Tablet Dissolution Testing

31-Jan-11 Tablet Dissolution Testing Official Requirements and Solutions offered by

Tablet Dissolution Testing Contents Contents General Requirements Qualification guidelines Dissolution Automation New PTWS 100 Dissolution Tester 2

Tablet Dissolution Testing Contents Contents General Requirements Qualification Guidelines Dissolution Automation New PTWS 100 Dissolution Tester 3

Tablet Dissolution Testing General Requirements What is Tablet Dissolution Testing? - Test Tablet Quality. Ensure Uniformity between Production Lots. - Optimisation of the amount of drug available to the body, i.e. its bioavailability - Check of the same biological availibility (bioequivalence) from one or different manufacturers. Biowaver Test. - Optimisation of therapeutic effectiveness during product development and stability assessment 4

Tablet Dissolution Testing General Requirements What is Tablet Dissolution Testing? 5

Tablet Dissolution Testing General Requirements What is Tablet Dissolution Testing? What is the Dissolution Instrument like? A typical tablet dissolution Instrument includes at least 6 testing stations, 6 stirrers, a heating device to heat the dissolution media to a constant temperature of 37 C and a speed control usually adjustable within a range of 20 to 200 rpm. The should be no measurable vibration within the dissolution vessel arrangement and access to the vessels should be suitable for manual or automated sampling. A Dissolution Instrument can take vessels of a volume ranging from 250 ml to 4000 ml. 6

Tablet Dissolution Testing General Requirements What is Tablet Dissolution Testing? Is the dissolution curve corresponding to the pregiven one? Is the amount of dissolved active ingredient at different timepoints comparable to the pregiven values? 7

Tablet Dissolution Testing General Requirements Pharmaceutical oral dosage form (tablet, etc.) Dissolving process Dissolution Media depends on the predicted location of Dissolution of the tablet In vivo Drug release 8

Tablet Dissolution Testing Contents Contents General Requirements Qualification Guidelines USP/FDA/EP Dissolution Automation New PTWS 100 Dissolution Tester 9

Qualification Guidelines USP/FDA/EP USP and EP Pharmacopoeia Both Pharmacopoeia require the same design features from a Dissolution Bath Dimensions and Shape of the Glass Vessels Dimensions, Material Quality of the Stirring Tools Heating and Stirring Precision Low Vibration Sampling Position Dissolution Media Degassing Instrument Suitability Test using USP Calibrator Tablets 10

Qualification Guidelines USP/FDA/EP Which Dosage Forms are Tested? tablets: round or oblong (coated or uncoated): fast or slow disintegrating dragees : sugar or film coated hard and soft gel formulations suppositories, creams and ointments Qualification Guidelines USP/FDA/EP trans-dermal (patches) How do we Sample? use a pipette use a purpose made sampler with filter and syringe 11

Qualification Guidelines USP/FDA/EP Why Filtration? Bigger undissolved particles should not reach the syringe, Vial or cuvette Which Filter Pore Size is Recommended? Powdered excipients have a particle size of at least 50 microns and above. Usually used are: 5 or 10 micron filter for UV measurements 0.45 micron filter for HPLC analysis 12

Qualification Guidelines USP/FDA/EP When do we Drop the Tablets? This depends on how the instrument is used. If an automated dissolution system is set-up with a parallel sampling system, the tablets have to be dropped also all at the same time. If the dissolution instrument is used for manual sampling a staggered start and sampling is necessary. USP and EP requirement is sampling from all Vessels in 2% of the timeoint. manual sampling: automated sampling: staggered start and sampling option parallel start and sampling 13

Qualification Guidelines USP/FDA/EP Where to Remove the Sample? Samples always have to be removed at the same position within a dissolution vessel: midways between liquid level and tool, not less than 1 cm off of the inner vessel wall. sampling position 14

Qualification Guidelines USP/FDA/EP OQ Operation Qualification To perform an OQ a number of certified equipment is needed: Speed Meter Thermometer Wobble Gauge Timer Calliper Bubble Level Vibration Testing Instrument.. All the instruments need to be calibrated against a traceable Standard 15

Qualification Guidelines USP/FDA/EP Performance Qualification What is required by the USP? The USP Monograph <1088> and <1092> give some information about the use of a Dissolution Apparatus and its qualification. Use USP Standard Tablets Prednisone Media Deaeration 16

Qualification Guidelines USP/FDA/EP Performance Qualification The USP requires a Performance Qualification (PQ) of a Dissolution instrument. This test needs the use of USP Reference Standard Tablets (RST), previously named Calibrator Tablets The PQ tests should prove, that a Dissolution Instrument is capable to operate and perform test results established for the Dissolution Tests using the RST Tablets and provide results which have to be within the Limits supplied with the RST Tablets. If the PQ test has passed it certifies that the OQ was correctly done Repeat the PQ Test each 6 months and whenever there was a major Service or change of position 17

Qualification Guidelines USP/FDA/EP Performance Qualification In order to do a successful PQ of a Dissolution instrument establish a Check-List which should include the following: OQ has been successfully finished The Spectrophotometer is calibrated The Cuvettes are cleaned and have the correct Path Length (10mm are used) The Reference Standard is correctly done The RST Tablets have no damage and no dust, they have been stocked in a Desiccator The Dissolution Media is deaerated The Media Volume is precise and considered the Media Density at 37 C An adequate Sampling Tool is available 18

Qualification Guidelines USP/FDA/EP Performance Qualification Both manual and automated Dissolution Instruments need to pass the IQ, OQ and PQ Test as described before In order to comply with the requirements established by the USP/EP you need: A suitable Tablet Dissolution Instrument, including certified accessories Instruments for Mechanical Calibration A Media Degassing System An actual Lot of RST Tablets A trained Operator 19

Qualification Guidelines USP/FDA/EP Performance Qualification Factors affecting the PQ results: Type Rating influence degree Temperature not too significant linear Speed significant 10-30% Vibration significant 10-40% Centricity reasonable ± 5-15% Dissolved Gas significant ± 50% Media ph reasonable ± 5-10% Media Contamination significant ± 20-45% Sampling Position not too significant 1-3% 20

Qualification Guidelines USP/FDA/EP Performance Qualification Impact of dissolved gas during a PQ of a Dissolution Bath using Prednisone Tablets 21

Qualification Guidelines USP/FDA/EP 22

Qualification Guidelines USP/FDA/EP Objectives Vibration studies Vibrational and Deaerated Media Effect Specifications for vibration and the degree of deaeration for media are not yet defined within the USP. FDA is currently performing vibration studies to implement tolerances. Recommendation is currently to be under 0.2 mil ~ 0.5 µm displacement (AAPS) Evaluation of Vibration Absorber The Prednisone Calibrator Tablet is designed to be sensitive to vibration. Many other dissolution tests are also sensitive to vibration.to minimise these effects a vibration absorber was introduced and evaluated. AAPS (American Association of Pharmaceutical Scientists) 23

Qualification Guidelines USP/FDA/EP Test Performance Materials USP Prednisone Tablets (10 mg) Lot P0E203 [Promochem, Germany]: Disintegrating Calibrator Tablet. Instruments - PTW S III C [Pharma Test, Germany] and PT-DT 8 [Pharma Test, Germany] - Media Deaeration System PT-DDS-4 [Pharma Test, Germany] - Vibration Meter [Model VM 110: Monitran, UK] - Spectrophotometer: Lambda 2 [Perkin Elmer, Germany] - 50W Amplifier and Tone generator (to generate vibrations) - Circulation pump (to generate vibrations) 24

Qualification Guidelines USP/FDA/EP 25

Qualification Guidelines USP/FDA/EP Dissolution Tests Process Based on USP requirements: the tests were performed using: - USP Apparatus 2 (Paddles) @ 50 rpm - 500 ml of preheated and deaerated water at 37 C - Wavelength @ 242 nm Results: (at time of publication): - The range of dissolved Prednisone: 37 70% for Lot P0E203 Types of Tests: Without vibration and with deaerated media the procedures are the same as mentioned above. With vibration an amplifier (with tone generator @ 50Hz) producing displacements approx. 0.4, 0.5, 0.6, 0.8 µm a circulation pump (50Hz) producing a displacement of 1.1 µm 26

Qualification Guidelines USP/FDA/EP Result and Discussion Vibration measurement Table 1. Absence of vibration exposure PTW S III C suspected to have higher internal vibration value than PT-DT 8. Some possible causes are: High vibration level on its paddle motor and drive belts (8 years old instrument) Older design with the water bath placed directly on work bench resting on a rubber mat Higher influence of environmental vibration sources Note: The vibration levels seen are still within proposed guideline levels. 27

Qualification Guidelines USP/FDA/EP Result and Discussion Vibration measurement PT DT 8. Lower vibration level, some causes are: lower vibration level on its paddle motor and drive belts (new instrument) Latest design with the water bath placed onto Vibration Absorbers (Vibroban ). 28

Qualification Guidelines USP/FDA/EP This vibration level remains the same because there are no absorbers on the older instrument This vibration level is minimised to background levels!! Please note that the measurements on the Table are made on the instrument support bench, and the Machine values are made at the interface of the vessel and the vessel support cover of the water bath. 29

Qualification Guidelines USP/FDA/EP Absorbance and % Dissolution Results (Without Vibration) Standard solution gave an absorbance of 0.87AU (represents 100% dissolved) Table 3a. Prednisone test (PTW S III C), vibration level = 0.32 µm (measured on the instrument) 30

Qualification Guidelines USP/FDA/EP Absorbance and % Dissolution Results (Without Vibration) Prednisone test without Vibration (using PT DT 8), vibration level = 0.21 µm (measured on the instrument) 31

Qualification Guidelines USP/FDA/EP 0.32µm displacement, PTWSIII 0.21µm displacement PT DT8 Differences between the two sets of results are not too significant!! It is about 0.3% 32

% Dissolution Qualification Guidelines USP/FDA/EP % Dissolution for PTWS 3C and PTDT 8 (Without Vibration) % dissolution test without vibration 103,00 70,00 37,00 4,00 1 2 3 4 5 6 Vessel PTW S III C PT-DT8 33

Qualification Guidelines USP/FDA/EP Absorbance and % Dissolution Results (With Vibration) Prednisone test (PT DT 8), vibration level = 0.5µm reduced to 0.22µm by vibration absorbers on the instrument Prednisone test (PTW S III C) vibration level = 0.5 µm 0.4-0.5 µm (both on the bench and at instrument) 34

% Dissolution Qualification Guidelines USP/FDA/EP Graphic of % Dissolution With Vibration) Prednisone Test with 0.5 µ m of Displacement (50Hz) 103,00 70,00 37,00 4,00 1 2 3 4 5 6 Vessel PT DT 8 % Differences between two results above = ± 30.3% PTW S III C 35

Qualification Guidelines USP/FDA/EP Prednisone test (PTW S III C), vibration level = 0.5 0.6 µm Prednisone test (PTW S III C), vibration level = 0.8 µm Note that with the older PTWS 3C, the vibration levels on the bench and the instrument are the same as the water bath is basically sitting on the bench. 36

Qualification Guidelines USP/FDA/EP Prednisone test (PTW S III C), vibration level = 1.1 µm (pump)** 37

% Dissolution Qualification Guidelines USP/FDA/EP Graphics of All the Prednisone Tests with Vibration Exposure 103,00 % Dissolution of Prednisone Test with Vibration Exposure 70,00 37,00 4,00 1 2 3 4 5 6 Vessel PTW S III C (0.8 µm) PT-DT 8 (0.22 µm) PTW S III C (1.1 µm) PTW S III C (0.4-0.5 µm) PTW S III C (0.5-0.6 µm) These results for the newer design PT DT8 are lower than the other sets regardless of the vibration levels 38

Qualification Guidelines USP/FDA/EP Summary of Prednisone Tests with and without vibration Summary of results showing the increased min. / max. ranges of Dissolution results with increased vibration exposure Min. / Max. Range: 2.72% 33.82% 36.97% 41.34% 43.81% Higher vibrational level Higher Absorbance and % Dissolution Results!! 39

% Dissolution Qualification Guidelines USP/FDA/EP Graphic comparison of All Prednisone Tests with and without Vibration Exposure 103,00 Prednisone Test with and without Vibration 70,00 37,00 4,00 1 2 3 4 5 6 PTW S III C (without vibr = 0.32µm) Vessel PT-DT 8 (without vibr = 0.21µm) PTW S III C (vibr = 0.8 µm) PT-DT 8 (vibr = 0.22 µm) PTW S III C (vibr = 1.1 µm) PTW S III C (vibr 0.4-0.5 µm) PTW S III C (vibr 0.5-0.6 µm) 40

Qualification Guidelines USP/FDA/EP Deaerated and Non Deaerated Media 50% increase from the results of deaerated medium *) This value is out of range: Note that this study was carried out when the Prednisone LOT POE203 ranges were : 37-70% for Apparatus 2 (paddles) 41

% Dissolution Qualification Guidelines USP/FDA/EP Graphic showing impact on results of Deaerated and Non Deaerated Media 103 % Dissolution of Prednisone Test with Deaeration and Non- Deaeration 70 37 4 1 2 3 4 5 6 Vessel Vessel 1 3 Deaerated Media Vessel 4 6 Non Deaerated Media 42

Qualification Guidelines USP/FDA/EP Basket Dimensions (certificates) Rotation Speed (Tachometer) Paddle Dimensions (Certificate) Maintenance Shaft Wobble (Watch) Basket Wobble (Watch) Paddle and Basket Depth (Certified 25mm balls) Vessel Temperature (Thermometer) Vessel Dimensions (Certificate) 43

Qualification Guidelines USP/FDA/EP Shaft Wobble The Shaft Wobble is tested 2cm above the Apparatus Basket Wobble The Basket Wobble is tested at the bottom of the basket. The Tolerance is +/- 1mm. Test is performed with a Wobble Gauge. 44

Qualification Guidelines USP/FDA/EP Vessel Centering Should be measured at 2 different points of the shaft Tolerances (+/- 1mm) from the axes. 45

Qualification Guidelines USP/FDA/EP Paddle and Basket Depth The Depth is checked with certified 25mm balls which are placed at the bottom of the vessel. Rotation Speed 2 different speeds are checked with a certified Tachometer. Vessel Temperature A certified Thermometer is used to check the temperature in the vessel. The temperature Tolerance given with 36,7 37,1 C at a set temperature of 37 C 46

New OQ Tests according to USP/FDA/AAPS Shaft Verticality Measure at 4 different points. Tolerances are 90 +/- 0,5 ) Measured with a digital level Vessel Verticality Also measured with a digital level. Tolerances are 90 +/-1 47

New OQ Tests according to USP/FDA/AAPS Vibrations Vibrations should be not significantly higher than 0,2mils (0,5microns) displacement. Official Tolerances will be published soon. 48

Vibration Absorbers (Pharma Test) Vibration Absorbers 49

New OQ Tests according to USP/FDA/ASTM Deaeration 40% of dissolved gases should be removed. Amount of Oxygen should be Less than 6ppm. Pharma Test DDS4 Media Preparator 25l, preheated, dosed and deaerated media 50

New OQ Tests according to USP/FDA/ASTM 51

Changes for Reference Standard Tablets -No Salicylic Acid Test Required -LOT POE203 is not valid anymore -New LOT P1I300 -New Test Procedure with new Tolerances -Single Stage Test -Second Stage Test 52

Changes for Reference Standard Tablets 53

Differences between FDA and USP Requirements USP FDA Speed Test 50 and 100 rpm +/- 1rpm 50 and 100 rpm +/- 2rpm Wobble Test Shaft 1cm above the paddle < 1mm 2cm above Paddle < 1mm Wobble Test Basket Bottom Basket < 1mm Bottom Basket < 1mm 54

Differences between FDA and USP Requirements USP FDA Temperature Test 37 C 36.7 37.1 C 37 C +/- 0,5% Vessel Centricity Shaft Verticality In Vessel, max 2cm under the vessel surface. +/- 2mm At 2 Positions 90 +/- 0.5 2 Positions (2mm and 80mm above the paddle) +/- 1mm At 2 Positions 90 +/- 0.5 55

Differences between FDA and USP Requirements USP FDA Hight Check 25mm +/- 2mm 25mm +/- 2mm Volume +/- 1% - Vessel Verticality At 2 Positions 90 +/- 0.5 At 2 Positions 90 +/- 1 56

Differences between FDA and USP Requirements USP FDA Deaeration.dissolved gases should be removed prior to testing USP 711 Medium should be degassed less than 60% saturation of total dissolved gases. Vibrations Table should have a high inertial mass to limit vibration..there should be no significant Vibrations in the dissolution apparatus or Medium 57

Changes for Reference Standard Tablets 58

Changes for Reference Standard Tablets USP Old Requirement USP New Requirement Prednisone 37-70% 27-38% 1 Stage CV%: 5,1 25-41% 2 Stage CV%: 6,8 (2 Stage Test with 6 Tablets) Salicylic Acid Used Not used anymore http://www.usp.org/uspnf/pvttoolstatement.html 59

Changes for Reference Standard Tablets 60

Changes for Reference Standard Tablets 61

Biowaiver Studies Biowaiver Tests the new opportunity 62

Biowaiver Studies What is a Biowaiver Study? It is an In Vitro dissolution test with 12 tablets in different buffers which are used to replace costly Bioequivalence Studies (includes In Vivo tests performed with human probands in hospitals). What is the Benefit of Biowaiver Studies? Companies can save a lot of money and time. 63

Biowaiver Studies What are the Requirements for a Biowaiver Study? Allowance of regulatory authorities like FDA, WHO etc. Drugs should have high solubility and high permeability according to biopharmaceutics classification system (BCS I). Other classification systems are part of current investigations Dissolution test in 3 different media (A. Buffer ph 1.2, SGF without enzymes or 0.1N HCl, B. Buffer ph 4.5, C. Buffer ph 6.8 or SIF without enzymes) all in 900ml and at 37 C 12 Samples in each media, paddle 50rpm or basket 100rpm Sampling time: 10, 15, 20, 30, 45 and 60 minutes The profiles of the test and reference products (for example original tablets if generic products are tested) must be similar in all three media The products are similar if the factor f2 50 and both products show 85% dissolution in 15 min 64

Biowaiver Studies Most of the Approved Actives for Biowaiver Studies are Substances with High Solubility! Tolmetin Selegiline Hydrochloride Ranitidine Hydrochloride Paracetamol Piroxicam Capsules Pindolol Tablets Pentoxifylline Extended-Release Tablets Naproxen Tablets Nadolol Tablets Metoprololtartrate Ketoprofen Capsules Indapamide Tablets Hydroxychloroquine Sulfate Tablets Guanabenz Acetate Glyburide Tablets Glipizide Tablets Gemfibrozil Capsules and Tablets Flurbiprofen Tablets Diltiazem Hydrochloride Tablets Diclofenac Sodium Delayed-Release Tablets Cimetidine Tablets Cefaclor Capsules and Suspensions Captopril Tablets Buspirone Hydrochloride Tablets Bumetanide Tablets Alprazolam Tablets 65

Biowaiver Studies 66

Biowaiver Studies Key Features: -Vibration Absorbers - 2 Additional Vessels for Standard and Blank - Built-in water diffuser for faster heating - Auto vessel centring inside the water bath cover -Tablet Drop Magazine including vessel covering - System Suitability Test (SST) 67

Thank You 68