Overview of CDER Nanotechnology-related Drug Database

Transcription

1 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

2 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

3 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

4 CDER Manual of Policies and Procedures for Drugs Containing Nanomaterials CDER MAPP: Reporting format for nanotechnologyrelated 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

5 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)? 11) List all methods used to characterize the nanomaterial? 5

6 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

7 # of Submissions Nanotechnology-related Submissions Liposomes (62) Nanoparticles (43) Nanocrystals (22) Micelles (11) SPIO (11) Nanoemulsions (5) Colloidal metals (3) Dendrimer (1) All (158) IND applications 7

8 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

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

10 % Submissions Routes of Administration Liposomes (62) Nanoparticles (43) Nanocrystals (22) Micelles (11) SPIO (11) Nanoemulsions (5) Colloidal metals (3) Dendrimer (1) All (158) IV Inhalation oral topical other inj 10

11 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

12 Multiple Parameters. Multiple Techniques 12

13 # of Submissions Particle Size Formats Reported in CDER Submissions Mean Mean range Mean +/- STD Cumulative Not available Liposomes (65) Nanoparticle (47) Nanocrystals (24) Micelle (12) SPIO (11) Nanoemulsions (5) Colloidal metals (3) Dendrimer (1) All (168) 13

14 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

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

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

17 % Submissions Reported Mean Particle Size For All Nanotechnology-related Submissions <100 (56) (46) (12) (0) >1000 (41) NA (3) nm 17

18 % Submissions Reported Mean Particle Size For Nanotechnologyrelated Submissions Under 1000 nm <100 (56) (46) (12) (0) nm 11 18

19 nm Distribution of Mean Particle Size in CDER Database Liposomes Nanoparticles Nanocrystals Micelles SPIO Nanoemulsions Colloidal Metals

20 nanoparticles up to nm. 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; nm in rats, nm in rabbits, nm in mice and 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) 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 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

21 Completed SRS Research to Address Regulatory Science Questions Dermal penetration studies in pigs, using formulated sunscreens containing nanoparticles of TiO2. Evaluation of the impact of particle size, on the dissolution and bioavailability of poorly soluble nanocrystalline drugs (such as Naproxen). 21

22 Ongoing and Planned Research Studies with Nanotechnology-Related Products FDA funded research project (CORES 2013) on the inhalation toxicity of spray sunscreens containing TiO2. collaboration with NIST, NIOSH, NCTR, CDER. Proposed FDA funded research project on the inhalation toxicity of spray cosmetics and mineral powders containing TiO2, ZnO and other potential nanoparticles. 22

23 Study Procedures Characterization studies at NCTR and NIST to evaluate of selected products have nanoparticles, and to characterize particle size. In vivo inhalation toxicology studies at NIOSH (The spray generation and animal exposure systems will be similar to those described in McKinney et al., Inhal. Toxicol. 24: , 2012). 23

24 Summary The Science and Research Staff (SRS) has done a preliminary analysis of nanotechnologyrelated drugs submitted for review. The SRS has completed a number of research projects to address regulatory gaps associated with the use of nanoparticles in drug products. There are ongoing research projects to address current regulatory gaps associated with the use of nanoparticles in FDA-regulated products. 24