anomedicines are medicinal or health products which
are developed using nanotechnology with the objective of diagnosing, monitoring, and treating diseases at
N
cines offer advantages over conventional medicines, including more
effective targeting of difficult-to-reach sites, improved solubility and
bioavailability, and reduced adverse effects. Hence, nanomedicines
can be used to achieve the same therapeutic effect at smaller doses
than their conventional counterparts. Two types of nanomedicines
are described in this chapter. They include nanocarriers used in drug
delivery, and nanosuspensions used in the improvement of drug solubility. While nanomedicines offer promising benefits, there are concerns that the inherent properties of nanoparticles such as their size,
the molecular level. Due to their nano size, nanomedi-
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
shape, agglomeration and aggregation potential, and surface chemistry can adversely affect the safety and quality of nanomedicines.
Currently, there are few regulatory guidelines which have been developed specifically for nanomedicines. This is due to inadequate knowledge regarding nanoparticle behavior, the absence of standardized
nomenclature, test methods, and characterization of nanoparticles,
as well as difficulty in determining primary jurisdiction for combination products. In addition, a shortage of trained personnel, a lack
of a nanomedicine-specific safety protocol, and ineffective control of
nanoparticle contamination challenge the current good manufacturing practice requirements governing the manufacture of nanomedicines. Some national regulatory authorities (NRAs) are in the midst
of improving their current framework for controlling the manufacturing processes, product quality, and safety of nanomedicines.
10.2. Advantages of Nanomedicines
Nanomedicines employ particles with nanometer dimensions
(about 100 nm or less) so that they are small enough to interact with
biomolecules, such as enzymes and receptors, to detect and treat
pathologic problems even before the expression of disease symptoms. Due to their small size, nanomedicines oer at least three
advantages over conventional medicines as described below.
10.2.1. Eective Targeting of Dicult-To-Reach Sites
Nanoparticles are small enough to sneak past the immune system
and enter certain sites in the human body that are less accessible to
conventional medicines, which employ micron-sized drug particles.
Manufacture and Supply, Science and Reg ulation of Nanomedicines
Thus, they are intensively researched to develop therapies that target
specific diseases such as cancer tumors, which generally have a more
permeable vasculature and an impaired lymphatic drainage. With
a size of only 10 to 100 nm, nanoparticles can exploit these tumors
to passively diuse and accumulate within the tumor. They can also
undergo surface modifications with antibodies and other ligands to
achieve specific targeting with tumor cells or tumor-bearing organs.
As a result, many nanomedicines are directed towards cancer treatment due to their potential in delivering highly potent and toxic
drugs to tumors, while minimizing non-specific damage and toxicity. The ability of nanoparticles to traverse the blood-brain barrier
has also been utilized to develop therapies for diseases of the brain.
10.2.2. Improved Solubility, Bioavailability, and Reduced Side Eects
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Many conventional drug candidates fail clinical or pre-clinical tests
due to their inherently poor solubility with consequences of low
bioavailability, poor delivery to target sites, and unpredictable toxicity. These issues can be resolved by sizing the drug particles to
the nano level so that their interface with the surrounding liquid
medium is drastically increased, with a resultant steep rise in dissolution rate and saturation solubility. The consequent improvement
in solubility enhances the drug’s bioavailability, side-eect profile,
and dose homogeneity to achieve better therapeutic outcomes.
10.2.3 Achieving the Same Therapeutic Eect with Smaller Doses
The chemical and biological reactivity of nanoparticles are greatly
enhanced due to their decreased size and increased specific surface
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
area. As such, a smaller number of nanoparticles can achieve the
same therapeutic eect as compared to microparticles of the same
mass dose due to the former’s greater interaction with biological
components. A smaller overall dose could reduce the need for frequent administration of drugs and its associated inconvenience.
The larger specific surface area and higher reactivity of nano-sized
drugs also confer upon them the advantage of a faster onset of drug
action.
10.3. Types of Nanomedicines
10.3.1. Nanocarrier Systems
Nanocarrier systems consist of a biodegradable and biocompatible casing that encapsulates or conjugates therapeutic and diagnostic agents to protect them against degradation in the body.
Often, functionalized moieties are attached to the nanocarriers to
improve the solubility of these agents in the bloodstream and to
guide them to specific locations. Once delivered to the target site,
the active ingredient is released either via erosion of the casing
due to pH changes, heat, light or magnetic fields, or direct diusion of the active ingredient through the casing into the tissues
or cells. Examples of nanocarriers are liposomes and polymeric
micelles.
A liposome is a sphere of amphiphilic bilayer membranes composed
of natural or synthetic lipids surrounding an aqueous core which
contains the active ingredient (see diagram on next page).
Manufacture and Supply, Science and Reg ulation of Nanomedicines
Diagram showing cross-section of a liposome
(extracted from www.bio.miami.edu)
Liposomes are particularly useful for the protection and transport
of biotechnological drugs that are unstable in the bloodstream.
Due to their small size and similar constituency as that of biological membranes, liposomes can escape opsonization and reside
long enough to transport their cargo across the cell membrane
successfully. An example of an approved liposome nanocarrier system is Doxil
®
, which contains doxorubicin used to treat Kaposi’s
Sarcoma — a cancer of the skin.
301
Polymeric micelles (5 to 100 nm) are generally smaller than
liposomes (20 to 1,000 nm) and consist of several hundred block
copolymers (see diagram on next page). These copolymers comprise a hydrophobic core and hydrophilic shell for encapsulating the
drug and ensuring micelle solubility, respectively. The hydrophilic
shell is usually made of poly(ethylene) oxide which prevents protein
adsorption and cellular adhesion. Sometimes, the drug may also be
covalently linked to the micellar surface. Micelle-based drugs have
potential for commercialization.