PHARMA TEST Dissolution Mechanical Calibration

Transcription

1 Pharma Test Dissolution Automatisation PHARMA TEST Dissolution Mechanical Calibration Dissolution Testers, Pumps and Spectrophotometers 24-Nov-11

2 Requirements EP, USP, FDA, ASTM Dissolution 2

3 24-Nov-11 Pharma Test Dissolution Automatisation

4 Requirements EP, USP, FDA, ASTM Dissolution EP Requirements Temperature 37 +/- 0,5 C - Distance between the Apparatus and the vessel bottom 25+/-2mm - Vessel Height: mm, Vessel diameter mm - Stirrer Speed +/-4% - Stainless Steel 316 or equivalent should be used for the parts in contact with the media - Shaft is positioned max 2mm from the axis 4

5 Requirements EP, USP, FDA, ASTM Dissolution -EP Requirements Dissolution Medium Volume Accuracy +/-1% - Remove Thermometer or valididate system with thermometer - Sampling position is min 1cm away from the vessel wall, half way between Apparatus and liquid level. - Where multiple sampling times are specified, replace the aliquots withdrawn for analysis with equal volumes of fresh dissolution medium at 37 c or if not necessary (not under -1% volume lost), the volume loss must be corrected in the calculation 5

6 Requirements EP, USP, FDA, ASTM Dissolution EP Requirements If bubbles have an influence on the dissolution test, gases must be removed prior to testing - Samples are to be withdrawn only at the stated times, within a tolerance of +/- 2 per cent. - Delayed-release solid dosage forms Method A Place 750ml 0,1M HCl in the vessel. After 2 h withdraw an aliquot and add 250ml of 0,2M Trisodiumphosphate Dodecahydrate Buffer (37 +/- 0,5 C!!) 6

7 Requirements EP, USP, FDA, ASTM Dissolution EP Requirements Quality in design, any irregularities such as vibration are to be avoided. - The performance of the dissolution test equippment may be monitored by testing a reference product which is sensitve to hydrodynamic conditions (!!!USP Prednisone!!!) or Salicylic Acid. - During testing, critical inspection and observation are required. - Conventional Release dosage forms: min 75% after 45min - Prolonged-reease dosage forms: 3 Testpoints, when 20-30per cent are dissolved, when around 50% are dissolved and endpoint (more than 80%) - Delayed release dosage forms: 1h and 2h in 0,1N HCl, after buffer change when the tablet is dissolved completely. 75% min. 7

8 Requirements EP, USP, FDA, ASTM Dissolution Additional USP requirements - Performance Verification Test (PVT), Apparatus 1 and 2 with Prednisone - Periodicity is 6 Month for mechanical calibration and PVT Prednisone test - Tests need to be repeated if the instrument is translocated or repaired. - Test starts if the tablet rests at the bottom of the vessel > Staggared - Media Should be deaerated for the Prednisone Test. Nitrogen sparging is not a suitable dearation procedure and therefor should not be used. - The volume should be controlled over a more accurate weight measurement as the weight is temperature-independent attention!! Which weight? 500g? Correct density at 37 C must be choosen >> DDS4 8

9 Requirements EP, USP, FDA, ASTM Dissolution 9

10 Requirements EP, USP, FDA, ASTM Spectrophotometer EP

11 Requirements EP, USP, FDA, ASTM Spectrophotometer EP

12 Requirements EP, USP, FDA, ASTM Spectrophotometer Control of wavelength 12

13 Requirements EP, USP, FDA, ASTM Spectrophotometer 13

14 Requirements EP, USP, FDA, ASTM Spectrophotometer Control of absorbance 14

15 Requirements EP, USP, FDA, ASTM Spectrophotometer 15

16 Requirements EP, USP, FDA, ASTM Spectrophotometer Straylight, resolution, Cells When using 2mm, 5mm or 10 mm kuvettes? If the concentration and the Absorbance of the solution is to high for a measurement with a spectrophotometer it s possible to dilute the sample or to take a smaller pathlength of the küvette. Law of Lambert Beer: A = e x b x c Where A is absorbance e is the extinction koefficient (the molar absorbtivity with units of L mol -1 cm -1 ) b is the path length of the sample - that is, the path length of the cuvette in which the sample is contained. c is the concentration of the compound in solution, expressed in mol L-1 Most of the spectrophotometers have an Absorbance measurement limit of ~1,2. If you take a look on the Equation the only possibility to change the Absorbance is to change b (the pathlength) or c (concentration by dilution) because e is a constant. Accurcy of the pathlength is +/- 0,005 cm! 16

17 PHARMA TEST Vibration and Deaeration Studies 17

18 Vibration Studies PHARMA TEST Vibration Studies - USP/FDA states that Vibrations have a significant influence on Dissolution Tests - No Tolerances given yet by USP/FDA and EP. - FDA is currently performing vibration studies to implement tolerances. - Only Recommendation is given by AAPS. Vibrations should be under 0.2 mil ~ 0.5 µm displacement - For the vibration study Prednisone Tablet are used as they are known to be extremely sensitive to vibrations. AAPS (American Association of Pharmaceutical Scientists) 18

19 Vibration Studies PHARMA TEST Test Performance Materials USP Prednisone Tablets (10 mg) Lot P0E203 [Promochem, Germany]: 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) 19

20 Vibration Studies PHARMA TEST 20

21 Vibration Studies PHARMA TEST Dissolution Tests Process Based on USP requirements: the tests were performed using: - USP Apparatus 2 50 rpm ml of preheated and deaerated water at 37 C 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 50Hz) producing displacements approx. 0.4, 0.5, 0.6, 0.8 µm displacement. A circulation pump (50Hz) producing a displacement of 1.1 µm 21

22 Vibration Studies PHARMA TEST Result and Discussion Vibration measurement 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 (AAPS). 22

23 Vibration Studies PHARMA TEST PT DT 8. Lower vibration level, some causes are: - lower vibration level on its paddle motor and drive belts (new instrument, different bearings) - Latest design with the water bath placed onto Vibration Absorbers (Vibroban ). - Vibrations caused by the Circulation Pump are minimized.. 23

24 Vibration Studies PHARMA TEST 24

25 Vibration Studies PHARMA TEST PTWS III Testresults without forced Vibration Standard solution gave an absorbance of 0.87AU (represents 100% dissolved) Vibration level = 0.32 µm (measured on the instrument) 25

26 Vibration Studies PHARMA TEST PT DT8 Testresults without forced Vibration Vibration level = 0.21 µm (measured on the instrument) 26

27 Vibration Studies PHARMA TEST 0.32µm displacement, PTWSIII PT DT8 0.21µm displacement Differences between the two sets of results are not significant!! It is about 0.3% 27

28 % Dissolution Vibration Studies PHARMA TEST % Dissolution for PTWS 3C and PTDT 8 (Without Vibration) % dissolution test without vibration 103,00 70,00 37,00 4, Vessel PTW S III C PT-DT8 28

29 Vibration Studies PHARMA TEST Results recieved with forced Vibrations (0,5 µm, Amplifier) 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 µm (both on the bench and at instrument) 29

30 % Dissolution Vibration Studies PHARMA TEST Graphic of % Dissolution between Table (With Vibrations) Prednisone Test with 0.5 µ m of Displacement (50Hz) 103,00 70,00 37,00 4, Vessel PT DT 8 PTW S III C % Differences between two results = 30.3% 30

31 Vibration Studies PHARMA TEST Vibration level = 0.6 µm displacement PTW S III C Vibration level = 0.8 µm displacement PTW S III C 31

32 Vibration Studies PHARMA TEST Vibration level = 1,1 µm PTW S III (with pump) 32

33 % Dissolution Vibration Studies PHARMA TEST 103,00 % Dissolution of Prednisone Test with Vibration Exposure 70,00 37,00 4, 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 ( µm) PTW S III C ( µm) These results for the newer design PT DT8 are lower than the other sets regardless of the vibration levels 33

34 Vibration Studies PHARMA TEST Higher vibrational level Higher % Dissolution Results!! The highest increase is between 0.32 and 0.5 µm displacement. 34

35 % Dissolution Vibration Studies PHARMA TEST 103,00 Prednisone Test with and without Vibration 70,00 37,00 4, 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 µm) PTW S III C (vibr µm) 35

36 Vibration Studies FDA 36

37 Vibration Studies FDA 37

38 Vibration Studies FDA 38

39 Vibration Studies FDA 39

40 Deaeration Studies PHARMA TEST Prednisone Test, Paddle 40

41 Deaeration Studies PHARMA TEST >50% increase between non deaerated and deaerated media *) 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

42 % Dissolution Deaeration Studies PHARMA TEST 103 % Dissolution of Prednisone Test with Deaeration and Non- Deaeration Vessel 42

43 Deaeration Studies USP Nithyanandan et al. (USP), Dissolution Technologies 2006,

44 High Precision Vessels ID no. Upper Diameter Lower Diameter Diameter Difference W W W W W W W Mean Standard deviation ID no. Upper Diameter Lower Diameter Diameter Difference Mean Standard deviation

45 High Precision Vessels Dissolution Tester DT7 Serial Nr Vessel Old Vessels 4/28/2011 New Vessels 5/2/2011 Abs Conc. Abs Conc Std Dev Average LOT Nr. P1l300 P1l300 Test Result Pass Pass %CV Upper 4.7% 5.0% GeoMean GeoMean Tolerance Min Max %Coefficient of Variation Max

46 Deaeration Studies USP 46

47 Deaeration Studies USP 47

48 Operation Qualification (OQ) and Mechanical Calibration 48

49 Mechanical Calibration Standard Measurements and Requirements - Basket Dimensions (Certificate) - Paddle Dimensions (Certificate) - Vessel Dimensions (Certificate) - Rotation Speed (Tachometer) - Shaft Wobble (Watch) - Basket Wobble (Watch) - Paddle and Basket Depth (Certified 25mm balls) - Vessel Temperature (Thermometer) - Maintenance 49

50 Mechanical Calibration 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. 50

51 Mechanical Calibration 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 is 37 +/- 0,5 C at a set temperature of 37 C. New USP requirement. All Temperatures must be in a range of 0,4 C 51

52 Mechanical Calibration Vessel Centering Should be measured at 2 different points of the shaft Tolerances (+/- 1mm) from the axes. 52

53 Mechanical Calibration Shaft Verticality Measure at 2 different points. Tolerances are 90 +/- 0,5 ) Measured with a digital level Vessel Verticality Also measured with a digital level. Tolerances are 90 +/-0,5 53

54 Mechanical Calibration Degrees out of Verticality = Arctan (X mm/ Y mm) = Angle (must be smaller than 1 ) 54

55 Mechanical Calibration Vibrations Vibrations should be not significantly higher than 0,2mils (0,5microns) displacement according to AAPS. Official Tolerances will be published soon. We PHARMA TEST recommend values under 0,4 microns displacement 55

56 Mechanical Calibration Vibration Absorbers 56

57 Mechanical Calibration Deaeration 40% of dissolved gases should be removed. Amount of Oxygen should be Less than 6ppm. PHARMA TEST DDS4 Media Preparator 24l, preheated, dosed and deaerated media 57

58 Mechanical Calibration 58

59 Mechanical Calibration - Prepared medium to reproducible standards - Pre-heated medium saves time for dissolution runs - Reproducible dispensed volumes (reduces any random errors - Programmable, up to 20 methods - GMP-stainless steel - Printer included (all necessary data such as Volumes, Date etc are mentioned - GMP-stainless steel - Volume up to 24 Liters - Gets you through the prednisone tests 59

60 Mechanical Calibration Preparing, deaerating, vacuum pump or ultrasonic Heating time Conventional Dissolution ~ 20 min. every dissolution run ~ 20 min. (from room temperature 25 C to 37 C) DDS4 ~ 40 min. for 4 dissolution runs 0 min. Appr. 40min/Dissolution Test Appr. 10min/Dissolution Test 60

61 Mechanical Calibration 61

62 Mechanical Calibration 62

63 Mechanical Calibration 63

64 Mechanical Calibration -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 64

65 Mechanical Calibration 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 65

66 Mechanical Calibration USP FDA Temperature Test 37 +/- 0,5 C (0,4 C Range e.g C) 37 C +/- 0,5% Vessel Centricity Shaft Verticality In Vessel, max 2cm under the vessel surface. +/- 2mm At 2 Positions 90 +/ Positions (2mm and 80mm above the paddle) +/- 1mm At 2 Positions 90 +/

67 Mechanical Calibration USP FDA Hight Check 25mm +/- 2mm 25mm +/- 2mm Volume +/- 1% - Vessel Verticality At 2 Positions 90 +/- 0.5 At 2 Positions 90 +/- 1 67

68 Mechanical Calibration USP FDA Deaeration Vibrations.dissolved gases should be removed prior to testing USP 711 Table should have a high inertial mass to limit vibration Medium should be degassed less than 60% saturation of total dissolved gases...there should be no significant Vibrations in the dissolution apparatus or Medium 68

69 Mechanical Calibration USP Old Requirement USP New Requirement Prednisone 37-70% 27-38% 1 Stage CV%: 5, % 2 Stage CV%: 6,8 (2 Stage Test with 6 Tablets) Salicylic Acid Used Not used anymore 69

70 Mechanical Calibration 70

71 Mechanical Calibration 71

72 Harness Testers Introduction Purpose - USP <1217> What Is the Purpose Of A Tablet Hardness Test? According to USP Monograph <1217>: Tablets must be able to withstand the rigors of handling and transportation experienced in the manufacturing plant, in the drug distribution system, and in the field at the hands of the end users (patients/consumers)., the mechanical strength of tablets is of considerable importance and is routinely measured. Tablet strength serves both as a criterion by which to guide product development and as a quality control specification. 72

73 Hardness Testers Introduction Purpose - EP <2.9.8> What Is the Purpose Of A Tablet Hardness Test? According to EP Monograph <2.9.8>: This test is intended to determine, under defined conditions, the resistance to crushing of tablets, measured by the force needed to disrupt them by crushing. 73

74 Hardness Testers Technical Details: Typical Expression Take 10 samples, place them between the jaws, taking into account the shape, the break-line and any inscription. The jaws must have the height of the sample for full contact. Express the results as mean, minimum and maximum values of the forces, all expressed in Newton. Indicate the apparatus and orientation of the tablet. Accuracy ± 1N. All Hardness Testers have a stainless steel finish to meet GLP criteria in the production area. 74

75 Hardness Tester Adjustment PTB-CAL15 3 5, 10 and 15kg Calibration Weight Calibration handle with interchangeable weights to allow for 5, 10 and 15kg configurations 75

76 Hardness Testers Calibration PT MT 2: The Instrument The PT-MT2 can be used to qualify each PHARMA TEST tablet tester: PTB 311/411 PTBA 211 PTB 302 WHT ME 76

77 Tablet and Ampoule Testing Instrument Range: What can we offer? Instrument Range: What can we offer? PTB 302 PTB 311 E PTB 320 WHT 3 ME PT-MT2 PTBA 211 E 77

78 Tablet and Ampoule Testing Physical Parameters: What will be measured? Physical Parameters: What will be measured? Instrument Hardness Width Diameter Weight PTB 302 Yes No No No PTB 311 E Yes Yes Yes No PTB 320 * Yes Yes Yes Yes* WHT 3 ME + WHTSM Yes Yes Yes Yes PTBA 211E Yes (ampoules No No No only) * Analytical Balance (Mettler or Sartorius) to be added All systems are also available as 500 N versions! 78

79 Disintegration EP Physical Parameters: Typical Values for Tablets and Capsules Raising and lowering smoothly at a constant frequency between 28 and 32 cycles per minute through a distance of 50 to 60 mm. Volume is such that in the highest position the wire mesh is 15 mm at least below the surface of the liquid and in the lowest position the wire mesh is 25 mm at least above the bottom of the beaker and the glass tubes remain above the surface of the liquid. Temperature of the disintegration liquid should be maintained at 36 C to 39 C. 79

80 Disintegration Time Testing Instrument Range: What Can We Offer? Instrument Range: What Can We Offer? PTZ S DIST 3 PTZ AUTO PTZ AUTO EZ PTS 3 E SPT 6 80

81 Disintegration Time Testing PTZ S and DIST 3: The Instruments PTZ S and DIST 3: The Instruments Disintegration Basket Plastic Disks for manual use 81

82 Fully Automated Tablet Disintegration Time Testing PTZ AUTO 1EZ- 4EZ Instrument The Automated Detection Principle The disintegration basket MKT for automated detection is different from a manual basket. The bottom sieves are split into 2 segments. The disks have a metal ring at the bottom end. A signal transfer cable is attached. Like with the manual baskets on top of the tablet a disk is placed. If the Tablet is disintegrated the metal ring gives a contact to the 2 sieve segments. 82

83 Suppository Testing Instrument Range Disintegration of Suppositories and Pessaries Disintegration and Penetration Time Test of Suppositories and Pessaries SPT 6 Penetration Time PTS 3 E Disintegration Time 83

84 Suppository Testing Instrument Range Disintegration of Suppositories and Pessaries Disintegration and Penetration Time Test of Suppositories and Pessaries SPT 6 Penetration Time PTS 3 E Disintegration Time 84

85 Friability Testing Instrument Range: What can we offer? Instrument Range: What can we offer? PTF 10 E/ER PTF 20 E/ER PTF 30/60 ERA PTF 1DR PTF 3DR 85

86 Friability Testing EP Physical Parameters: Typical Values Tablets weighing up to 0.65 g take a sample of 20 tablets, for tablets weighing more than 0.65 g take 10 samples remove any loose dust (sieve no. 1000, soft brush, aid of air pressure). Rotate drum 100 times, at speed of 25 rotations per minute,remove tablets of the drum and any loose dust. Maximum loss of 1 per cent of the mass of the tablet is accepted. If test failed repeat twice and calculate the average of all the runs. For Tablets of a Diameter > 16 mm use a 10 angle to test. 86

87 PTG S4 EP The Instrument A4 PTG-ER2 Stirrer Funnel Release flap Powder cone h2 Powder receipt phi h1 ø100 Light barrier for the measurement of the cone height Powder overflow Collector Balance PTG S3 h1 = Pouring cone height h2 = 100mm phi = Cone angle zul. Abw. Oberfläche Maßstab Gewicht Verwendungsbereich ISO DIN 7151 IT 12 Gez. Datum ISO 1302 Ra Reihe 1 Name Werkstoff Benennung Operation diagramme 87

88 PTG S4 What will be measured 3. What will be measured? The automated powder analyzer PTG S4 is capable to test: powder flow time of a pre-defined mass powder cone volume powder cone density cone angle (angle of repose) powder flowability as per EP <2.9.16> amount of sample flow (g/in preset time) flow chart of sample (g/time) 88

89 PTG S4 USP and EP 2. USP and EP USP <1174>, EP <2.9.36> and ISO 4324 (12/83) Powder flow and Angle of repose Flow Properties and Corresponding Angles of Repose Flow property Angle of repose (degrees) Excellent Good Fair aid not needed Angle of repose Passable may hang up Poor must agitate, vibrate Very poor Very, very poor > 65 89

90 PTG S4 USP and EP USP and EP EP <2.9.16> Flowability 2. EP stainless steel funnel 1. Plastic Beaker 3. Pouring nozzle 10, 15, 25 mm 90