Roller Compaction: New trends, challenges and solutions

Transcription

1 Roller Compaction: New trends, challenges and solutions TODD STUTZMAN, PHARM.D. R.PH. DIRECTOR, PHARMACEUTICS SARAH PYSZCZYNSKI, PH.D. PRINCIPAL SCIENTIST 21FEB Catalent Pharma Solutions. All rights reserved.

2 Outline Introductions Fundamentals of Roller Compaction OptiPact Overview Example #1 Example #2 Questions 1

3 Fundamentals of Roller Compaction

4 Development of Solid Oral Dosage Forms API Direct Compression Wet Granulation Dry Granulation Blend Prepare solution Blend Granulate Compact Dry Mill Mill Blend Tablet Blend Capsule 3

5 Development of Solid Oral Dosage Forms API Direct Compression Wet Granulation Dry Granulation Blend Prepare solution Blend Granulate Compact Dry Mill Mill Blend Blend 4

6 Development of Solid Oral Dosage Forms API Direct Compression Wet Granulation Dry Granulation Blend Prepare solution Blend Granulate Compact Dry Mill Mill Blend Blend 5

7 Development of Solid Oral Dosage Forms API Direct Compression Wet Granulation Dry Granulation Blend Prepare solution Blend Granulate Compact Dry Mill Mill Blend Blend 6

8 Advantages of Dry Granulation Direct Compression Wet Granulation Dry Granulation Improves physical properties Improves uniformity, limits segregation Suitable for Moisture Sensitive API Suitable for Heat Sensitive API Energy efficient Environmentally friendly Ease of scale-up 7

9 Development of Solid Oral Dosage Forms: Poorly Water Soluble APIs Preparation of an amorphous solid dispersion (ASD) Improves apparent solubility Improves dissolution rate Enhances bioavailability Limits downstream processing options ASDs prepared by spray drying Small, uniform particles with large surface area Likely have poor flow and low bulk density Roller compaction improves manufacturability of the ASD Catalent Pharmatek SD Spray Drying Technology 8

10 Introduction to Dry Granulation via Roller Compaction Slip Region Blend Nip Region Nip Angle Release Region 9

11 Factors Influencing Ribbon Quality Particle Size Particle Shape Plastic/Elastic Flowability Roller Design Roll Speed Feeding Force GAP Force Roll Diameter Screen Size 10

12 Formulation Development for Roller Compaction: API Goal: Maximize flowability and compactibility of the blend Low Potency API (high drug load) Blend properties largely influenced by the API May be more challenging to develop if API does not have good flow/compactibility properties High Potency API (low drug load) Blend properties largely influenced by the excipients More opportunity to manipulate blend properties with excipients 11

13 Formulation Development for Roller Compaction: Excipients Goal: Maximize flowability and compactibility of the blend Intragranular Extragranular Filler Binder Glidant Improve flow and compactibility Helps form better granules Improve flow May lead to segregation Disintegrant Promotes acceptable disintegration times and dissolution rates Lubricant Lubricates rolls and other RC components Lubrication for compression process 12

14 Process Development: Feeding and Orientation of Rollers Goal: Continuous, uniform feeding Gravity feeding Particles freely flow toward rollers Vertical feeding systems only Force feeding One or more screws facilitate movement of the blend Suitable for blends with poorer flow properties Better control Deaeration Removal of trapped air in the powder Stronger, more uniform ribbons Reduce the amount of fines Improve throughput 13

15 Process Development: Roller Design Smooth May be preferred when sticking is observed Often require less lubricant Less effective gripping Inadequate feeding Lower throughput Non-smooth Includes axial-grooved, corrugated, knurled Improves grip of powders on rollers May result in more sticking 14

16 DoE for Formulation Development Factors Formulation API and excipient levels Roll pressure Roll gap Roll speed Screw speed Screen size Blend time Lubrication time Main compression force Turret speed Responses Flow rate Bulk and tap density Particle size distribution Ribbon porosity Blend uniformity Dissolution Content uniformity Tablet Hardness Friability Fractional factorial: 2 (8 4) = 16 batches center point batches = 19 batches 15

17 Development Challenges with Roller Compaction APIs that are unstable at high pressures Unintended amorphization resulting from mechanical stress Increased hygroscopicity Decreased chemical and physical stability Low potency APIs requiring high drug loads Limits ability to improve properties of the pre-rc blend via excipients Changes in API properties may necessitate additional development Higher potency APIs with very poor physical properties Limits compactibility of a blend if final dosage form is a tablet 16

18 OptiPact Overview

19 What is OptiPact? Integration of roller compaction formulation and process development, scale-up, clinical manufacturing, and commercialization by Catalent Kansas City Physical characterization of API and excipients Selection of proper roller compaction feed system Characterization of pre-roller compaction blend, ribbons, and roller compacted granules Scale up from development to commercial 18

20 Physical Characterization: API and Excipients Particle size and shape Sieve analysis Laser diffraction Microscopy Bulk and Tap Density Flow properties Johanson Flow Indicizer Cohesive properties Hang Up Indicizer A B C D 19

21 Selection of a Roller Compactor Gerteis Hopper agitator Horizontal auger Diagonal tamping screw Single-stage, inline oscillating mill 20

22 Selection of a Roller Compactor Alexanderwerk Hopper agitator Horizontal auger Two-stage, inline Roman mill

23 Selection of a Roller Compactor Freund/Vector Vertical auger Single-stage, inline Roman mill 22

24 Selection of a Roller Compactor: Technologies at Catalent Kansas City Description Quantity Batch Size Gerteis Mini-Pactor GMP kg Alexanderwerk WP-200 GMP kg Alexanderwerk WP-120 GMP kg Freund/Vector TF-156 GMP kg Freund/Vector TF-Mini Experimental kg 23

25 Selection of a Roller Compactor: Gerteis In-process controls Manual mode: screw speed and roll speed controlled independently Gap control: rollers Torque control: horizontal and vertical screws Vacuum deaeration: horizontal screw Density control: ribbon Inline oscillating mill Speed of rotation Degree of movement Clockwise and counter-clockwise 24

26 Selection of a Roller Compactor: Alexanderwerk In-process controls Manual mode: screw and rollers controlled independently Gap control: rollers Vacuum deaeration: horizontal screw Two-stage Roman milling system Speed of rotation 25

27 Selection of a Roller Compactor: Freund/Vector In-process controls Force setting (gap) Screw speed Roll speed Inline Roman mill Fixed speed 26

28 Physical Characterization Pre-roller compaction blend Uniformity Flow properties Bulk/Tap density Ribbons True density Envelope density Solid fraction Impacts compressibility and dissolution Less critical to capsules Porosity Thickness 27

29 Physical Characterization Milled granules Bulk/Tap density Particle size distribution Flow properties Final Blend Uniformity Bulk/Tap density Flow properties

30 Physical Characterization: Flow Analysis Johanson Flow Indicizer Based on deaerated state Specific dimensional application 80cc of material required Bin Diameter Vertical Axis Angle Θ Discharge Diameter Aerated Granulation Deaerated Granulation 29

31 Physical Characterization: Flow Analysis Johanson Hopper Indicizer Provides vertical angle required to maintain mass flow instead of funnel flow Johanson Hang-Up Indicizer Provides outlet required to prevent rat-holing or arching 60cc of material required Mass Flow Funnel Flow Rat-holing Arching 30

32 Physical Characterization: Flow Analysis Critical to development Establish pre-roller compaction blend transfer issues from bins Help identify appropriate roller compaction feed system Facilitate selection of appropriate milling/sizing parameters Critical to scale up Reduce risk during scale up to commercial batch sizes Generate data for any size hopper, bin, or feeder 31

33 Scale up: Development to Commercial Summary/Key Takeaways Pre-roller compaction blend Blend uniformity CQA Lubrication efficiency Closed system bin transfers Solid Fraction Same manufacturer, different model (higher throughput) Different configuration due to change in API (across manufacturers) Critical for compressibility in tablet dosage forms Maintain dissolution profile Particle size distribution of granules Impact on flow for downstream processing (encapsulation or compression) Surface Area/Impact on dissolution 32

34 Example #1 Scale up from Vector TF-Mini to Alexanderwerk WP-120

35 Example #1: Characterization of Ribbons Dosage: Xmg and XXmg tablets Development: Freund/Vector TF-Mini GMP: Alexanderwerk WP-120 Roller Compactor Roller Force Ribbon Porosity (%) Envelope Density (g/cm 3 ) True Density (g/cm 3 ) Solid Fraction TF-Mini 30 kg/cm WP bar WP bar

36 % w/w Retained Example #1: Particle Size Distribution Dosage: Xmg and XXmg tablets Development: Freund/Vector TF-Mini GMP: Alexanderwerk WP TF Mini WP /25 600/30 425/40 250/60 150/ /63 Pan Microns/#mesh 35

37 % Released Example #1: Dissolution Dosage: Xmg and XXmg tablets Development: Freund/Vector TF-Mini GMP: Alexanderwerk WP TF-Mini: X mg tablet TF-Mini: XX mg tablet WP-120: X mg tablet WP-120: XX mg tablet Time (minutes) 36

38 Example #2 Change in API properties leads to change in equipment selection

39 Example #2: Characterization of Pre-RC Blend Dosage: XXmg capsule, Size 0 GMP 1: Gerteis Mini-Pactor GMP 2: Freund/Vector TF-156 Material Arching Index (in.) Rat-holing Index (in.) Flow Rate (kg/sec) Bulk Density (g/cc) Pre-roller compaction blend (50% w/w) Pre-roller compaction blend (50% w/w) Original API supplier New API supplier

40 Example #2: Characterization of Ribbons Dosage: XXmg capsule, Size 0 GMP 1: Gerteis Mini-Pactor GMP 2: Freund/Vector TF-156 Roller Compactor Roller Force Ribbon Porosity (%) Envelope Density (g/cm 3 ) True Density (g/cm 3 ) Solid Fraction Gerteis Mini-Pactor 3.0 kn TF psi

41 % w/w Retained Example #2: Particle Size Distribution Dosage: XXmg capsule, Size 0 GMP 1: Gerteis Mini-Pactor GMP 2: Freund/Vector TF TF-156 Gerteis /25 600/30 425/40 250/60 150/ /63 Pan Microns/#mesh 40

42 % Released Example #2: Dissolution Dosage: XXmg capsule, Size 0 GMP 1: Gerteis Mini-Pactor GMP 2: Freund/Vector TF TF-156: XXmg Capsule Gerteis: XXmg Capsule Time (minutes) 41

43 Summary Roller compaction is an excellent development solution for many APIs, including amorphous solid dispersions. Formulation, process development, and scale-up require: Thorough characterization of API, excipients, pre-rc blend, ribbons, granules, and final blend Careful selection of excipients to maximize flow and compressibility Careful selection of equipment and processing parameters Catalent Kansas City is uniquely equipped to partner with clients to successfully develop roller compaction processes. Blend Compact Mill 42

44 Q & A 43

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