AMIT - QbD, a case study

1. AMIT MUKHARYA February 2016 QUALITY BY DESIGN ( QbD ) – A CASE STUDY 1

2. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE WHY HYPERTENSION? WHY LACIDIPINE? WHY SD-FBP TECHNOLOGY? WHICH ARE PRIOR ARTS? HYPOTHESIS & OBJECTIVES 2

3. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE WHY HYPERTENSION? WHY LACIDIPINE? WHY SD-FBP TECHNOLOGY? WHICH ARE PRIOR ARTS? HYPOTHESIS & OBJECTIVES 3

4. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE WHY HYPERTENSION? WHY LACIDIPINE? WHY SD-FBP TECHNOLOGY? WHICH ARE PRIOR ARTS? HYPOTHESIS & OBJECTIVES Molecular dispersions, as solid dispersions represent the last state on particle size reduction resulting in high surface area & an increased dissolution rate and, consequently, improved bioavailability . Higher Porosity of Drug Particles resulting in a higher dissolution rate and hence bioavailability. Improved Wettability In particular, high surface coverage of hydrophobic drug with hydrophilic carrier is assumed to give good wetting properties with narrow contact angles. Drugs in Amorphous State Resulting in enhancement of drug release as no energy is required to break up the crystal lattice during the dissolution process. 4

5. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE WHY HYPERTENSION? WHY LACIDIPINE? WHY SD-FBP TECHNOLOGY? WHICH ARE PRIOR ARTS? HYPOTHESIS & OBJECTIVES patent WO1995/08987 discloses compositions comprising one or more 1, 4 dihydropyridine derivatives; water-soluble carrier such as derivatives of saccharides; a “ disintegrant ” selected from polacrilin potassium, sodium starch glycolate and/or cross-linked carboxy methylcellulose and “ surfactant ” selected from sodium lauryl sulfate, poloxamers and/or higher fatty acids polyoxyethylene sorbitan esters [i] . Another patent WO2006/113309 utilized agglomerated particles of LCDP having smaller particle size in its formulation [ii] . All the above mentioned prior art disclosed pharmaceutical composition comprising of lacidipine by using surfactant(s) and/or disintegrant (s) or micronized Lacidipine . Thus, it would be significant improvement in the existing art to provide oral pharmaceutical dosage form of lacidipine without the use of surfactant(s) and/or disintegrant (s) or without micronization of Lacidipine per se . This will also reduce the cost of production also. The development of solid dispersion is a practically viable method to enhance solubility of poorly & to reduce bio-variability of selected drug candidate, lacidipine , where drug is dispersed in the hydrophilic matrix which enhances wettability and porosity. 5

6. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE WHY HYPERTENSION? WHY LACIDIPINE? WHY SD-FBP TECHNOLOGY? WHICH ARE PRIOR ARTS? HYPOTHESIS & OBJECTIVES Only a FEW PRODUCTS based on Solid Dispersion have been marketed so far commercially which are: Griseofulvin : Gris-PEG®, Nabilone : Cesamet ®, Nimodipine Nimotop ®, Itraconazole : Sporanox ®, Tacrolimus : Prograf ®, Etravirine : Intelence ®, Ritonavir: Norvir ® and Everolimus : Certican ®. The rare occurrence of solid dispersion based pharmaceutical dosage forms in the clinic are DUE TO IMMENSE CHALLENGES IN: Robust formulation development with controlled critical material attributes Controlled reproducible manufacturing process with controlled critical processing parameters Scale-up of manufacturing processes and Consistent physical and chemical stability of solid dispersion composition. A thorough understanding of processes that occur on the molecular level during manufacturing and upon storage of solid dispersion composition is a prerequisite for more efficient design of solid dispersions. 6

7. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE WHY HYPERTENSION? WHY LACIDIPINE? WHY SD-FBP TECHNOLOGY? WHICH ARE PRIOR ARTS? HYPOTHESIS & OBJECTIVES MAIN OBJECT of the present research work is to provide a stable & efficacious robust formulation of lacidipine with controlled critical material attributes having desired dissolution, bio-availability & controlled stability profile in intended commercial pack without the use of disintegrant (s) and/or surfactant(s) and/or without micronization of the active ingredient per se . This should be value addition to existing knowledge in the formulation field involving LCDP. ANOTHER OBJECT of this research work is to provide a sophisticated smooth & reproducible manufacturing process for the preparation of said pharmaceutical dosage form by Quality by Design (QbD) concept focusing on thorough understanding of the process with online characterization tools by which it is developed and scaled up along with a knowledge of the risks (critical processing parameters ) involved in manufacturing by FMEA (Failure Mode Effective Analysis) study of the product with respect to process and how best to mitigate those risks by developing design space with DoE and MVDA with outlined control strategy at pilot scale developmental stage itself to prevent product failure at larger commercial scale. 7

8. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE WHY HYPERTENSION? WHY LACIDIPINE? WHY SD-FBP TECHNOLOGY? WHICH ARE PRIOR ARTS? HYPOTHESIS & OBJECTIVES 8

9. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE SOLUBILITY & PARTITION COEFFICIENT HOT STAGE MICROSCOPY DIFFERENTIAL SCANNING CALORIMETRY X-RAY DIFFRACTO METRY FOURIER TRANSFORM IR SPECTROSCOPY Concentration of SDS (%, w/v) 0.05 0.1 0.25 0.5 0.75 1 Solubility (μg/mL) ND* 0.07 6.1 35.8 78.1 125.1 160.2 Solubility of Lacidipine at different concentrations of P olysorbate 20 in water. Partition Coefficient of LCDP: was found to be 5.5 by shake flask method, which indicates that LCDP is lipophilic. So it can pass cell membrane easily once it got solubilized. Optimization of Drug to Carrier ratio 9

10. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE SOLUBILITY & PARTITION COEFFICIENT HOT STAGE MICROSCOPY DIFFERENTIAL SCANNING CALORIMETRY X-RAY DIFFRACTO METRY FOURIER TRANSFORM IR SPECTROSCOPY 10

11. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE SOLUBILITY & PARTITION COEFFICIENT HOT STAGE MICROSCOPY DIFFERENTIAL SCANNING CALORIMETRY X-RAY DIFFRACTO METRY FOURIER TRANSFORM IR SPECTROSCOPY 11

12. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE SOLUBILITY & PARTITION COEFFICIENT HOT STAGE MICROSCOPY DIFFERENTIAL SCANNING CALORIMETRY X-RAY DIFFRACTO METRY FOURIER TRANSFORM IR SPECTROSCOPY 12

13. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE SOLUBILITY & PARTITION COEFFICIENT HOT STAGE MICROSCOPY DIFFERENTIAL SCANNING CALORIMETRY X-RAY DIFFRACTO METRY FOURIER TRANSFORM IR SPECTROSCOPY 13

14. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE DRUG TO CARRIER RATIO INTRA TO EXTRA LACTOSE LEVEL OF LUBRICANT % WEIGHT GAIN IN FILM COATING 14

15. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE DRUG TO CARRIER RATIO INTRA TO EXTRA LACTOSE LEVEL OF LUBRICANT % WEIGHT GAIN IN FILM COATING 15

16. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE DRUG TO CARRIER RATIO INTRA TO EXTRA LACTOSE LEVEL OF LUBRICANT % WEIGHT GAIN IN FILM COATING 16

17. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE DRUG TO CARRIER RATIO INTRA TO EXTRA LACTOSE LEVEL OF LUBRICANT % WEIGHT GAIN IN FILM COATING 17

18. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION AS PER QbD SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE FISHBONE ANALYSIS CPP DOE CONTOURS & CUBES DESIGN SPACE 18

19. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION AS PER QbD SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE FISHBONE ANALYSIS CPP DOE CONTOURS & CUBES DESIGN SPACE 19

20. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION AS PER QbD SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE FISHBONE ANALYSIS CPP DOE CONTOURS & CUBES DESIGN SPACE 20

21. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION AS PER QbD SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE FISHBONE ANALYSIS CPP DOE CONTOURS & CUBES DESIGN SPACE 21

22. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION AS PER QbD SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE FISHBONE ANALYSIS CPP DOE CONTOURS & CUBES DESIGN SPACE FLUIDIZATION AIR VELOCITY (CFM) -1 ( 2 ) (5) +1 ( 8 ) -1 ( 1 ) 0 ( 2 ) +1 ( 3 ) x LIQUID SPRAYING RATE ( gm /min) ATOMIZING AIR PRESSURE (bar) -1 (50) 0 (75) +1 (100) (-1,0,+1) (0,-1,-1) (+1,0,-1) (0,+1,-1) (-1,-1,0) (-1,+1,0) (+1,+1,0) (+1,-1,0) (-1,0,+1) (0,-1,+1) (0,+1,+1) (+1,0,+1) (0,0,0) DESIGN: BOX-BEHNKEN NO. OF FACTORS :3 NO. OF LEVELS :3 TOTAL RUNS :17 22

23. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION AS PER QbD SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE FISHBONE ANALYSIS CPP DOE CONTOURS & CUBES DESIGN SPACE Actual Equation for Response Y1: Granule size (D90) in Terms of Coded Factors: Granule Size =+398.40 +115.50*A-21.25*B-14.25*C-42.50*A*B-26.50*A*C +0.000*B*C+35.30*A^2-6.20 *B^2+17.80 * C^2 Reduced Equation for Response Y1: Granule size (D90) in Terms of Coded Factors: Average Granule Size= +398.40 +115.50*A-21.25*B-42.50*A*B-+35.30*A^2 23

24. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION AS PER QbD SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE FISHBONE ANALYSIS CPP DOE CONTOURS & CUBES DESIGN SPACE Actual Equation for Response Y2: Process Efficiency (in %) in Terms of Coded Factors: Process Efficiency=+97.20 +2.50*A-0.12*B-2.13*C-0.50*A*B+1.00 *A*C-0.75*B*C -1.47*A^2-0.22*B^2-3.22*C^2 Reduced Equation for Response Y2: %Process Efficiency in Terms of Coded Factors: Process Efficiency=+97.20 +2.50 *A-2.13*C-3.22*C^2 24

25. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION AS PER QbD SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE FISHBONE ANALYSIS CPP DOE CONTOURS & CUBES DESIGN SPACE 25

26. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE EFFECT OF DISSOLUTION MEDIA pH EFFECT OF PADDLE STIRRING SPEED EFFECT OF POLYSORBATE CONCENTRATION Prototype F-15 was subjected to dissolution testing using USP apparatus 2 at 50 rpm in 900 mL of various media including water, 0.1 N HCl , pH 4.5 phosphate buffer, and pH 6.8 phosphate buffer.. The drug release profile of prototype F-15 shows pH-independency This is not surprising considering that the drug substance is poorly soluble. Therefore, the effect of pH was not studied further during the development of a predictive dissolution method & Purified water was selected as the dissolution medium since this medium is often used for poorly soluble drug products. 26

27. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE EFFECT OF DISSOLUTION MEDIA pH EFFECT OF PADDLE STIRRING SPEED EFFECT OF POLYSORBATE CONCENTRATION An in vitro discriminatory test would be the test to reflect differences in physical characteristics of the test products (formulation/manufacturing) with no direct or definite consequences in vivo. Thus, first the drug release of prototype F-15 was evaluated at 25 rpm in 900 mL of purified water. Coning was observed at the bottom of the vessel during dissolution testing. This observation was reflected in extremely variable drug release profiles as shown in Figure . Therefore, 25 RPM rpm could not be used as the stirring speed. Thus, A higher stirring speed i.e. 50 rpm & 100 rpm was explored to develop discriminatory dissolution for Test formulation F-15 and the Reference product. 27

28. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE EFFECT OF DISSOLUTION MEDIA pH EFFECT OF PADDLE STIRRING SPEED EFFECT OF POLYSORBATE CONCENTRATION To develop an in vivo discriminatory test or a bio-relevant test, the drug release of prototype F-15 was evaluated using purified water containing different polysorbate concentrations i.e. 0.25%, 0.50% & 1.00%. The stirring speed of paddle was kept 50 rpm & temperature was maintained at 37±0.5ºC in each case. The poor solubility of drug substance LCDP provides saturation condition in even at 900 mL of water. Therefore, increasing the Polysorbate concentration in dissolution medium improve the predictive power of the dissolution test using USP apparatus 2 at 50rpm 28

29. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE In Vivo Drug Release by Pilot PK Study A randomized, open-label, two-treatment, two-period, two-sequence, single dose, two-way crossover bioequivalence study on Lacidipine 4 mg tablets (containing Lacidipine 4 mg) of Cadila Pharmaceuticals Ltd.India was compared with Motens ® 6 mg Tablets (containing Lacidipine 4 mg) of Boehrengeir Ingelheim in 24 healthy, adult, male, human subjects under fasting condition with at least 07 days washout period between two periods for each group between the age group of 18-45 years were enrolled in the study. Single dose of 4 mg of test or reference product was administered along with 200 ml of drinking water after an over night fasting of at least 10 hours in each period. Sampling Time Points: In each period, a total of 19 blood samples (5 mL each) were collected. One blood sample was collected prior to drug administration (0.0) followed by post dose samples at 0.25, 0.50, 0.75, 1.0, 1.25, 1.50, 1.75, 2.0, 2.25, 2.50, 3.0, 4.0, 6.0, 8.0, 12.0, 24.0, and ambulatory sample at 48.0,72.0 hrs. 29

30. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE Summary of PK parameters from BE study comparing prototype F-15 (Test Product) with respect to Motens, 4 mg (Reference product) Test/ Reference ratio AUC 0 to t AUC 0 to inf Cmax Prototype F-15 1.03 0.98 1.05 30

31. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE ACCELERATED STABILITY PHOTO STABILITY IN USE STABILITY 31

32. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE ACCELERATED STABILITY PHOTO STABILITY IN USE STABILITY 32

33. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE ACCELERATED STABILITY PHOTO STABILITY IN USE STABILITY 33

34. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE ACCELERATED STABILITY PHOTO STABILITY IN USE STABILITY 34

35. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE ACCELERATED STABILITY PHOTO STABILITY IN USE STABILITY 35

36. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE ACCELERATED STABILITY PHOTO STABILITY IN USE STABILITY 36

37. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE ACCELERATED STABILITY PHOTO STABILITY IN USE STABILITY 37

38. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE ACCELERATED STABILITY PHOTO STABILITY IN USE STABILITY 38

39. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE 39

40. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE BATCH SIZE AND EQUIPMENT FLUIDIZATION AIR FLOW SCALE UP SPRAY RATE & ATOMIZATION AIR PRESSURE SCALE-UP Scale up from small laboratory sized fluid-bed machines can be made much easier if the same line of equipment is to be used. Though efforts were in need to be spent on modifying process parameters, because of differences in air flow pattern, expansion chamber geometry, gun spray pattern etc. Thus, for Top Spray equipment minimum and maximum batch size could be approximated as per equation no.(1) and (2) Smin = [V x 0.3 x BD] = [500 x 0.3 x 0.4] = 60 kg………………….……(1) Smax = [V x 0.7 x BD] = [500 x 0.7 x 0.4] = 140 kg ………………..….. (2) Where; S is batch size in kilograms, V is the product bowl working volume in liters BD is the bulk density of finished granules in gm /cc; 0.3= Minimum occupancy of 30% in product bowl 0.7= Maximum occupancy of 70% in product bowl 40

41. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE BATCH SIZE AND EQUIPMENT FLUIDIZATION AIR FLOW SCALE UP SPRAY RATE & ATOMIZATION AIR PRESSURE SCALE-UP To maintain the same fluidization velocity, the air volume in a larger unit was increased, based upon the cross-sectional area of the product bowl. In this case, the cross-sectional area of the base of the larger container was 0.64m2 and the smaller was 0.02 m2. Thus, correct air flow was calculated as per equation no. (3) AF2 = [AF1 x (A2/A1)] = [80 x (0.64/0.02)] = 2560 CMH ~ 2600 CMH.… (3) Where; AF 1 is Fluidization air flow in the laboratory scale equipment, AF2 Fluidization air flow in the scaled-up equipment, A1 is cross-sectional area of the laboratory scale equipment, A2 is cross-sectional area of the scaled up equipment. 41

42. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE BATCH SIZE AND EQUIPMENT FLUIDIZATION AIR FLOW SCALE UP SPRAY RATE & ATOMIZATION AIR PRESSURE SCALE-UP Spray rate scale-up was determined by the drying capacity of the equipment which is directly proportional to cross sectional area of the air distribution plate rather than by the increase in batch size. At a given atomization pressure and air flow volume, change in liquid spray rate directly affects droplet size which in turn impacts particle agglomeration and may cause lumping. Thus, Cross-sectional areas of the air distribution plate were used for approximation of scale up spray rate as per equation no (4). SR 2 = [SR 1 x (A 2 /A 1 )] = [5 x (0.64/0.02)] = 160gm/min...............................(4) Where; SR 1 is spray rate in the laboratory scale equipment, SR 2 is spray rate in the scaled-up equipment, A 1 is cross-sectional area of the laboratory scale equipment, A 2 is cross-sectional area of the scaled up equipment. To maintain the same particle size, the “triple-headed nozzle” in scale up could spray at the same pilot-unit spray rate at a same atomization air pressure. However, this could result in a longer process time. So another approach to maintain a similar droplet size was utilized to achieve granule size D90 of 400um with maintenance of the mass balance of spray rate and the atomization pressure by increasing the atomization pressure to 2*(3) = 6 bar , the spray rate could be increased to 160* (3) = 480~500 grams per minute at production scale (where 3 indicates number of nozzle heads) keeping the same droplet size and hence obtaining granulation with desired CQAs 42

43. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE IN PROCESS CQAs FINISHED PRODUCT CQAs 43

44. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE FLUID BED GRANULATION TABLET COMPRESSION FILM COATING 44

45. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE FLUID BED GRANULATION TABLET COMPRESSION FILM COATING 45

46. SCALE UP & CONTROL STRATEGIES PACKAGING & STABILITY STUDIES IN VITRO IN VIVO RELATIONSHIP FLUID BED PROCESS OPTIMIZATION SOLID DISPERSION FORMULATION DEVELOPMENT PREFORMULATION STUDIES INTRODUCTION & RATIONALE FLUID BED GRANULATION TABLET COMPRESSION FILM COATING 46

47. FROM RESULTS OF SOLID STATE CHARACTERIZATION STUDY, it can be concluded that the enhancement of dissolution rate was obtained by solid dispersion containing 1:10 mass ratio of LCDP: PVP K29/32. The results of DSC and XRD indicated that LCDP was presented in an amorphous or molecular state in the solid dispersions and the presence of hydrogen bonding interaction between the >N-H of LCDP and -C=O of PVPK29/32 in solid dispersions were confirmed by combining FT-IR. The amorphous state of LCDP coupled with presence of hydrogen bond between LCDP and PVPK29/32 was the main cause for the markedly enhancement of dissolution rate. These results confirmed that LCDP–PVP K29/32 solid dispersion prepared by the solvent evaporation could be used as a means of enhancing LCDP dissolution rates. CONCLUSION 47

48. FROM RESULTS OF FORMULATION OPTIMIZATION STUDY, it can be concluded that optimized solid oral pharmaceutical composition with desired disintegration and dissolution rate comprises of lacidipine , carrier, diluent and lubricant wherein the weight ratio of lacidipine to carrier is 1:10, with specific intra-granular lactose to extra-granular lactose ratio of 80:20 and magnesium Stearate (0.25%); without size reduction and without use of any surfactant(s) and/or disintegrant (s). FROM RESULTS OF PACKAGING OPTIMIZATION STUDY, Optimized formulation showed long term, intermediate, accelerated stability, photo-stability & in-use stability in fom -packed Alu-Alu Blister as compared to HDPE container. Thus, Alu-Alu blister is proposed for commercial intended primary pack for developed formulation. CONCLUSION 48

49. FROM EXHAUSTIVE USE OF RISK “ASSESSMENT” TOOLS: Qualitative Matrix Analysis & Quantitative Failure Mode Effective Analysis (based on Probability, Severity & Detectability ), it was unquestionable that Fluid Bed Granulation is the most critical step for achieving consistent QTPP in case of formulation of poorly soluble & highly bio-variable drug LCDP by solid dispersion approach. TO CONTROL SEVERITY OF RISK irrespective of the scale, detailed experimental study of CPPs was carried out by Box Behnken experimental Design (BBD) to develop Design Space (DS) with acceptable proven ranges, which reduce probability of risk respected CPPs affecting quality and/or performance of In Process/ Finished Product (IP/FP) CQAs. TO INCREASE DETECT ABILITY OF RISK, performance of Fluidized Bed Process could be inline monitored by Process Analytical Technology (PAT) tools: in situ Focused Beam Reflectance Measurement (FBRM) for inline Particle Size measurement during granulation & in situ Fourier Transform Infra-Red Spectroscopy (FTIR) for inline Blend Uniformity (BU) at Blending stage & Content Uniformity in Finished Product Stage, which ensure that Fluidized Bed Granulation process is working as anticipated to deliver product quality attributes as predicted by the design space. CONCLUSION 49

50. PAT IMPLEMENTATION PROCESS ANALYTICAL TECHNOLOGY FOR MANUFACTURING LINE SIFTER FOR DELUMPING FLUID BED PROCEOR SIFTER CUM MULTI MILL BIN BLENDER COMPRESSION MACHINE COATING MACHINE TEMPERATURE & RELATIVE HUMIDITY by At Line Thermo-hygrometer RATE OF GRANULATION (Speed / Time) by In Line Lasentec FBRM or PVM API / EXCIPIENT PURITY by In Line BRUKER FT-NIR API / EXCIPIENT PARTICLE SIZE DISTRIBUTION by In line Lasentec FBRM RATE OF DRYING (Temperature / Time) FOR by In Line BRUKER FT-NIR RATE OF BLENDING (Speed/ Time) by In Line BRUKER FT-NIR RATE OF COMPRESSION (Speed & Hardness ) by In Line Compression Force Sensor with Servo motor in Se-Jong/ Fette for Auto matic control of Weight & Hardness OR Bruker Tandem FT-NIR OR At Line Weight variation , Hardness, Friability & Disintegration Testing RATE OF COATING (Spraying rate / Atomization pressure) by In Line Raman Spectrometer probe in Glatt -PAM coater OR At Line Electolab Disintegration test & Sartorious Halogen Moisture Balance 50

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52. Focus on Quality, Not on Money; Quality Automatically Brings Money. Thank You So much for Your Kind Attention !!! 52