US-Nanotechnology Characterization LabScott McNeil, PhD

Director

Workshop Session 7: EU-US and International cooperation

NMBP 14-2017: Regulatory Science Framework for assessment of risk benefit ratio of Nanomedicines and Biomaterials

Thematic brokerage workshopsWorkshop 7: EU-U.S Cooperation

EU Brokerage Event on Kets in Horizon 2020Strasbourg, 1st October 2015

101/10/2015 - BE KETs Regulatory Science Framework for Nanomedicines and Biomaterials

US-NCL Mission

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The NCL was established in 2004 as an interagency collaboration among NCI, NIST, and FDA. The lab’s primary mission has been to accelerate the translation of promising nanotech cancer drugs and

diagnostics using a standardized “Assay Cascade.

Big Pharma

Academic PIs

Biotech Companies

Government

R & D Community

In Vivo Characterization

In Vitro Characterization

Physicochemical Characterization

Clinical

Regulatory

Commercialization

Support

Assay Cascade

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• Equivalence testing for nanosimilars • Addressing FDA’s scientific questions• NBCDs

• Collaborations with Pharma, CMOs & industry consortia

• Immunotox• Active targeting

• Working with instrument manufacturers

• Provides “pharmaceutical mentorship” for materials scientists and engineers

• Other indications, EHS, etc.

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Over 300 Nanomaterials Characterized

Types of Samples

• NCL has characterized over 300 different nanomaterials and a wide range of various platforms.

• NCL has an average of 15 active collaborations at any given time.

• NCL characterizes an average of 75 samples each year.

• NCL testing is tailored to the platform properties, API, route of administration, and intended therapeutic outcome of the individual nanomedicine.

NCL testing links physicochemical properties to biological outcomes.

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In clinical trials

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NCL-FDA RelationshipNCL is trusted source for preclinical data on nanomaterials.

• NCL allows FDA to preview what’s in pipeline for nanotech INDs/IDEs.

• Quarterly interactions (visits, working groups) with FDA to maintain collaboration.

• Collaborations with FDA to fill gaps/better inform regulatory process: methods development, basic research and grand challenges

• Addressing regulatory concerns facilitates commercialization.

• FDA provides input on NCL’s assay cascade and is represented on NCL’s scientific oversight committee.

• NCL participates in FDA public meetings on topics related to nanomedicine.

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NCL Supports Translation/Regulation

• Preclinical Characterization

• Regulatory Concerns

• Clinical Characterization

• Exploring Alternate Indications

• Next-Generation Nanoparticles

Historical NCL knowledge used to make recommendations in many areas, helping sponsors gain regulatory approval.

Nanomedicine Developers

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NCL-FDA Scientific Collaborations

• Immunological reactions to nanomaterials in non-human primates.

• Dermal penetration of nanomaterials in sunscreens and cosmetics.

• Compared endotoxin levels in experimental nanomaterial products to levels in FDA-approved products.

• Penetration of nanoscale TiO2 particles in rodents, pig skin, and human skin.

• Characterization and purification of dendrimers for a dermal penetration study.

• Effects of sterilization procedures (autoclave, gamma irradiation, etc.) on silver colloids.

• Upcoming collaboration to study bioequivalence of follow-on nanomedicine products.

Office of Generic Drugs

Endotoxin screening should be included whenever biological assessments of the materials are going to be performed.

NCL pre-screened all ENMs used in this study.

NCL ParticleDesignation

Nanomaterial

Endotoxin, Kinetic Turbidity LAL

First test lots

New, Large-scale lots

NIEHS-120 nm, citrate

stabilized silver42.7 EU/mL < 0.5 EU/mL

   

NIEHS-220 nm, PVP

stabilized silver113 EU/mL ≤ 2.2 EU/mL

   

NIEHS-3110 nm, citrate stabilized silver

0.42 EU/mL < 0.5 EU/mL

   

NIEHS-4110 nm, PVP

stabilized silver144 EU/mL < 0.5 EU/mL

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Coordination between Agencies

Characterization in pristine vs. biological setting matters.

BET = Brunauer, Emmet, and Teller

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Vendor used BET for measuring size –BET is a surface area measurement, not accurate for size measurements.

Formula: CeO2

Purity: 99.5% minimum (based on rare earth oxide impurities)Formula Weight: 172.12 g/molMelting Point: 2600°CDensity: 7.132 g/mL

Form: 15-30 nm average particle size, powder

Manufacturer-Stated Specs:

What the Material Actually Looks Like:

• Micron-sized aggregates/agglomerates• Largely insoluble in aqueous media

Pristine vs. Biological Settings

Transmission EM

Scanning EM

Centrifugal Field-Flow Fractionation

CNTs will exist in a variety of sizes, shapes, and agglomeration states.

Vendor specs: OD 10-20 nm, length 0.5-2 μm

Vendor specs

Reality

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Manufacture vs. Experimental

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• Need better protocols for dispersing poorly soluble ENMs; better reproducibility between labs. 

• Many labs will sonicate and use immediately, (hopefully) before ENMs settle out. 

• Some add coatings to help solubilize, but can these influence other factors.

Problem: Poorly soluble ENMs

This is an important step in correlating PCC to biological properties.

Recommendations

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• Very limited PCC and size tools are available for many poorly soluble ENMs.

• Most require an aqueous resuspension.

• For example, MWCNTs typically only report TEM measurements on a very select population.

Problem: Limited characterization tools

Need consistency across labs in measuring and reporting PCC.

• How should size of polydispered samples be reported?• Size by XRD vs TEM vs DLS can all be very different.

Problem: Size reporting for polydispersed samples

Recommendations

29/11/2013 - BE KETs Adressed challenge/PPP 14

Systematic investigations of the mechanisms and effects of engineered nanomaterial interactions with living systems and/or the environment36 partners across the globe working together to study more than two dozen different ENMs

NCL’s Role, Testing 15 ENMsPhysicochemical Characterization

• Size/Size Distribution• DLS• TEM

• Surface Charge• Zeta Potential

• Composition• EDS

In Vitro Cytotoxicity• MTT Cell Viability Assay• LDH Membrane Integrity Assay

• Porcine Renal Proximal Tubule (LLC-PK1) Cells• Human Hepatocellular Carcinoma (HepG2) Cells

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Cooperation with EU-NCLExpansion of resources for nanomedicine developers.

•Expanded visibility

•Greater quality control & harmonization

• Reduced risk of an adverse event in nanomedicine• EU-NCL will facilitate interaction with EMA

NCL will work closely with EU-NCL to establish SOPs, keep lines of communication open.

Contact Person: Scott McNeil, PhDDirector

Organisation Nanotechnology Characterization Laboratory

AddressP.O. Box BFrederick, MD 21703United States

Phone nr (301) 846-6939

E-mail ncl@mail.nih.gov

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Contact Details