Nanotechnology-related Drug Database Nakissa Sadrieh, Ph.D. - PowerPoint PPT Presentation

Overview of CDER Nanotechnology-related Drug Database Nakissa Sadrieh, Ph.D. Director, Cosmetics Staff, OCAC/CFSAN/FDA (Previously, Associate Director for Research Policy and Implementation, OPS/CDER/FDA) FDA/PQRI workshop 2014 1

What has been the impact of nanotechnology-containing drugs on CDER applications? – How can CDER evaluate product attributes which might describe nanotechnology-related drugs? • FDA guidance document • CDER MAPP – Which drug products might possess aspects of nanotechnology-related characteristics? • CDER database of nanotechnology-related products – How can CDER help address the data gaps? • Research 2

Outline • What product attributes describe nanotechnology-related properties? – CDER MAPP • Which drug products might possess aspects of nanotechnology-related characteristics? – CDER nanotechnology drug database • How can CDER help address existing data gaps? – Dermal penetration of nanoscale TiO2 in sunscreens. – Development of discriminating dissolution methods for nanocrystals with different particle sizes. – Inhalation toxicology of spray sunscreens and cosmetics. 3

CDER Manual of Policies and Procedures for Drugs Containing Nanomaterials • CDER MAPP: “Reporting format for nanotechnology - related information in CMC reviews” (June 2010) • Purpose of the MAPP: – To collect in CDER CMC reviews, data submitted on nanotechnology-related information. • Criteria used for data collection: – If the particle size of the product is reported in the submission as being under 1000 nm, then the CMC review should contain a table included in the MAPP. 4

Nanotechnology Product MaPP Attachment A 1) This review contains new information added to the table below: _______Yes _______No Review date: _____________ 2) Are any nanoscale materials included in this application? (If yes, please proceed to the next questions.) Yes______; No______ ; Maybe (please specify)____________________ 3 a) What nanomaterial is included in the product? (please refer to attachment B for examples of nanomaterial)_______________________________________________________________ 2 b) What is the source of the nanomaterial?________________________________________ 4) Is the nanomaterial a reformulation of a previously approved product? Yes_________ No_________ 5) What is the nanomaterial functionality? Carrier_________________; Excipient__________________; Packaging________________ API____________________; Other____________________ ____________________________________________________________________________ 6) Is the nanomaterial soluble (e.g., nanocrystal) or insoluble (e.g., gold nanoparticle ) in an aqueous environment ? Soluble __________________; Insoluble___________________ 7) Was nanomaterial particle size or size range included in the application? No_______(please go to 9); Yes________ (please complete 8). 8) What is the reported particle size? Mean particle size___________ ; Size range distribution___________; Other___________________, 9) Please indicate the reason(s) why the particle size or size range was not provided: ____________________________ ____________________________ 10) What other properties of the nanoparticle were reported in the application (See Attachment E)? ____________________________ 5 11) List all methods used to characterize the nanomaterial? ___________________________

Evaluation of CDER Nanotechnology Database • Drugs that use nanotechnology include: – New molecular entities formulated with components in the nanoscale. – Reformulations of already approved products: • a decrease in the particle size may change some aspect of the drug (such as targeted drug delivery, pharmacokinetic profile, a more convenient dosage form thus better patient compliance). • Typical platforms include, but are not limited to: – Liposomes, nanocrystals, nanoemulsions, dendrimers, metal oxides (superparamagnetic iron oxide, titanium dioxide, zinc oxide), gold and silver nanoparticles. 6

Nanotechnology-related Submissions 128 140 120 # of Submissions 100 80 IND 52 60 applications 39 30 40 14 10 9 8 20 6 5 4 4 3 2 1 1 0 0 0 ) ) ) ) ) ) ) ) ) 1 3 1 5 2 1 8 2 3 4 ( 1 ( 5 6 2 1 ( ( ( ( s r ( ( 1 s e s O n s s ( s l m a e o e l e l a I t l P i l i A m l e c s r t l s e m d i S l o t u y c r n s a r i m l e M c o a p e D o d p o o n i i n L o n a a l N a l N o N C 7

Nanotechnology-related Platforms Dendrimer 0.6% Colloidal metals 1.9% Nanoemulsions 3.2% SPIO 7.0% Micelles 7.0% Liposomes 39.2% Nanocrystals 13.9% Nanoparticles 27.2% 8

Indications Others 22.2% Cancer 38.0% Cholesterol 3.2% Anemia 3.8% Diabetes 3.8% Immunosupp 4.4% MRI 5.7% Pain 10.1% Infection 8.9% 9

Routes of Administration 1 00 100 91 IV % Submissions 82 73 80 68 Inhalation 60 56 60 51 oral 40 33 33 33 40 28 topical 23 1 8 20 1 0 9 9 9 9 9 9 9 8 6 7 6 other inj 5 4 0 0 Dendrimer (1) Nanoparticles (43) SPIO (11) Nanoemulsions (5) Liposomes (62) Nanocrystals (22) Micelles (11) Colloidal metals (3) All (158) 10

Characterization • Many parameters may require characterization. • But size specification of nanoparticles in bulk material and formulated drug product are important in understanding a drug’s PK and PD profile. • Size can be reported differently (mean or distribution). • Different size measurement methodologies can have varying degrees of limitations. 11

Multiple Parameters…. Multiple Techniques 12

Particle Size Formats Reported in CDER Submissions Mean Mean range Mean +/- STD Cumulative Not available 80 76 70 # of Submissions 60 48 50 40 35 29 30 1 9 1 6 20 1 2 1 2 1 0 1 0 8 7 7 6 6 6 10 5 4 4 3 3 2 2 1 1 1 1 1 1 0 ) ) ) ) ) ) ) ) ) 1 7 5 5 2 1 8 4 3 4 1 ( ( 6 2 1 6 ( ( ( ( ( s r ( 1 s e e n e O ( s s l a m o l e l l l c a l I t l e P i m i A i e s r t t c d r s S m l o u a y i n M s p r m l e o c a o D e o p d n o n i i L a o n a N l a l N o N C 13

Assumptions Used In Analysis Of CDER Database • Our analysis considered only one value for the mean, assuming that all measures of mean values were equivalent: – Mean, mean range, mean+/-SD, median • Our analysis did not consider that different methods used to assess mean values (such as DLS, TEM, FFF, etc…) would introduce different degrees of variability, because of fundamental differences in the methods. • Our analysis did not take into account inherent differences in formulations (e.g. suspensions versus powder) that would be impacted by the particle size measurement methodologies. 14

Percentage of Submissions With Some Form of “Mean Particle Size” Information Size available (155) Size not available (3) 2% 98% 15

Particle Size Methodologies Used in Nanotechnology-Related Submissions Dynamic light scattering 24% NA 55% Laser diffraction 10% Microscopy 6% others Cascade 2% Impactor 3% 16

Reported “Mean” Particle Size For All Nanotechnology-related Submissions 60 50 % Submissions 40 35 29 26 30 20 8 10 2 0 <100 (56) 100 - 300 (46) 300 - 600 (12) 600 - 1000 (0) >1000 (41) NA (3) nm 17

Reported “Mean” Particle Size For Nanotechnology - related Submissions Under 1000 nm 60 49 50 40 % Submissions 40 30 20 11 10 0 <100 (56) 100 - 300 (46) 300 - 600 (12) 600 - 1000 (0) nm 18

Distribution of “Mean” Particle Size in CDER Database 700 600 500 400 nm 300 200 100 0 Liposomes Nanoparticles Nanocrystals Micelles SPIO Nanoemulsions Colloidal Metals 0 1 2 3 4 5 6 7 8 19

Examples of Biological Responses Subject To Size Limitations Biological responses Size limits Comments Glomerular filtration 5-10 nm Physiologic upper limit by renal clearance Nanoparticles transport through liver sinusoid 300 nm Liver fenestrae act as a sieve plate and can control the passage of nanoparticles, allowing only those particles smaller than the fenestrae to reach the liver cells. Size distribution of sinusoidal fenestrae among different species; 75 - 300 nm in rats, 45 - 255 nm in rabbits, 55 - 320 nm in mice and 50 - 300 in humans . Particle shapes and rigidity may further affect the size limit, for example, liposome sizes of up to 400 nm were able to cross the liver fenestrae. Enhanced permeability and retention (EPR) 300-600 nm EPR effects may vary depending on the species, tumor implantation sites and tumor types. Pore size may also be different in xenografts than in natural tumors. Nanoscale particles up to 300 nm in diameter extravasate through leaky tumor vasculature and selectively accumulate in tumor tissue via EPR effect . In study involving liposomes, sizes up to 600 nm in diameter were able to permeate through the tissues. Thus, average pore sizes may be approximately assumed in 300 - 600 nm range. Reticuloendothelial system (RES) uptake 300 nm Nanoparticles are cleared by size dependent phagocytosis by the cells in reticuloendothelial system. Extended blood residence time for surface modified nanoparticles up to 200 – 300 nm .