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
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)
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
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
Transdermal Drug Delivery Systems: Adhesive StrengthSeveral 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
Size NameType
(Drug-In-Adhesive; Reservoir) Application period Shape
3.5 cm2 CATAPRES-TTS-1 Reservoir 1 time/ week square
9.375 cm2 CLIMARA Drug-In-Adhesive 1 time/ week octagon
22.0 cm2 VIVELLE Drug-In-Adhesive 2 times/ week oval
2.5 cm2 VIVELLE-DOT Drug-In-Adhesive 2 times/ week rectangular
40 cm2 DURAGESIC Reservoir 72 hours rectangular
2.5 cm2 TRANSDERM SCOP Reservoir 3 days circular
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
Measuring API Particle Size in the Presence of Particulate ExcipientsRaman Chemical Imaging Of Aqueous Nasal Spray SuspensionRegion of Interest2
Raman Shift (cm-1)
Arb
itrar
y In
tens
ity
1630 1640 1650 1660 1670 1680 1690 1700
Brightfield Reflectance Image Polarized Light Image
10m
Normalized Imaging Spectrometer Raman Spectra Brightfield / Raman Image Overlay
Drug Peak
Raman Chemical Image of BDP
Figure 7. BDP Aqueous Nasal Spray Suspension – ROI 2
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
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
Lot Date Mean (n=6)
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 28-54DPA/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.
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
IRMS- Isotope Ratio Mass Spectrometry
Naproxen: d13C vs d18O
-34
-32
-30
-28
-26
-24
-5 0 5 10 15 20
d18O (‰ vs VSMOW)
d13C
(‰
vs
VP
DB
)
India,Mfr A
Ireland,Mfr E
Italy,Mfr C
India,Mfr B
USA, Mfr F
Italy,Mfr D
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.
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
Terahertz Spectrometry
Partial Least Squares Fit
Content (mg) by NIR PLS Calibration from HPLC
TH
z P
red
icte
d C
on
ten
t (m
g)
Ab
sorb
an
ce
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
Computational Chemistry (Chemometrics)
Examples:• Understanding chemometric software packages• Understanding limitations and benefits of multivariate
techniques
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, 2nd Derivative, 3 Factors
Tablet Transmittance – limited spectral range
PLS – Mean Centered, Direct Spectra, 3 Factors
Re
flect
an
ce
Tra
nsm
itta
nce
Energy (cm-1)Energy (cm-1)
Content Measured by HPLC Content Measured by HPLC
Ca
lcu
late
d
Co
nte
nt
Ca
lcu
late
d
Co
nte
nt
Data Range: 4000 – 10000cm-1 Data Range: 8600 – 10000cm-1