fiberoptic uv dissolution ken boda method development … · 2016-09-11 · fiberoptic validation...
TRANSCRIPT
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Fiberoptic UV Dissolution
Method Development
Ken Boda
Dissolution Applications Engineer
Agilent Technologies, Inc.
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Agenda
• Background of Fiber Optic Dissolution (FOD) testing.
• What are the benefits of Fiberoptic testing?
• What factors need to be considered with FOD testing?
• Agilent Cary60 Fiberoptic Dissolution System
• Developing a Fiberoptic Method
2
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Background of Fiber Optic
Dissolution testing
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Fiber Optic Background.
• Dissolution testing can be a
labor intensive and time
consuming process.
• Traditionally we have looked
to automate with off line
fraction collector systems, or
on line UV & LC systems.
• These systems have proved
to be extremely popular, but
have limitations.
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Fiber Optic Background – Traditional Sample Method
Limitations
• Sampling speed
• Pumping systems
• Micro/Nano Particles
• Aggressive, organic & high
viscosity media’s
• Small volumes
• Analysis cost
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Fiber Optic Background – A New Approach
• Fiber optic dissolution systems
started to appear in the mid 1990’s.
• They eliminate the need to remove
the sample from the vessel.
• Light is “pumped” into the vessel
from the spectrophotometer for “in
situ” analysis, then back to the
spectrophotometer where the
absorbance is measured.
• They offer significant advantages for
many dissolution tests.
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What are the benefits of Fiber
Optic Dissolution testing?
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Fiber Optic Benefits
• Rapid Sampling Time
• Immediate Results
• Poor Stability Compounds
• Few Consummables/Low
Upkeep/Easy Cleaning
• Handles high surfactant media,
viscous media
• Can be converted to small and
large volume
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Samples Suited for Fiberoptics
• Multiple timepoints needed for Immediate-Release Drugs
• Profile mapping of new formulations
• Nano and Microparticle API in Formulation (can’t be handled
w/ conventional filters)
• Poor Stability Samples
• Challenging Medias for Pumps
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Samples Not Suitable for Fiberoptics
• HPLC Required for Separation
• Samples requiring pathlengths <1mm or with large dilutions
• Colloidal Media (milk)
• Excipients with Refractive Properties (rare)
Typically, UV FO will work in about 85-90% of samples where
UV is currently used
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What factors need to be considered with
Fiber Optic dissolution testing?
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Fiber Optic System Considerations
• Spectrophotometer Linear Range and Wavelength
Range
• Fiberoptic Probe Type
• Flexibility for Different Methods (hardware +
software)
• Ease of setup and changeover of system
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Spectrophotometer Linear Range
Linear Range Reflects the Total
Absorbance, in Fiberoptics it is made
up of:
• API Absorbance
• Absorbance of Excipients and
Undissolved Materials (no filter)
• Absorbance of Probes themselves
Need to choose UV which allows high
linear range after reductions from
probes and excipients
0
0.5
1
1.5
2
2.5
Active Excipients Fibers Total
AB
S (
AU
)
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Spectrophotometer Wavelength Range
The Spectrophotometer chosen
should work within the desired range,
in particular be able to read:
• Max absorbance (<210nm can be
difficult with some systems/methods)
• Area where no API absorbance
exists for baseline correction
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UV Spectrophotometer Type
Diode Array • Quicker – constant readings
• Lower Wavelength Range, but full
scans
• Lower Linear Range
• High Solarization Damage to
Fiberoptic Probes
Scanning Spectrophotometer • Quick – Every 30 seconds
• Wide Wavelength Range
• High Linear Range – up to 3.5AU
• Low Solarization Damage – longer
life probes
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Fiberoptic Probe Types
There are 2 Styles of Probes Typically
Available:
• Dip Probe
• Arch-shaped Probe
Dip Probes are usually ideal because
they are adaptable to multiple volumes,
and pathlengths are easily changed
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Other Probe Considerations
• Is the Probe Resident?
• What is the absorbance of the fiber
itself?
• What Pathlengths available?
• UV cutoff with probe?
• Expected Life of Probe (solarization)
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Flexibility of System
• Hardware
• Small/Large Volume?
• Pathlengths Available?
• Non-resident Probes?
• Software
• Dissolution Specific Software?
• App 1/2/5/6?
• Media changeover?
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Agilent Cary60 UV-Fiberoptics
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Agilent Cary60
• Linear over 3.5 absorbance units
• High intensity Xenon flash lamp
• No warm-up time
• Scanning Spectrophotometer
• 80 readings a second
• Scanning speed up to
24,000 nm/min
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Agilent Cary60
• Very large dynamic working range, 0.0001 – 3.5 AU
• Lamp only flashes when taking a reading – very long lamp life 8+ years
• Very low baseline noise
• Long-lived FO probes – limited solarization due to UV design
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Agilent Cary60
• 12 channel system for dual bath capability
• 30 sec timepoints for single system
• Purpose built for dissolution testing & Cary 60
• Each Fiber is individually connected to the multiplexer
• Highest Optical Transmission on the market
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Agilent Fiberoptic Probe Design
• Specially designed for dissolution testing
• 600 micron silica/silica Fibers for optimised transmission down to 190 nm
• 1, 2, 5, 10, 20mm tips available
• Streamlined to minimize hydrodynamic influence
• Non-resident when used with Agilent dissolution units
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Agilent Fiber Optic Probe Design
• Different pathlengths can be quickly swapped at low cost.
• Mirrors raised to avoid particle build up.
• Fibers encased in 316 stainless steel making them incredibly robust, and “QC friendly”.
• Simple and easy to clean and exchange.
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Developing a Fiberoptic
Method
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Same Validation Requirements as Traditional UV
• Linearity
• Range
• Limit of Detection
• Limit of Quantitation
• Specificity
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Main Differences Between Fiberoptic and
Traditional UV Measurement
• Apparent Dissolution vs. Filtered Dissolution
• Pathlength chosen may differ
• Deaeration Requirements
• Resident Probe Impact (if applicable)
• Standards and Blanks run only before and after run
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Specificity
Specificity is the ability to determine
the amount of API in the presence
of other components that may be
expected to be present such as:
• Impurities
• Degradation products
• Excipients
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Detection and Quantitation Limit
Detection Limit (LOD) is the lowest
amount of your compound which
can be detected, but not
necessarily measured. Typically
set at 3:1 signal to noise ratio.
Quanititation Limit (LOQ) is the
lowest amount of your compound
which can be measured with
acceptable prevision and
accuracy. Typically 10:1 signal to
noise ratio.
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Linearity and Range
Linearity is the ability to elicit test results which are directly (or
by a well-defined mathematical transformation) proportional
to the concentration of analyte within a given range
Range is the interval between the highest and lowest levels on
analyte to be determined with appropriate accuracy,
precision, and linearity
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Fiberoptic Validation – Apparent Dissolution
Dissolution Spectra vs. Time
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
240 250 260 270 280 290 300
Wavelength (nm)
Ab
so
rban
ce (
AU
)
Fiberoptics contains no filters, so your
total absorbance is made up of:
• Dissolved Drug Absorbance
• Undissolved Particles
• Excipients
• Media
• Fiberoptic Probes
We can adjust the data to get a
corrected reading for the API only
through a baseline correction
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Baseline Correction
0
0.2
0.4
0.6
0.8
1
240 290 340
Wavelength (nm)
Ab
so
rba
nc
e (
AU
)
Undissolved particles generally will
absorb equally across all
wavelengths
A solid particle blocks all wavelengths
equally – and does not have a
specific chromophore
If a baseline is flat, we can correct
based on it
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Baseline Correction
Typical Drug Spectrum
0
0.1
0.2
0.3
0.4
0.5
230 250 270 290 310 330 350 370 390
Wavelength (nm)
Ab
so
rba
nc
e
True drug absorption
= measured - excipients
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Baseline Correction
Baseline correction can account for most undissolved particles
and other interferences, but does not work in all situations.
• Colloidal particles
• Reflecting/Diffracting Particles
• Total absorbance needs to be in Linear range
Validation should be done to show that filtered samples give
them same result as baseline corrected fiberoptic data
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Comparison to Filtered Results
Results can be compared between
filtered and FO results in a number
of ways, concurrent sampling
tends to be the most popular.
You can also do:
• Spiked Placebo
• F2 Analysis (intermediate
precision)
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Pathlength Selection
• 1, 2, 5, 10, and 20mm sizes
available
• Choose tip size which will give
appropriate linearity 1 – 125%
• Cary60 typically aim 100% dissolved
to be b/w 0.5 – 2 AU
• Other systems may only work up to
1AU
• The larger the opening, the less
susceptable they are to air bubble
formation (5mm and above
unlikely to form bubbles)
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Fiberoptic Validation - Deaeration
Bubbles cannot be optically corrected for
All Fiberoptics are susceptable to air bubbles to varying degrees
Minimize air bubble impact:
• Deaerate so there is no significant formation
• Choose larger tip size if practical
• Face probes towards or away from shaft – maximize current ACROSS
probe to sweep anything which may have settled
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The Resident Probe Effect
Resident Probes can greatly alter hydrodynamics and alter results vs.
manual methods
Higher % Dissolved and more variability
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Validation Resident Probe Effect
For each method:
• Perform n=12 dissolution manually
• Perform n=12 dissolution w/ automation
• Compare mean of n=12 data and obtain f2 value
• f2 must be greater than 50, perhaps higher
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Standards and Blanks
Standards and Blanks are used to calibrate each probe prior to
the run, and can be checked at the end of the run
To run FO with a method you should:
• Demonstrate stability of reading over time
• Ensure SOP allows for “non-bracketed” samples
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Fiberoptic Cleaning
Easy!
Squirt down with Water, Ethanol, or other solvent
Wipe mirror w/ kimwipe gently
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Summary
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Summary
• Fiberoptics offers many
advantages to traditional
approaches
• Timepoint frequency reduced
• Ability to work w/ unfilterable
samples
• Poor stability samples
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Summary
As with other automation and analysis components:
• Needs to be accurate and precise
• Minimize or eliminate bias
• Appropriate selection of pathlength, wavelengths, etc. is
chosen for best test performance
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Agilent vs. Other FO systems
The Agilent FO solution offers cost advantages vs. other
vendors:
• Fewer pathlengths needed
• Lower cost when needing more pathlengths
• Longer life fiberoptic probes
• No lamp replacements
• Solution incorporates standard Cary 60 UV-Vis – not a
customized spectrophotometer that could be difficult to
service
• Single vendor solution
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December 7, 2013
Thank you for your attention!
Any Questions?
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