Embed Size (px)
Citation preview
Dissolution Failure
Investigation
Ken Boda
Dissolution Applications
Engineer
Dissolution Failure Investigation
Whenever a dissolution test fails to meet specifications, an
investigation should be performed to determine the cause(s) of
the failure.
Failure can be due to:
•Man (analyst)
•Machine (dissolution apparatus)
•Method (SOPs)
•Materials (standards, buffers, dosage form, etc.)
Conducting an Investigation
Investigations should be performed in
a sequential process to ensure all
potential sources of error are
investigated
•Review data as a whole
•Perform investigation in reverse
chronological order
Aerial View of the Data
The Error itself can help narrow the
focus of the investigation:
•Entire data set trending high/low
•1 outlier
•High %CV
•Data which makes no sense
Data trending high/low
•Bad lot
•Calculation Error
•Standard Prep Error
•Improper Filtration
•System misalignment (overall)
•Poor evaporation control
0
20
40
60
80
100
120
1 2 3 4 5 6
1 Outlier
•Misalignment/Bad Component in
Single Position
•Filter fell off
•Bad sample reading
•Transcription Error
•Bad individual dosage form
•Contamination
•Wrong volume poured
0
20
40
60
80
100
120
1 2 3 4 5 6
High % CV
•Sampling Inconsistencies
•Poor techniques
•Vibration
• Improper Degassing
•System Misalignment (tends to
trend)
• Issues w/ formulation
0
20
40
60
80
100
120
1 2 3 4 5 6
Data that doesn’t make sense
•Filtration Issues
•Bad Sample Readings
•Air bubble
•Contamination
0
20
40
60
80
100
120
1 2 3 4 5 6
Determinant vs. Non-Determinant Errors
Determinant Errors are known and
controllable
Determinant errors when found will
lead to a simpler investigation and
require the least re-work
Indeterminate errors are unknown,
suspected, or beyond control
Indeterminate errors cannot be
proven, and the burden of retesting is
often higher
Investigating in Reverse
•Last thing done, first investigated
•Limits scope of investigation, if
determinant error found – can stop
•Last things done can often allow
salvaging of the run
•All samples/standards/etc. should be
kept until results have been checked
and approved or fully investigated
Investigation Track
•Calculations
•Analysis
•Sampling and Filtration
•Run Observations
•Media Prep and Sample Handling
•Pre-Run Checks
•Dissolution Unit Mechanicals
•SOP and Materials
Checking Calculation Errors
•Check for transcription errors
•Are the right values being used for:
–Standard Conc.
–Label Claim
–Dissolution Volume
•Verify calculations by hand
•Ensure proper calculations are being
used
Calculations without Media Replacement
T1 % Dissolved = ((((A1 x V) /As) x C) / W) x 100 T2 % Dissolved = (((((A2 x (V - R)) + (A1 x R)) /As) x C) / W) x 100 T3 % Dissolved = (((((A3 x (V – (R x n))) + ((A1 + A2) x R)) /As) x C) / W) x 100
Where, A1 = the absorbance of the first sample pull A2 = the absorbance of the second sample pull An = the absorbance of the nth sample pull As = the average absorbance of the standard V = the initial media volume, ml C = the concentration of the standard, mg/ml W = the weight of the active, mg (label claim) R = the volume of media being withdrawn for a single sample pull, ml n = the number of the sample pull taken
Calculations with Media Replacement
T1 % Dissolved = ((((A1 x V) /As) x C) / W) x 100
T2 % Dissolved = (((((A2 x V) + (A1 x R)) /As) x C) / W) x 100
T3 % Dissolved = (((((A3 x V) + ((A1 + A2) x R)) /As) x C) / W) x 100
Where,
A1 = the absorbance of the first sample pull
A2 = the absorbance of the second sample pull
An = the absorbance of the nth sample pull
As = the average absorbance of the standard
V = the initial media volume, ml
C = the concentration of the standard, mg/ml
W = the weight of the active, mg (label claim)
R = the volume of media being withdrawn for a single sample pull, ml
n = the number of the sample pull taken
Check Original UV/HPLC readings
•Right Wavelength and/or LC
conditions used?
• If sample/standard readings were on
UV, check scan if available
• If sample/standard readings were on
HPLC, review chromatogram for:
– Proper peak shape
– Non-parent peaks
– Contaminants
Reanalyze Samples/Standards
• If available, reanalyze samples in
question
•Reanalyze standard
•Compare standard against a fresh
standard to ensure original standard
was prepared correctly
– Make sure dilutions and purity are
properly factored
– Dilution error possible?
Standard Preparation
•Create new standard to compare
against one used for run
•Ensure adjustments are made for
moisture and purity
•Right pipet/flask used?
•Within expiration period?
Storage
•Were samples within expiration
period?
•Covered?
•Stored Properly?
•Labeled?
Sampling and Filtration
Sampling and Filtration are one of the
most common causes of dissolution
failures:
•USP Position
•USP Timing
•Filtration
USP Sampling Area
Sampling takes practice and
attention!
All samples must be withdrawn:
•½ way between top of
paddle/basket and media
•No closer than 1cm from vessel
wall
•Recommend not sampling within
1cm of spindle
Imagine A Donut
Sample Timing
•Must sample (and filter) within 2% of
the timepoint or 15 minutes,
whichever is less
•Paddles/baskets must still be stirring
while sampling
Filtration
•Is the filter validated?
– Efficiency
– Leaching
– Adsorption
•When was the sample filtered?
– At time of sampling?
– Immediately after sampling?
– After time point collected?
Autosampling
Autosampling can reduce many of the
errors associated with manual
sampling:
•Position constant
•Timing within 2%
•Consistent pull force
•Documentation
Dissolution
Observations
Observations
Observations of the dosage form are
key in order to diagnose potential
issues with the dosage form.
Observations can tell why something
happened, % dissolved issues can
only tell you what happened.
When should you take observations?
Ideally, observations should be taken
at all critical timepoints of the run
•Wetting/Dose Dumping
•Release Profile
•Complete Release/Asymptote
•Whenever sampling manually
0
10
20
30
40
50
60
70
80
90
100
110
0 30 60 90 120 150 180 210 240 270
% D
isso
lved
Time (minutes)
Brand to Brand Differences in Dissolution Profiles
Brand A
Brand B
Brand C
What to look for
Initial Stages:
•Floating or Moving?
•Coning?
•Dispersion Profile?
•Dissolved Gasses?
•Cross-linking?
•Compare appearance of all dosage
forms
Floating/Moving Dosage Forms
• If a dosage form is floating or
moving, it adds additional sources
of energy to the dosage form and
increases variability
•Sinkers should be used when
floating, spinning, dancing, etc.
occurs
•Use validated sinker
Coning
•Cones should be loose
•Cone should be in consistent
location (bottom center)
•Look for consistent behavior across
vessels, any trending noticed?
• In cases of severe coning, method
alteration may be needed
– Higher RPM
– Peak vessel
Dispersion Profile and Dissolved Gasses
•Are air bubbles on stirring element, vessel, dosage form?
•How are particles distributed in vessel (top, middle, and
bottom)
•Are particles floating?
•Presence of air bubbles may indicate degassing method is not
sufficient
Cross-linking
Cross-linking of capsule shells can
result in hardened and chemically
resistant shells. Very common to see
in stability testing.
•Delay opening
•Trap Drug Product
•Pellicle Formation
If Cross-Linking is seen, testing with
pepsin or pancreatin should be
performed
Compare Results of all 6-8 Vessels
•Take observations as a complete set, just like data
•Write observations down
•Is there any atypical behavior?
•Trending of observations?
Observations During Release Profile
•Size of dosage form/particles
•Distribution of dosage form
•Consistency of the dosage forms
•Anything changed?
Observations at End of Run
•Any material left?
•Describe material
•May be beneficial to assay dosage form post-mortem in
formulation development or investigation of strange data or
observations
Media Preparation
•Degassing Procedure validated?
•Time of degassing vs. time of use
•Pouring Technique
Sample Handling
•When exposed to air?
•Weighed?
•Inspected?
•Where placed?
•How handled?
– Bare hands
– Gloves
– Tweezers
Instrument Checks
Pre-run checks of the instrument are
always recommended.
Pre-run checks are actually required
if following the FDA or ASTM
Mechanical Qualification procedure.
Recheck these same parameters in
the event of a run failure
Dissolution Mechanical Qualification Standards
Prior to each dissolution test, the guidelines generally agree,
requiring documentation for:
• Vessel examination
• Paddle examination
• Baskets and basket shaft examination
• Vessel medium temperature measurement
• Vibration evaluation
• Water bath (USP)
• Speed measurement on single position (USP)
Dissolution Mechanical Qualification Standards
Vessel Examination, must be free from:
• Scratches
• Cracks
• Pits
• Residue
• Surface irregularities
Centering Device, should also be:
• Complete
• Tight to Vessel Plate
Vessel Examination
Dissolution Mechanical Qualification Standards
Paddle Examination, must be free of:
• Defects
• Rusting
• Corrosion
• Peeling or loose coating
• Knicks, dents or misshapen appearance
Stainless Steel Paddles – Minor Rusting
Stainless Steel Paddles – Advanced Corrosion
Teflon Paddles – Good, Okay, and Terrible
Dissolution Mechanical Qualification Standards
Basket and Basket Shaft, must be free from:
• Defects
• Rusting
• Corrosion
• Loose wires
• Clogged mesh openings
• Dented sides or bottom
• Knicks, dents or misshapen appearance
• O-ring are not compliant; three clips required
Baskets – From New to Dead
Basket – Bad Example
Dissolution Mechanical Qualification Standards
Other Requirements:
• Vessel Temperature: The temperature of the medium inside each vessel
is measured at the time of use. Media temperature must be ±0.5ºC from
target.
• Vibration: There can be no significant vibration in the dissolution
apparatus or medium. Possible sources of vibration are the surrounding
environment, the dissolution unit itself or one of its components or an
external water bath circulating heater.
Perform Mechanical Checks on System
•If no issues w/ individual
components is noted, investigation of
the system’s overall alignment and
performance should be reviewed
•MQ tolerances, particularly height
and centering can be susceptible to
change
•If height/centering is out, can have
major impacts on hydrodynamics
Dissolution Mechanical Qualification
Specifications and Tolerances
Parameter ICH
Harmonized
(USP, JP, EP)
FDA
DPA-LOP.002
ASTM
E2503-07
USP Toolkit
Ver 2.0
Basket and
Paddle Depth
25 ± 2 mm 25 ± 2 mm
25 ± 2 mm
(or <8%)
23-27 mm
Rotational
Speed
± 4% of
specified rate
± 2 rpm of
target
± 2 rpm or
within 2% of
target (larger)
± 1 rpm of
target
Shaft Wobble No significant
wobble
≤ 1.0 mm total
runout
≤ 1.0 mm total
runout
≤ 1.0 mm total
wobble
Shaft
Verticality
Not measured ≤ 0.5° from
vertical
(x and y 90º)
Within Bubble
(x and y 90º)
Not measured
Basket Wobble ± 1 mm ≤ 1.0 mm total
runout lower
rim
≤ 1.0 mm total
runout lower
rim
≤ 1.0 mm total
wobble
Dissolution Mechanical Qualification
Specifications and Tolerances
Parameter ICH
Harmonized
(USP, JP, EP)
FDA
DPA-LOP.002
ASTM
E2503-07
USP Toolkit
Ver 2.0
Vessel/Shaft
Centering
NMT 2 mm
from center
axis
≤ 1.0 mm from
center line
(upper/lower)
≤ 1.0 mm from
center line
(upper/lower)
NMT 2.0 mm
difference (4-
90°positions)
Vessel
Verticality
Not Measured ≤ 1.0° from
vertical (2 - 90°
positions)
≤ 1.0° from
vertical (2 - 90°
positions)
NMT 0.5° from
vertical
Vessel Plate
Level
Not Measured Not Measured
Not Measured
NMT 0.5° from
horizontal
Performance
Verification
Test (PVT)
USP
Prednisone
Tablets RS
Not Measured Not Measured
USP
Prednisone
Tablets RS
SOP investigation
In the event a failure can not be diagnosed, and several failures
have occurred, SOP/validation review may be needed:
•Filter choice
•Chemicals specified
•Is the method over-discriminatory?
•Was intermediate precision evaluated for:
– Chemist to chemist variability
– Manual vs. autosampling
– Resident vs. non-resident probes
– 3-clip vs. O-ring baskets?
SOP Investigation
•Carryover?
•Cleaning method established?
– Dissolution apparatus
– Sampling equipment
Investigation Conclusion
•In the event of a determinant error, failing run can be aborted
and test re-run
•In the event of a non-determinant error
– Multiple runs may be needed
– Analyst re-training may be advisable
Special Thanks/Reference
“Dissolution Aberrant Data Investigation”, Bryan Crist,
Pharmaceutical Canada, March 2004, vol. 4, no. 4., pp. 7-12
Questions?
919-677-6797
1-888-826-5351
Dissolution Discussion Group
www.dissolution.com
Upcoming Events
http://www.chem.agilent.com/en-US/promotions/Pages/dissoseminar.aspx
