|
Items in cart [0] |
Questions? Call 888-624-8373 |
| Copyright © 2009. National Academy of Sciences. All rights reserved. Terms of Use and Privacy Statement |
Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 21
New Directions in
Manufacturing and Delivery
Manufacturing and delivery are integral parts of the expensive, risky, and
lengthy drug development cycle (roughly 15 years and $800 million for a new
drug) regulated by the Food and Drug Administration. The cost of pharmaceuti-
cals to U.S. consumers is rising rapidly (15 percent per year) and is a major factor
in the rate of increase in healthcare costs. There is pressure to control prices of
pharmaceuticals, which requires more efficient systems for drug development,
manufacture, and delivery. Advances in chemical technology are effectively shift-
ing healthcare cost from medical labor to medical technology. Considerable
progress has been made in the last 20 years in manufacturing and delivery of
pharmaceuticals and biomedical devices.
A major opportunity to control costs resides in more efficient processes for
manufacture of new pharmaceuticals and development of new delivery systems
that release drugs at a target site, at a predetermined rate, over a predetermined
time. Spatial and temporal control of drug delivery may extend the life of older
drugs by avoiding side effects while delivering higher concentrations to a local
site. Extending the useful life of a pre-existing drug may reduce costs as well.
Diagnostic systems that identify disease earlier will likely reduce treatment costs
by requiring less drugs and other medical intervention.
Recent advances that have improved manufacturing and delivery include
development of
· large-scale, controlled cultivation of animal and plant cells;
· efficient production of therapeutic proteins and first generation systems
for their controlled delivery;
· more effective methods for synthesis of new and more complex pharma-
21
OCR for page 22
22
HEALTH AND MEDICINE
ceuticals, such as solid-phase synthesis, chiral catalysts, oligosaccharide chemis-
try, catalytic antibodies, and enzymes better adapted to specialized environments;
· improved membrane and chromatographic methods to separate and purify
complex molecules more effectively;
· theoretical and experimental techniques to engineer cellular metabolism
("metabolic engineering") in order to produce biochemicals at higher yields or
novel products;
· biomaterials that act as scaffolds for tissue engineering or as improved
matrixes;
· computational and bioinformatic tools to assist in drug discovery and in
development of manufacturing processes; and
· first generations of tissue-engineered products (artificial skin and carti-
lage).
MANUFACTURING CHALLENGES
The challenges to the manufacturing process arise from the increasing cost of
R&D, the need to develop information systems that exploit benefits from
genomics and bioinformatics, pressure on pricing and fierce competition in the
industry, the relatively inefficient output of new products due to failure in clinical
trials, technical barriers for targeted delivery, and the crude ability to control
complex biological processes such as cellular differentiation and organization.
While many of these challenges apply to both pharmaceuticals made by chemical
synthesis and bioprocesses, there are also separate issues based on mode of manu-
facture. Production of therapeutic proteins from mammalian cells is particularly
challenging. Many of these new products require intricate post-translational pro-
cessing steps (e.g., addition of oligosaccharides) to be effective. Currently we do
not understand how to scale up these processes to maintain uniform glycosylation
(i.e., same oligosaccharide modifications) at all scales of production. Many of
these products, such as therapeutic antibodies, may be required in large amounts.
These current production processes are inefficient and require large facilities.
Overcoming these challenges will require a better understanding of how cul-
ture conditions can be manipulated to improve productivity in mammalian cells
while maintaining a consistent product, or we must seek alternative production
systems. Examples of alternative systems include yeast (Pichia pastoris), insect
cell systems, transgenic plants, or transgenic animals. All of these alternatives
present barriers in terms of authenticity of the product (e.g., human-like form),
cost (especially for transgenic animals), and ability to meet regulatory standards
for reproducibility. Additionally, use of transgenic animals brings up the unre-
solved issue regarding the potential of contamination (e.g., priors) from diseased
animals to patients and the fact that prions are extremely difficult to detect ana-
lytically.
There are also manufacturing challenges related to nonprotein natural prod-
OCR for page 23
NEW DIRECTIONS IN MANUFACTURING AND DELIVERY
23
ucts from plants and marine organisms. While one example of a large-scale
(75,000 L) bioreactor system exists (for production of the anticancer agent Taxol
from plant cell culture), extension to other valuable, complex, nonprotein phar-
maceuticals is yet to be established. Many marine products, particularly from
marine bacteria and algae, show promise in clinical trials. Some of these com-
pounds are too complex for large-scale production using traditional synthetic or-
ganic chemistry, and established methods for large-scale culture of the producing
organism do not exist. In some cases the metabolic engineering of easy-to-grow
cells may provide an effective alternative. The ability to do rational metabolic
engineering needs to be improved through a more fundamental understanding of
cellular metabolism and its interaction with the external environment.
In other cases hybrid manufacturing processes, the practice of combining
chemical synthesis and biocatalysis (e.g., enzymes), are being developed to pro-
duce pharmaceuticals of increasing purity (particularly chiral purity). Removing
potentially harmful forms of the pharmaceutical that are not therapeutically ac-
tive is increasingly important. In many cases biocatalysts must be modified to
perform satisfactorily in a nonbiological environment (e.g., in the presence of
high levels of an organic solvent). The availability of such biocatalysts is often
dependent on advances in protein engineering (e.g., "directed evolutional. An-
other biomanufacturing challenge is the production of organized tissues using
tissue engineering. While processes to produce tissue-engineered skin have been
commercialized, it is clear that the economic viability of these manufacturing
processes must be improved. An increasingly more precise understanding of how
to manipulate cellular organization and differentiation will support development
of more effective manufacturing processes. Further, challenges in the manufac-
turing process are an effective separation, on a large scale, of complex and sensi-
tive molecules. While both chromatographic and membrane methods have greatly
advanced and are particularly important for the recovery and purification of thera-
peutic proteins, new advances will be needed to increase throughput and effi-
ciency while reducing cost. Many of these advances will come through new ma-
terials and modes of operation.
The manufacturing process needs to be identified early in the drug develop-
ment process. With advances in combinatorial methods and genomic technolo-
gies, the number of possible drug leads has expanded dramatically. Advances in
high-throughput screening and parallel synthetic methods, coupled with the abil-
ity to generate crystal structures or nuclear magnetic resonance structures of a
protein target with and without a ligand, place synthetic chemists in a position to
contribute further to generation of more chemicals for evaluation as possible phar-
maceuticals. Consequently, methods to predict which of these drugs are going to
be effective in the clinic are increasingly critical. Bioinformatics and computa-
tional modeling are expected to play increasingly significant roles in drug target
validation, including preclinical pharmacology and toxicology. In fact, early at-
tempts to combine discovery with simultaneous optimization of potency, selec-
OCR for page 24
24
HEALTH AND MEDICINE
tivity, optimization of Adsorption-Distribution-Metabolism-Elimination-Toxic-
ity (ADMET), and safety is the key to reducing the time from discovery to prod-
uct (which may dramatically decrease cost). Formation of such human surrogates
can improve the fraction of drug leads that become actual products.
NEW DELIVERY OPPORTUNITIES
New technologies are being developed to deliver drugs to people more effec-
tively and safely. Synthetic polymers are being used as a delivery system for
drugs. They are biocompatible, which means that material can be implanted into
tissues with little biological response. For example, ethylene-co-vinyl acetate, an
industrial polymer, is inert when implanted in tissues throughout the body. It is
hydrophobic, biocompatible, and nondegradable. These kinds of materials last a
long time in the body, do not change, and can be used to make physical matrixes
in which a drug of interest is encapsulated or dispersed throughout a continuous
polymer phase. The five-year implantable birth control system Norplant is the
best known example. One of the major advances over the last few decades has
been to miniaturize these systems and make them into tiny particles that can be
injected. This is usually accomplished with degradable polymers such as poly
(lactide-co-glycolide), which will degrade over the course of several months once
exposed to water. One can change the rate of release of the drug from this mate-
rial by changing how it is fabricated. These particles can be injected and used to
release drugs locally. It is now routine to make ~1 micron particles that have
functional DNA within the solid matrix.
Biomedical imaging is a technology that will greatly impact drug delivery.
Two-photon microscopy has been used to visualize the dynamics of nerve growth
hormone (NGF) diffusion in brain slices, for example. These direct measure-
ments allow for monitoring of mechanisms of transport in the tissue and record-
ing changes that occur with conjugation of the protein. NGF and other proteins
can be stabilized in tissue by conjugation to polymers such as polyethylene gly-
col (PEG). Another method for increasing the effective volume of treatment is to
split the delivery system up into small units and spread them out over a larger
volume. By changing the spacing between the units, one could spread out active
agent over some larger volume in the brain, being careful not to get the sources
too far apart leaving regions untreated. This is another opportunity to match drug
delivery systems with imaging science. Many diseases are not only local, but
occur in complex geometries. In these cases, one could envision approaches in
which multiple microscopic delivery systems are arranged into a spatial configu-
ration that matches the disease process.
Knowledge of material synthesis from the microelectronics industry can be
used to create smarter delivery systems (see Sidebar 3.1J. For example, people
have been using electronic materials in the brain for a long time. These materials
can be made into drug delivery systems by putting microfluidic channels into the
OCR for page 25
- - Bl
NEW DIRECTIONS IN MANUFACTURING AND DELIVERY
_ ~ Ala: ~ : _
: :::: : : : : ::~: : : i: i:::: ::
~ ~~ ~~ Sidebar 3.1
Smarter Drug;Delivery Systems through Microelectronics
Excerpt from "Drug Delivery"
TOW. Mark Sattzman
Yale University ~
Material synthesis knowledge from the microelectronics industry
could be used to make smarter drug delivery systems. For example elec-
tronic materials such as stimulation :recording devices and
neuroprostheses ~ have been used in the brain~for some time. These
Materials can be made into drug delivery syste:ms~by putting m~crofluidic
channels into the material. Drug delivery can~proceed by injection of tfu-
ids; tight control over delivery can be achieved Gusto external control
with a fluid phase. Another approach is to Enable the material to turn
Delivery on and off at venous times. With DNA, for example a microelec-
trode in the material can be used to create a focal voltage difference that
modulates the rate of release of the drug Jerome the material: the drug
r eleases quickly when the voltage Is on and slowly when the voltage is
~off. One of the advantages of the overall approach of using microeJec-~
tronic matenals is that the drug delivery System Icon be easily combined
with a probe that senses local conditions Such Was local conditions ~ of i;
Voltage or chemistry allowing release of a :drug in response to that local:
condition.]
1Saltzman, W./l., Olbricht, W.O. 2002. Building drug delivery into tissue engi-
neering. Nature Reviews~Drug Discovery 1:177-186. :
25
:\
material. Drug delivery can proceed by injection of fluids; tight control
over delivery can be achieved because it is controlled externally with a fluid
phase. Another approach is to enable the material to turn on and turn off delivery
at various times. With DNA for example, a microelectrode in the material can be
used to create a local voltage difference which then modulates the rate of release
of the drug from the material: drug releases fast when the voltage is on and slow
when the voltage is off. One of the advantages of this overall approach using
microelectronic materials—is that the drug delivery system can be easily com-
bined with a probe that senses local conditions, either local conditions of voltage
or chemistry, allowing release of a drug in response to that local condition.
DELIVERY CHALLENGES
Significant drug delivery challenges still exist. Intracellular delivery is an
important problem because of the difficulty of getting DNA into cells. The gen-
OCR for page 26
26
HEALTH AND MEDICINE
eral approach has been to try to complex DNA with something (usually a lipid or
a polymer) in order to make complexes that can enter the cell. However, once in
the cell, there are other barriers. Internalized DNA often ends up in endosomes
where it can be digested. There is a trend now to focus on designing systems in
cell culture in situations where particles can be delivered immediately adjacent to
the target cell. That is rarely going to be achievable in real tissue. There is evi-
dence that approaches such as using receptors for targeting or using pH-depen-
dent materials to trigger release from the endosome at the right time might be
useful. Alternately, polymer particles that are ~100 nm in size can also be used to
deliver agents directly to the cytoplasm of the cell. One of the advantages of this
approach is that agents can be released intracellularly over time.
Degradable polymers have been in use for years and much is known about
assembling them with different classes of drug molecules. However, since the
methods of fabrication remain imperfect, one usually obtains a complex mixture
of particles of different sizes and shapes. Matching methods of particle formation
with drugs has been one of the major challenges in this area. Many different ways
to make small particles are now in the literature. Unfortunately few of these meth-
ods are compatible with most drugs. Finding better ways to make controlled par-
ticles that are compatible in drug incorporation is a challenge for the future.
While injection remains the primary route for protein delivery, oral or pul-
monary delivery would be less expensive and more convenient for the patient.
Oral delivery for proteins requires stabilizing the protein while it passes through
the stomach followed by selective uptake through the gastrointestinal tract and
into systemic circulation. While some success has been observed (e.g. edible vac-
cines from plants where the plant material may provide protection through the
stomach for a sub unit vaccine), oral delivery is still problematic. Pulmonary
delivery has also shown early promise, yet issues such as the control of particle
size remain barriers to a generally effective system. No generally effective method
for gene therapy exists today. Although nucleotide delivery in both viral and non-
viral vectors can lead to transfection, obtaining the correct dose in the right loca-
tion and time frame without disturbing other cellular processes remains an elu-
sive goal (e.g., induction of cancer due to loss of control of cell cycle arrest).
Representative terms from entire chapter:
local conditions
