Dissolution Failure Investigation. Ken Boda Dissolution Applications Engineer

Transcription

1 Dissolution Failure Investigation Ken Boda Dissolution Applications Engineer

2 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.)

3 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

4 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

5 Data trending high/low Bad lot Calculation Error Standard Prep Error Improper Filtration System misalignment (overall) Poor evaporation control

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

7 High % CV Sampling Inconsistencies Poor techniques Vibration Improper Degassing System Misalignment (tends to trend) Issues w/ formulation

8 Data that doesn t make sense Filtration Issues Bad Sample Readings Air bubble Contamination

9 Determinant vs. Non-Determinant Errors Determinant Errors are known and controllable Indeterminate errors are unknown, suspected, or beyond control Determinant errors when found will lead to a simpler investigation and require the least re-work Indeterminate errors cannot be proven, and the burden of retesting is often higher

10 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

11 Investigation Track Calculations Analysis Sampling and Filtration Run Observations Media Prep and Sample Handling Pre-Run Checks Dissolution Unit Mechanicals SOP and Materials

12 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

13 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

14 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

15 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

16 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?

17 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?

18 Storage Were samples within expiration period? Covered? Stored Properly? Labeled?

19 Sampling and Filtration Sampling and Filtration are one of the most common causes of dissolution failures: USP Position USP Timing Filtration

20 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

21 Imagine A Donut

22 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

23 Filtration Is the filter validated? Efficiency Leaching Adsorption When was the sample filtered? At time of sampling? Immediately after sampling? After time point collected?

24 Autosampling Autosampling can reduce many of the errors associated with manual sampling: Position constant Timing within 2% Consistent pull force Documentation

25 Dissolution Observations

26 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.

27 % Dissolved When should you take observations? Ideally, observations should be taken at all critical timepoints of the run Wetting/Dose Dumping Brand to Brand Differences in Dissolution Profiles Release Profile Complete Release/Asymptote Whenever sampling manually Brand A Brand B Brand C Time (minutes)

28 What to look for Initial Stages: Floating or Moving? Coning? Dispersion Profile? Dissolved Gasses? Cross-linking? Compare appearance of all dosage forms

29 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

30 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

31 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

32 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

33 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?

34 Observations During Release Profile Size of dosage form/particles Distribution of dosage form Consistency of the dosage forms Anything changed?

35 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

36 Media Preparation Degassing Procedure validated? Time of degassing vs. time of use Pouring Technique

37 Sample Handling When exposed to air? Weighed? Inspected? Where placed? How handled? Bare hands Gloves Tweezers

38 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

39 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)

40 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

41 Vessel Examination

42 Dissolution Mechanical Qualification Standards Paddle Examination, must be free of: Defects Rusting Corrosion Peeling or loose coating Knicks, dents or misshapen appearance

43 Stainless Steel Paddles Minor Rusting

44 Stainless Steel Paddles Advanced Corrosion

45 Teflon Paddles Good, Okay, and Terrible

46 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

47 Baskets From New to Dead

48 Basket Bad Example

49 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.

50 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

51 Dissolution Mechanical Qualification Specifications and Tolerances Parameter Basket and Paddle Depth Rotational Speed Shaft Wobble Shaft Verticality ICH Harmonized (USP, JP, EP) FDA DPA-LOP.002 ASTM E ± 2 mm 25 ± 2 mm 25 ± 2 mm (or <8%) ± 4% of specified rate No significant wobble Not measured Basket Wobble ± 1 mm ± 2 rpm of target 1.0 mm total runout 0.5 from vertical (x and y 90º) 1.0 mm total runout lower rim ± 2 rpm or within 2% of target (larger) 1.0 mm total runout Within Bubble (x and y 90º) 1.0 mm total runout lower rim USP Toolkit Ver mm ± 1 rpm of target 1.0 mm total wobble Not measured 1.0 mm total wobble

52 Dissolution Mechanical Qualification Specifications and Tolerances Parameter Vessel/Shaft Centering Vessel Verticality Vessel Plate Level Performance Verification Test (PVT) ICH Harmonized (USP, JP, EP) NMT 2 mm from center axis Not Measured FDA DPA-LOP mm from center line (upper/lower) 1.0 from vertical (2-90 positions) ASTM E mm from center line (upper/lower) 1.0 from vertical (2-90 positions) USP Toolkit Ver 2.0 NMT 2.0 mm difference (4-90 positions) NMT 0.5 from vertical Not Measured Not Measured Not Measured NMT 0.5 from horizontal USP Prednisone Tablets RS Not Measured Not Measured USP Prednisone Tablets RS

53 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?

54 SOP Investigation Carryover? Cleaning method established? Dissolution apparatus Sampling equipment

55 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

56 Special Thanks/Reference Dissolution Aberrant Data Investigation, Bryan Crist, Pharmaceutical Canada, March 2004, vol. 4, no. 4., pp. 7-12

57 Questions? Dissolution Discussion Group

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