Division of Pharmaceutical Analysis

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Division of Pharmaceutical Analysis
Lucinda F. Buhse, Ph.D., Director

• Research in support of the Critical Path
  Dimensions
• Ensuring Safety
• Demonstrating Medical Utility
• Industrialization Process

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Division of Pharmaceutical AnalysisCritical 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)

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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

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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

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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 panel Rolls Rolling time Test
panel cleaning Angle of pull Pull speed Dwell
time Environment
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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

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Measuring API Particle Size in the Presence of
Particulate Excipients
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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

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Dissolution Less variability is needed
Lot Date Mean (n6) SD () USP Limit ()
M 4/00 34.8 2.2 28-42
M 10/00 28.9 0.9 28-42
N 12/01 35.7 1.6 28-54
N 11/02 35.4 1.4 28-54
N 6/03 28.0 0.7 28-54
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. 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. 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. 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. 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.

• 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

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Drug Authenticity and Anti-counterfeiting
Techniques

• 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

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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.
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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

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Terahertz Spectrometry

• Non-Destructive and Penetrating
• Imaging of Biological Tissue
• On-Line or At-Line Quality Control including
  whole tablet imaging

Acetaminophen tablet content 65 135 mg scanned
by NIR and Terahertz Absorbance.
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Computational Chemistry (Chemometrics)

• Examples
• Understanding chemometric software packages
• Understanding limitations and benefits of
  multivariate techniques

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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
Tablet Transmittance limited spectral range
Data Range 4000 10000cm-1
Data Range 8600 10000cm-1
Reflectance
Transmittance
Energy (cm-1)
Energy (cm-1)
PLS Mean Centered, 2nd Derivative, 3 Factors
PLS Mean Centered, Direct Spectra, 3 Factors
Calculated Content
Calculated Content
Content Measured by HPLC
Content Measured by HPLC
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Division of Pharmaceutical AnalysisSt. Louis,
Mo. and White Oak, Md.