for the Batch Manufacture

Transcription

1 Tim Freeman Managing Director Freeman Technology IFPAC January 2015 Evaluating the Design Space for the Batch Manufacture of an OTC Medicine

2 Background Rapidly rising demand for an OTC pharmaceutical product Insufficient capacity, in particular High Shear Wet Granulation & Tablet Press Unable to achieve maximum tablet press speed, which has impacted throughput Objective Identify critical material attributes/process parameters that impact blend flow, compressibility and tablet press speed Investigate feasibility of APC/troubleshooting to improve blend quality and compression throughput (not presented here)

3 Wet Granulation Converts fine powders into larger granules. Benefits include: - Improved flow Reduced segregation Better content uniformity Improved compression properties Reduced dusting Granulation via high shear is traditionally a batch process (although continuous becoming popular) Water is introduced whilst the powder is sheared Process variables: - Solid to Water Ratio Impeller Speed Kneading Time Binder Temperature

4 DOE Campaign on Pilot Scale Equipment Impeller Speed (rpm) Binder Temp (deg C) Kneadin g Time (mins) Solid-to- Water Ratio BFE Wet Granules, mj Batch# Run Order Center Point B B B B B B B B B B B Ranges/values of DOE factors are derived from full scale manufacturing parameters

5 Process Steps & Granule Property Evaluation Powder Rheology, Sieve Analysis, Bulk/Tap Density Evaluated at Each Stage of Manufacture to characterize granule rheology, bulk flow properties, permeability, compressibility, PSD Post Granulation Post FBD Post Milling Post Final Blend < 20 mesh > 20 Mesh Final Mix / Lubrication HSWG FBD Milling Compression PAT Employed: - NIR, impeller torque, APC, hyperspectral imaging Tablet Weight, Hardness, Thickness

6 Process and Data Analysis Post operation analytical data analysis Sieve analysis Bulk / Tap Density testing Powder Rheology PAT data analysis (not presented here) NIR Torque on Granulator Impeller Statistical / Multivariate analysis ANOVA, Effect Estimates and Optimization MVA of available data

7 Rheological Test Results

8 Granules were characterised using a Powder Rheometer The Powder Rheometer measures the resistance that the powder, or granules exert on the blade, as the blade forces its way through the sample. This resistance is expressed as Flow Energy, which is calculated from the direct measurements of Torque and Force

9 Flow Energy is influenced by: - Friction between particles / granules Mechanical interlocking of particles / granules Strength of capillary bonds Strength of cohesive forces In high shear wet granulation, the addition of water and work (shear) results in larger, denser, more adhesive granules. This means that more water and more work input results in higher flow energy as granules are harder to move (denser, larger, stickier and less compressible). Wet mass (50:50 lactose/mcc blend) 20% water w/w 40% water w/w

10 Rheological Testing Results BFE Wet Granules, mj BFE Dry Granules, mj ΔP Dry Granules, mbar Aeration Energy Dry Granules, mj Batch# Run Order Cohesion, kpa FF B B B B B B B B B B B > Data presented to a maximum of 3 significant figures (less where appropriate)

11 Effect Estimate on Flow Energy (Wet) Actual v Predicted

12 Post Granulation Characterisation Dynamic testing can be used to evaluate the characteristics of wet granules Testing in the wet state allows early in-process evaluation of batches The Flow Energy (BFE) of the wet granulate has shown to be a function of the following process parameters: - Solid to water ratio Impeller speed Binder temperature Robust relationship allows Critical Process Parameters to be identified and Control Space to be determined

13 Other Measured Powder Properties Aeration & Permeability Aeration and Permeability introducing air into the bottom of the powder σ Aeration Base ΔP Air in Aeration test Air in Permeability test Aeration Control Unit

14 Other Measured Powder Properties Shear Behaviour Rotation at controlled normal stress for shearing the powder Applied Force Shear Cells (Normal Stress, s) Rotation (Shear Stress, t )

15 Effect Estimates on Permeability (Post FBD) Actual v Predicted

16 Effect Estimates other parameters (Post FBD) Response: Aeration Energy Response: FF Response: Cohesion

17 Post FBD Characterisation Dry granules are more suitable for characterisation with an increased number of test methods Testing in the dry state allows relatively early in-process evaluation of batches although it is an additional step beyond post-granulation characterisation The Permeability of dry granulate shows a robust relationship with the manufacturing parameters Binder temperature Solid to water ratio Kneading time The Shear (Flow Function and Cohesion) and the Aeration behaviour of the dry granules can also be predicted from the manufacturing parameters

18 Summary of granule manufacturing data Results indicate it is possible to predict important granule properties from a knowledge of the process parameters Solid-to-Water Ratio most influential parameter Best correlations for BFE (Wet) and Permeability (Dry) as also observed in earlier studies Potential to work well for Aerated Energy and FF/Cohesion of dry granules for these materials How do these granule characteristics influence the tablet quality?

19 Tableting results Tablet press run at constant 35rpm to accommodate all batches Given the wide range of granule flow properties, in order to achieve similar weights and hardness, it was necessary to change the fill depth and pressures. A variation in tablet thickness was observed as a result Weight Weight Weight Hardness Hardness Hardness Pre Main Ejection Fill Main Tablet Batch Code Avg SD %RSD Avg SD %RSD Pressure Pressure Force Depth Thickness

20 Influence of Process Parameters on Tablet Quality Given that several process parameters changed simultaneously, the relationship between granule and tablet properties is convoluted. However, hardness will be dependant on: - Fill depth (influenced by granule density and powder flow properties) Blend permeability & compressibility (influencing tablet thickness) Press Pressure (influenced by granule strength/compressibility and the limits on dwell time due to the fixed operation speed) In order to evaluate the relationship between granule properties and tablet quality, it was necessary to compensate for these differences in process parameters. An adjusted measure of the tablet hardness was adopted HHHHHHHH AAAAAAAA HHHHHHHH = TTTTTTTTT PPPPPPPP WWWWWW

21 Tablet Hardness with Respect to Dynamic Properties of Wet Granules

22 Tablet Hardness with Respect to Dynamic Properties of Dry Granules

23 Summary of tableting data The flow properties of the wet and dry granules are well correlated with the tablet (adjusted) hardness Previous studies of batch granulation have also demonstrated the link between granule properties and tablet quality (O.E. Cassidy & W.I. Thomas, Journal of Pharmacy and Pharmacology, 54 (2002), pp 25-46) This link between granule properties and tablet quality has also been recently observed in a continuous wet granulation study (T. Freeman, A. Birkmire & B. Armstrong, Procedia Engineering, 2015, in press)

24 Conclusions 1. Powders (wet or dry) are complex materials and have many characteristics. 2. The multiple operations in batch tableting processes subject raw materials and intermediates to a range of different environments. 3. Each stage of the process, from initial granulation to final compression needs to function efficiently in order that product of the desired properties can be manufactured. Problems at any stage have the potential to translate downstream, ultimately affecting tablet properties or manufacturing throughput. 4. Each process operation provides the opportunity to adjust settings in order to improve process efficiency and/or to alter the properties of the material leaving that stage of the process. 5. In the wet granulation process, different processing regime and formulations have been shown to correlate to the resultant granule properties. 6. Changing the process settings allows for the precise control of the granule properties for a given formulation. 7. The granule properties (using the BFE) are a direct indicator of the resultant tablet quality. 8. With sufficient understanding of the relevant material properties and critical process parameters, it is possible to employ a QbD/Design Space approach to batch granulation and tablet manufacture.

25 Thank you for your attention Thanks also to Polina Kishinevskaya & Drs. Jun Huang & Mojgan Moshgbar (Pfizer) John Yin & Dr. Brian Armstrong (Freeman Technology) For further information, please visit us at