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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

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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

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High % CV

•Sampling Inconsistencies

•Poor techniques

•Vibration

• Improper Degassing

•System Misalignment (tends to

trend)

• Issues w/ formulation

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1 2 3 4 5 6

Data that doesn’t make sense

•Filtration Issues

•Bad Sample Readings

•Air bubble

•Contamination

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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

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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?

Ken.Boda@Agilent.com

919-677-6797

Dissolution.Hotline@Agilent.com

1-888-826-5351

Dissolution Discussion Group

www.dissolution.com

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