1. Division of Pharmaceutical Analysis Research in support of the Critical Path Dimensions Ensuring Safety Demonstrating Medical Utility Industrialization Process Lucinda F. Buhse, Ph.D., Director

2. Division of Pharmaceutical Analysis Critical Path Initiatives Characterize Novel Dosage Forms/ Complex Drug Substances Measurement and ID of Micro and Nanoparticles Establish Appropriate Surrogate Measurements Techniques Drug Authenticity and Anti-counterfeiting Techniques Process Analytical Technologies for Manufacturing Computational Chemistry (Chemometrics)

3. Characterization of Novel Dosage Forms/ Complex Drug Substances Examples: Liposomes –characterization after chemical and physical changes Transdermals – physical characterization of adhesive strength Conjugated Estrogens – improvement of LCMS comparison method Protein Products -Detection of Aggregation and Degradation Regulatory Accomplishments: Input into Conjugated Estrogens Guidance

4. Monitoring Liposomal Drug Products (LDPs) Under Manufacturing Stress Conditions LDPs (PEGylated Doxil ®, Conventional DaunoXome ® ) Stress Conditions –Thermal –Oxidative –Acid and Base –Light –Sonication –Detergent Analytical methods for Monitoring quality – Drug Substance (HPLC-UV) – Encapsulation Efficiency (fluorescence) – Lipid Composition (HPLC-ELS) – Particle Size – Zeta Potential

5. Transdermal Drug Delivery Systems: Adhesive Strength Several sizes of patches, types of drug delivery, application periods, and shapes. Example of drug-in-adhesive Example of reservoir Test method development variables and constants: Test panelRollsRolling time Test panel cleaning Angle of pullPull speedDwell time Environment

6. Measurement and ID of Micro and Nanoparticles Examples: Sunscreens – evaluation of particle size in the formulation Nasal Sprays –evaluation of Raman Microimaging for particle sizing of active pharmaceutical ingredient –evaluation of Andersen Cascade Impactor configuration for use in assessing the distribution of fine particles Regulatory Accomplishments: Input into Nasal Spray BA/BE Guidance Development of compendial method for cyclosporine particle size

7. Measuring API Particle Size in the Presence of Particulate Excipients

8. Establishment of Appropriate Surrogate Measurement Techniques Example: Mefloquine HCl – evaluation of polymorphs of API with respect to BA of finished dosage form Megestrol Acetate – evaluation of dissolution media to detect BE/BA differences Evaluation of variability in Dissolution testing – search for an alternative technique to establish BE/BA Regulatory Accomplishments: Input into resolution of prophylaxis failure of military use product Input into resolution of generic manufacturer equivalency challenge

9. Dissolution: Less variability is needed The current USP 10-mg Prednisone Calibrator Tablets exhibit slower dissolution over time Acceptance limits are so large, that improper mechanical calibration may not be detected Differences in product testing can often be traced to improper mechanical calibration and/or degassing LotDateMean (n=6) SD (%) USP Limit (%) M4/0034.82.228-42 M10/0028.90.928-42 N12/0135.71.628-54 N11/0235.41.428-54 N6/0328.00.728-54 DPA/FDA Data using Apparatus 2; data from only one apparatus shown. Note the USP adjusts the limits of each new lot of calibration tablets to reflect the anticipated decrease in dissolution.

10. Example: Assessment of technologies for detection of counterfeit (IRMS, NIR, TGA, Terahertz) Regulatory Accomplishments: Quality of foreign Active Pharmaceutical Ingredients program Foreign Internet Sample Studies Drug Authenticity and Anti-counterfeiting Techniques

11. IRMS- Isotope Ratio Mass Spectrometry IRMS can provide the source of active pharmaceutical ingredients (APIs). In the bivariate isotope ratio graph shown, the typical clustering of the data is consistent with manufacturer-based isotopic provenance.

12. Process Analytical Technologies for Manufacturing Examples: Assessment of technologies for PAT (Terahertz, NIR) Effect of coating composition and thickness on PAT measurements Effect of excipient and excipient/drug interaction

13. Terahertz Spectrometry Partial Least Squares Fit Content (mg) by NIR PLS Calibration from HPLC THz Predicted Content (mg) Absorbance Energy (5 - 45cm -1 ) Terahertz Absorption Spectra Acetaminophen tablet content: 65 – 135 mg scanned by NIR and Terahertz Absorbance. Non-Destructive and Penetrating Imaging of Biological Tissue On-Line or At-Line Quality Control including whole tablet imaging

14. Computational Chemistry (Chemometrics) Examples: Understanding chemometric software packages Understanding limitations and benefits of multivariate techniques

15. Critical Path - Chemometrics Near Infrared Reflectance and Transmittance of formulated tablets Multivariate models in PAT – Partial Least Squares (PLS) analysis Uncoated Acetaminophen tablets in 9 dosage levels 65 – 135mg. Tablet Reflectance – full range PLS – Mean Centered, 2 nd Derivative, 3 Factors Tablet Transmittance – limited spectral range PLS – Mean Centered, Direct Spectra, 3 Factors Reflectance Transmittance Energy (cm -1 ) Content Measured by HPLC Calculated Content Data Range: 4000 – 10000cm -1 Data Range: 8600 – 10000cm -1

16. Division of Pharmaceutical Analysis St. Louis, Mo. and White Oak, Md.