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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
10.3.2. Nanosuspensions
Diagram of a polymeric micelle
(extracted from www.surmodicspharma.com)
As previously mentioned, drug solubility and stability can be
improved through the use of nanocarriers. However, many nanocarriers face challenges in their manufacture due to low encapsulation
rates. Nanosuspensions provide an alternative means for enhancing
drug solubility and stability via a reduction of the drug particles to
the sub-micron range. This is followed by coating with a stabilizing
agent to form nanocrystals suspended in a liquid medium. Nanocrystals are small enough to be injected intravenously, thereby achieving a 100% bioavailability without the need for specific solubilizing
agents, which may be toxic if administered in high concentrations.
Abraxane
breast cancer treatment. The original product Taxol
®
is a well-known example of a nanosuspension used for
®
contains the
active ingredient paclitaxel, a water-sensitive molecule that can only
be solubilized by Cremophor EL in ethanol. However, as Cremophor
Manufacture and Supply, Science and Reg ulation of Nanomedicines
EL is a toxic solvent, it cannot be infused directly; hence, dilution of
the ethanolic solution with an isotonic solution must be done prior
to infusion. This greatly limits therapeutic doses and treatment
options. With Abraxane
®
, paclitaxel is added to an aqueous solution
of albumin using low-speed homogenization. High-pressure homogenization is then applied to reduce the size of the paclitaxel particles before they are attached to the albumin coating via disulfide
bonds, leaving an aqueous suspension of nanoparticles of approximately 130 nm in diameter. This does away with the need for using
Cremophor EL and eliminates the hypersensitivity reaction associated with it. With a longer shelf-life, Abraxane
compared to Taxol
®
.
®
is also more stable
303
Being a nanosuspension, Abraxane
®
also has a faster onset and
improved bioavailability. Small particles have an increased tendency to adhere to mucosal surfaces at the absorption site over a
longer period as compared to larger particles, resulting in enhanced
permeation and uptake. This, coupled with trans-endothelial transport via the albumin binding protein, enables paclitaxel to accumulate suciently in the tumor to exert its therapeutic eect. The
high specific surface area of nanoparticles also facilitates faster drug
release and action. Clinical studies have shown that Abraxane
®
doubles the therapeutic response rate, delays metastatic progression,
and increases overall survival in breast cancer patients.
10.4. Future of Nanomedicines
Currently, nanomedicines are only a prelude to truly innovative
future technology. Nanomedicines are constantly evolving in terms
of their intricacy in structure and function such as nanorobots and
pulsatile delivery systems. However, advanced nanomedicines are
304
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
likely to enter the market much later due to the complexity of clinical tests and conservatism in adopting revolutionary technology.
10.4.1 Properties of Nanoparticles: Eects on Safety and
Quality of Nanomedicines
While nanomedicines oer promising possibilities, there are concerns that they might also cause adverse eects not encountered
with conventional medicines. In order to verify the certainty of
these claims, the principal properties of nanoparticles, namely,
their size, shape, agglomeration and aggregation potential, and surface chemistry, have been studied in laboratories to gain insights
into their behavior.
(a) Size
Nanoparticles are small enough to be distributed to sites previously
inaccessible to microparticles, including cells, erythrocytes, lungs,
spleen, liver, heart, and brain. Their ease of accumulation in organs,
coupled with their large specific surface area and high reactivity,
may enhance intrinsic toxicity due to greater contact with biological components. However, toxicity usually occurs only after the
absorption and accumulation of a massive amount in the body.
Thus, manufacturing personnel who are adequately protected are
unlikely to experience any toxicity associated with nanoparticles.
The concerns regarding inflammatory responses evoked by nanoparticles may be overhyped.
(b) Shape, Agglomeration and Aggregation Potential
Studies have shown that the shape of nanoparticles may play a role
in toxicity, but findings are varied and the exact mechanism of toxicity is still unknown. The shape of nanoparticles can be influenced
Manufacture and Supply, Science and Reg ulation of Nanomedicines
by factors related to their manufacture and biological environment.
Thus, further validated tests should be performed to ensure that the
shape of nanoparticles in nanomedicines does not pose any safety
concerns.
(c) Surface Chemistry
Surface chemistry is an important factor in determining the extent
of organ and cellular uptake as well as intracellular interactions.
For instance, surface charges of nanoparticles can disrupt cell membranes and cause possible adverse eects. Besides the influence of
shape, uncoated nanoparticles also have a high tendency to agglomerate and aggregate, aecting their re-dispersibility in formulations. These agglomerates and aggregates may also be too large to
be internalized by macrophages, evoking a chronic immunological
response. Fortunately, this agglomeration and aggregation propensity may be prevented through the use of appropriate coatings or
functional groups to stabilize particle-particle interactions through
electrostatic or steric means. Appropriate coatings or functional
moieties can also be applied or attached to nanoparticles to enhance
their biocompatibility in the body. The coatings should be evaluated
for their possible wear and tear over time and under certain environmental conditions. Otherwise, free nanoparticles in the form of
wear debris may be released which can cause adverse health eects.
305
10.5. GMP Requirements Governing Nanomedicines and Challenges
The properties of nanoparticles mentioned above are known to
aect the safety and quality of nanomedicines. However, the harmful eects of nanoparticles can be prevented through the implementation of protective measures such as the wearing of personal
306
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
protective equipment to prevent entry of nanoparticles into the
body during manufacture, and the application of appropriate and
durable coatings on the surfaces of nanoparticles to ensure their
release at the intended site. Like other pharmaceutical products,
nanomedicines must undergo an approval process by regulatory
authorities to establish their safety, ecacy, and quality before
entry into the market. Their manufacturing processes are also
required to adhere to GMP requirements to ensure consistency in
production and control and, ultimately, to achieve quality standards. Currently, nanomedicines and conventional medicinal products are subject to the same GMP requirements. Discussed below
are some challenges faced by manufacturers involved in the manufacture of nanomedicines.
10.5.1. Lack of Trained Personnel to Operate Manufacturing Processes
GMP requires that manufacturing plants have sucient qualified
trained and experienced personnel to assure the production of safe,
ecacious, and good-quality nanomedicines. However, due to the
relative infancy of the field of nanomedicine, there is currently a
dearth of suciently trained personnel in the nanomedicine industry. As nanotechnology develops, new knowledge regarding nanoparticles will be gained. Manufacturing personnel should undergo
training to be updated with the essential skills in managing and
controlling the manufacture of nanomedicines so that quality and
safety standards are met. Continued training tailored to the context
of their operation processes should also be conducted. Thus, manufacturing companies must be prepared to invest heavily in both
time and money to ensure that their manufacturing processes meet
minimum GMP requirements.
Manufacture and Supply, Science and Reg ulation of Nanomedicines
10.5.2. Lack of Safety Protocol for Manufacturing Personnel
In general, the processes generating nanomaterials in aerosols
or powders pose the greatest risk for releasing nanoparticles.
Sanitization of production equipment can also release deposited
nanoparticles into the manufacturing environment. These free nanoparticles have been shown to demonstrate potential health hazards. The safety of manufacturing personnel needs to be ensured.
For instance, studies have shown that certain nanoparticles are
more likely to trigger or exacerbate attacks in people with impaired
respiratory function. They may also produce free radicals in the
body when penetrated through the skin. Therefore, there is a need
to have a detailed protocol stipulating prerequisites to protect the
personal health of the workers. For example, all manufacturing personnel should be examined for medical conditions of the skin and
respiratory system before they are employed. They should also be
adequately protected to prevent the entry of nanoparticles through
the oral, nasal, and dermal routes during the manufacture of nanomedicines. Personal protective equipment should be cleaned using
a suction device to prevent the release of free nanoparticles into
the manufacturing environment during cleaning. Manufacturing
methods should exclude or minimize the formation of aerosols to
avoid intake of nanoparticles by inhalation.
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10.5.3. Challenges in Controlling for Nanoparticle Contamination
There may be a greater level of contamination at the nano level due
to unexpected interactions of drug molecules with contaminant
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
molecules. The control of nanoparticle contamination is crucial
because ineective cleaning of equipment is a common source of
cross-contamination that may adversely alter the quality of subsequent batches. In order to ensure the quality and purity of the
products, manufacturing companies should only use starting materials that have been assessed for their safety and quality. Protocols
for proper handling and storing of nanomaterials by manufacturing personnel should also be developed to reduce contamination
caused by human factors. Essentially, manufacturing companies
must be prepared to invest more time and money in sanitizing production equipment.
10.6. Conclusion
Nanomedicines oer promising breakthroughs in the health
care industry due to several advantages over conventional medicines. These advantages include a more eective targeting of dicult-to-reach sites, improved bioavailability and side-eect profile,
as well as a smaller dose needed to achieve the same therapeutic
eect. Although nanomedicines have several applications in health
care, attention has also been drawn towards the safety of nanoparticles and the challenges in controlling the quality of nanoformulations. Even though NRAs recognize these concerns, many
are not yet able to develop inspection and regulatory guidelines specifically tailored for nanomedicines due to inadequate knowledge
about nanoparticles in general. As nanomedicines are expected
to become more complex in terms of their structure and function, NRAs will have to work closely with the industry, international counterparts, academia and research institutions, and other
Manufacture and Supply, Science and Reg ulation of Nanomedicines
stakeholders to come up with an appropriate regulatory framework
for nanomedicines.
Attribution: This article is an adapted and concise version of a full
paper entitled “A Review of the Current Scientific and Regula-
tory Status of Nanomedicines and the Challenges Ahead”, by Sia
Chong Hock, Yan Mei Ying and Chan Lai Wah. The full paper was
originally published in PDA J Pharm Sci and Tech 2011, 65, 177–195.
Copyright PDA, Inc. (March–April 2011). Republished with permission of PDA, Inc.
309
310
Chapter 11
Novel and Traditional Vaccines
11.1. Historical Development and Evolution of Traditional and Novel Vaccines
mallpox was a terrible and dreaded disease for many centuries. A third of people infected with smallpox died. Those
who survived had scars, sometimes severe, painful, pro-
S
In 1796, Edward Jenner observed that milkmaids who had cowpox
were protected from smallpox. Dr. Jenner took cowpox pus from
the hands and arms of Sarah Nelmes, a milkmaid, and inoculated
it into the arm of James Phipps, the eight-year-old son of his gardener. Months later, Jenner “challenged” Phipps several times to the
smallpox virus; Phipps did NOT develop smallpox. Jenner had successfully vaccinated Phipps against smallpox (see diagram on next
page).
longed and permanent.
Novel and Traditional Vaccines
311
Dr. Edward Jenner — father of vaccination
Sarah
Nelmes is a
milkmaid
infected with
cowpox.
James Phipps
is inoculated
with cowpox
pus from
Nelmes.
Phipps
falls ill
with a mild
case of
cowpox
infection.
Source: https://en.wikipedia.org/wiki/Edward_Jenner#/media/File:Edward_Jenner-_Smallpox.
svg (credit to Srcyr16, CC BY-SA 4.0)
Scabs are
collected
from a
smallpox
patient.
Phipps is
inoculated
with the
scabs of
smallpox.
Phipps is
unaffected
by
smallpox.
Protection
plete.
is com