Pharma/medical Breakout Report-Out Workshop on Instrumentation, Metrology, and Standards for Nanomanufacturing, 10/17-19/06 Scope & Importance/Impacts Health and toxicity of nanomaterials is a highly visible public and consequently political issue Health and toxicity of nanomaterials is a highly visible public and consequently political issue Significant potential benefits: Significant potential benefits:  Sustaining and growing U.S. pharma industry  Diagnosing (e.g. early and self-diagnosis), preventing and treating disease – increasing efficacy and lowering toxicity of medical treatments  Homeland security and bioterrorism (i.e. effective biosensor development)  Creating new market for instrumentation and fabrication tools Lack of uniform international standards in nanotoxicity could undermine the economic benefit of nanotechnologies – U.S. must take the lead to be globally competitive Lack of uniform international standards in nanotoxicity could undermine the economic benefit of nanotechnologies – U.S. must take the lead to be globally competitive

Pharma/medical Breakout Report-Out Workshop on Instrumentation, Metrology, and Standards for Nanomanufacturing, 10/17-19/06 Current State of the Art Within nanomedicine pipeline in 2005, approx. 15 applications were in various stages of approval by FDA Within nanomedicine pipeline in 2005, approx. 15 applications were in various stages of approval by FDA  Two are currently in the marketplace Encouraging increase in rate of development of nanomedicine concepts Encouraging increase in rate of development of nanomedicine concepts Use of nanocoatings on capsules and tablets Use of nanocoatings on capsules and tablets Increased awareness that greater understanding of nanotoxicity issues is needed Increased awareness that greater understanding of nanotoxicity issues is needed Beginning of interagency coordination within the government -- need increased sharing of data and knowledge for different aspects of nanotoxicity Beginning of interagency coordination within the government -- need increased sharing of data and knowledge for different aspects of nanotoxicity Current pharma resources are inadequate to make the transition to personalized medicine Current pharma resources are inadequate to make the transition to personalized medicine

Pharma/medical Breakout Report-Out Workshop on Instrumentation, Metrology, and Standards for Nanomanufacturing, 10/17-19/06 Vision for the Future Superior early-stage detection Superior early-stage detection More effective pharmaceutical – higher efficacy, lower dosage/cost and minimize side-effects More effective pharmaceutical – higher efficacy, lower dosage/cost and minimize side-effects Better integration/coordination of government agencies Better integration/coordination of government agencies Availability of uniform standards for Availability of uniform standards for Design and functionalization of nanoparticles based on well- understood structure/activity relationships and using available computer models (i.e., understand systems biology) Design and functionalization of nanoparticles based on well- understood structure/activity relationships and using available computer models (i.e., understand systems biology) Nano-bio technology will routinely operate at the peptide level Nano-bio technology will routinely operate at the peptide level Effective ongoing teaming between industry, government and academia Effective ongoing teaming between industry, government and academia

Pharma/medical Breakout Report-Out Workshop on Instrumentation, Metrology, and Standards for Nanomanufacturing, 10/17-19/06 S & T Barriers: Standards Few standard processes for creating uniform nanoparticles for test and characterization Few standard processes for creating uniform nanoparticles for test and characterization Lack of common vocabulary – ontologies for disseminating and presenting data, models and knowledge Lack of common vocabulary – ontologies for disseminating and presenting data, models and knowledge Few test guidelines related to final application of nano/bio entity (diagnostic, prevention, etc... ) Few test guidelines related to final application of nano/bio entity (diagnostic, prevention, etc... ) Lack of participation of all “stakeholders” in test guideline definition and development Lack of participation of all “stakeholders” in test guideline definition and development Need allowed statistical windows/requirements Need allowed statistical windows/requirements Guidelines re: sample size statistics, error bars, tolerances, frequency, etc....for functionalized bio Guidelines re: sample size statistics, error bars, tolerances, frequency, etc....for functionalized bio Lack of standards regarding sample preparation for assays Lack of standards regarding sample preparation for assays No standard approach to determine toxicity and interaction issues No standard approach to determine toxicity and interaction issues

Pharma/medical Breakout Report-Out Workshop on Instrumentation, Metrology, and Standards for Nanomanufacturing, 10/17-19/06 S & T Barriers: Instrumentation & Metrology Incompatibility of instruments with the environment required for living biological samples Incompatibility of instruments with the environment required for living biological samples Instrumentation needed for detailed measurement/characterization of single nanoparticles Instrumentation needed for detailed measurement/characterization of single nanoparticles Lack of instrumentation for observing nanoparticle formation required to support development of models for formation process Lack of instrumentation for observing nanoparticle formation required to support development of models for formation process

Pharma/medical Breakout Report-Out Workshop on Instrumentation, Metrology, and Standards for Nanomanufacturing, 10/17-19/06 S & T Barriers: Manufacturing Challenge of scaling-up production processes for nanoparticles for biological and medical applications Challenge of scaling-up production processes for nanoparticles for biological and medical applications Lack of tools for real-time monitoring of manufacturing process Lack of tools for real-time monitoring of manufacturing process Nano-bio technology must be able to manipulate/operate at the peptide level Nano-bio technology must be able to manipulate/operate at the peptide level How can nanotech. address systems biology? How can nanotech. address systems biology?

Pharma/medical Breakout Report-Out Workshop on Instrumentation, Metrology, and Standards for Nanomanufacturing, 10/17-19/06 S & T Barriers: Characterization More detailed characterization is needed to build and validate models More detailed characterization is needed to build and validate models No standard methodology to define size, shape, concentration, and other physical parameters No standard methodology to define size, shape, concentration, and other physical parameters No universal consensus on cell toxicity assessment No universal consensus on cell toxicity assessment Limited nano characterization capabilities available to manufacturers, esp. for biological testing Limited nano characterization capabilities available to manufacturers, esp. for biological testing A good causal understanding of structure/property relationships remains elusive A good causal understanding of structure/property relationships remains elusive Life-cycle toxicity as well as efficacy for nanoparticles must be addressed Life-cycle toxicity as well as efficacy for nanoparticles must be addressed

Pharma/medical Breakout Report-Out Workshop on Instrumentation, Metrology, and Standards for Nanomanufacturing, 10/17-19/06 Future R&D Directions Greater emphasis on physical and biological characterization: Particle fabrication chemistry Particle fabrication chemistry  Understanding and modeling relationship between synthesis process and product properties  Once understood, establish process control Ascertain determinant nanoparticle features, e.g., shapes and sizes, atomic and molecular structures, surface chemistry, stability, surface charge... Ascertain determinant nanoparticle features, e.g., shapes and sizes, atomic and molecular structures, surface chemistry, stability, surface charge... Greater understanding of interactions of particles with different environments -- Greater understanding of interactions of particles with different environments --  Within biological environments, e.g. humans, etc...  Physical environment, i.e. Long-term storage and dispensing Better repeatability from batch-to-batch of manufactured lots Better repeatability from batch-to-batch of manufactured lots

Pharma/medical Breakout Report-Out Workshop on Instrumentation, Metrology, and Standards for Nanomanufacturing, 10/17-19/06 Future R&D Directions (2) New emerging technologies, aside from nanoparticles, may show potential for treatment and medical devices – may not even be in FDA pipeline yet and are still unproven New emerging technologies, aside from nanoparticles, may show potential for treatment and medical devices – may not even be in FDA pipeline yet and are still unproven Define applicability/feasibility of microfluidics techniques for manufacturing processes and in addressing EHS concerns Define applicability/feasibility of microfluidics techniques for manufacturing processes and in addressing EHS concerns

Pharma/medical Breakout Report-Out Workshop on Instrumentation, Metrology, and Standards for Nanomanufacturing, 10/17-19/06 Infrastructure Needs Distributed repository of biological and physical characterization data for nanoparticles, esp. toxicity Distributed repository of biological and physical characterization data for nanoparticles, esp. toxicity Meta-data; ontology/data dictionaries (e.g., similar to program in place already in the cancer research community); XML-based applications and object- models Meta-data; ontology/data dictionaries (e.g., similar to program in place already in the cancer research community); XML-based applications and object- models Development of SRMs for nanoparticles Development of SRMs for nanoparticles Interoperability between data from experiments and simulation Interoperability between data from experiments and simulation National facilities for pre-clinical characterization of nanoparticles (build on NCL model) National facilities for pre-clinical characterization of nanoparticles (build on NCL model)

Pharma/medical Breakout Report-Out Workshop on Instrumentation, Metrology, and Standards for Nanomanufacturing, 10/17-19/06 Cross-Cutting Issues Text Text

Pharma/medical Breakout Report-Out Workshop on Instrumentation, Metrology, and Standards for Nanomanufacturing, 10/17-19/06 Summary/Conclusions/Priorities Text Text

Pharma/medical Breakout Report-Out Workshop on Instrumentation, Metrology, and Standards for Nanomanufacturing, 10/17-19/06 Participants/Contributors Text Text

Pharma/medical Breakout Report-Out Workshop on Instrumentation, Metrology, and Standards for Nanomanufacturing, 10/17-19/06 Sidebars for Report/Assignments Deb Newberry – issue of incompatibility of instrument test environment with active biological samples Deb Newberry – issue of incompatibility of instrument test environment with active biological samples Mike Gaitan – microfluidics Mike Gaitan – microfluidics Annette Kolodzie – Michael Thompson will contact her and ask Annette Kolodzie – Michael Thompson will contact her and ask Kambic Pourrezaei – nanoscale imaging of living systems without killing them (will contact Leica for example) Kambic Pourrezaei – nanoscale imaging of living systems without killing them (will contact Leica for example) Michael Thompson – nanoscale imaging of cryo living systems Michael Thompson – nanoscale imaging of cryo living systems Ask Anne Plant for living systems imaging example Ask Anne Plant for living systems imaging example Jessong Huang/Lori Goldner for single protein molecule in a cell – confocal imaging Jessong Huang/Lori Goldner for single protein molecule in a cell – confocal imaging Raman example (Angela Hight Walker) Raman example (Angela Hight Walker) Silver particles w/ anti-bacterial properties (Michael Thompson) Silver particles w/ anti-bacterial properties (Michael Thompson) Functionalized nanoparticles targeted at tumor cells (e.g., sentinal lymph node effort – per Marty Frittz; will put us in touch w/ someone at NCI to draft it) Functionalized nanoparticles targeted at tumor cells (e.g., sentinal lymph node effort – per Marty Frittz; will put us in touch w/ someone at NCI to draft it)

Pharma/medical Breakout Report-Out Workshop on Instrumentation, Metrology, and Standards for Nanomanufacturing, 10/17-19/06 References Text Text

Pharma/medical Breakout Report-Out Workshop on Instrumentation, Metrology, and Standards for Nanomanufacturing, 10/17-19/06 Implementation Strategies: Federal (F), Academia (A), Industry (I), SDOs & NGOs (S), Roadmap (R) Strategic item #1- Coordination between industry and government agencies – coordination between all pertinent government agencies xxx Strategic item # 2 - Need for development of new methods for nanoparticle formulations that meet medical requirements XxXx Strategic item #3 – Develop collaborations to define requirements for development of nanotoxicity testing platforms XXx Strategic items #4 - Develop Microfluidic technologies to observe, optimize and understand the formation of nanoparticles #5: Coordinate development of prioritized list of standard reference materials XXX Strategy Element F – A – I – S - R

Pharma/medical Breakout Report-Out Workshop on Instrumentation, Metrology, and Standards for Nanomanufacturing, 10/17-19/06 Implementation Strategies: Federal (F), Academia (A), Industry (I), SDOs & NGOs (S), Roadmap (R) #6: Coordinated development of standard test protocols (Federal/NIST w/ SDOs, industry, academia); e.g., what is needed for nanotox. XXXX #7: Coordinate development of terminology standard for disseminating and presenting data, models and knowledge (common vocabulary – ontology is part of current ISO effort) XXXX #8: Coordinate development of prioritized list of computer models/simulation (e.g., systems biology) XXX #9: Communicate with instrument developers re: requirements for imaging of living biological samples (e.g., workshop with bio/phrma researchers, companies) XXX #10: Develop network of databases linking size, shape, concentration, and other physical parameters to properties/functions/toxicity XXXX Strategy Element F – A – I – S - R

Pharma/medical Breakout Report-Out Workshop on Instrumentation, Metrology, and Standards for Nanomanufacturing, 10/17-19/06 Implementation Strategies: Federal (F), Academia (A), Industry (I), SDOs & NGOs (S), Roadmap (R) #11: Develop strategy for educating the public so they can better understand the information they get on issues associated with potential toxicity of nanoparticles or nano-enabled products XXXX Strategy Element F – A – I – S - R