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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

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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-

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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-

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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

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- - 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 materialsis 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-

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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).