Benefits and Opportunities of Continuous Manufacturing

Transcription

1 Benefits and Opportunities of Continuous Manufacturing Dr. Gert Thurau MSD Manufacturing Division 1

2 Continuous Manufacturing is in the Spotlight Continuous processing is well controlled and the controls are not just equal to, but are superior to batch methods. Sources: Pham Tech Sept 2008 Next Wave Model ( One lot a week:, Pharmamanufacturing.com,

3 Definition of Continuous Manufacturing = In contrast to batch manufacturing Many variations Fully continuous - flow Semi-continuous with or without buffer For drug substance ( flow chemistry ) and drug product Oral solid dosage and biologics processes 3

4 Focus of Today s talk: Drug Product Continuous Manufacturing Potentially Available/Available Technologies Unit Operations Feeding Equipment Technologies/Vendors Gericke, K-Tron, Scheneck-Accurate, Colortronic Blending Granulation Drying Coating Acrison, Buck, Gericke, Hosokawa, Lestreis, Lodige, Patterson-Kelley, Company s Internal proprietary continuous mixers Glatt, Hosokawa, Lodige, LB Bhole, GEA Consigma Glatt, Lodige, GEA Consigma Radio-Frequency, Witt.. O Hara, Thomas Engineering.. 4

5 We are already routinely using some (quasi-) continuous unit operations Roller compaction Tablet compression Encapsulation Packaging lines Experiences gained with operation of these unit operations can translate into fully integrated continuous systems 5

6 Fully Integrated Lines Commercially Available Courtesy of GEA/Consigma Product Line 6

7 Fully Integrated Lines Commercially Available Courtesy of GEA/Consigma Product Line 7

8 Continuous Manufacturing Processes: A Technological Reality Company A (large scale global pharma) has developed 1 : 3 continuous drug substance manufacturing lines 3 continuous drug product manufacturing lines Company B (mid-size European pharma) 1 Initially developed drug substance continuous process Based on success now working on drug product All top 10 pharma companies have development programs on continuous manufacturing 2 However: Number of actual implementations is still very limited 1: AAPS workshop on Continuous Processing, Baltimore, US, : GEA Pharmasystem promotional material 8

9 Potential Benefits of Continuous Processing Typical benefits quoted include: 1. Development cycle benefits (i.e. scale-up, tech transfer) 2. Operational benefits (capital/cost savings) 3. Quality benefits (Consistency of output material) 9

10 1. Development Cycle Benefits Scale-up for new products has typical challenges Engineering scale-up challenges Volume projection for new products unreliable how much scale do I need? Material output of continuous system is dependent on scale and run time By increasing continuous run time could compensate for smaller scale Potential to delay or defer use of larger scale equipment Allows to avoid or reduce scale-up challenges For products not dependent on clinical timelines potential for fast to market Technology transfer In principle smaller foot print systems are more portable from R&D to Manufacturing site 10

11 2. Operational Benefits Smaller foot print = improved manufacturing space utilization Significant resulting cost reduction for buildings and utilities/running costs Prospect of more portable systems Manufacturing line in container? Batch size determined by run time (Much increased) flexibility to volume demand fluctuations Generally less in-process material Reduced waste generated Faster processing times ( From powder to tablet in 20 min ) Quicker response to demand (Drug substance, flow chemistry) catalyst can be immobilized on substrate Less loss of expensive catalysts, reduced work-up of product 11

12 3. Quality Benefits A continuous process in steady state will deliver very consistent material No batch trajectory to compensate for Drug substance reactions enabled by flow Fast heat transfer beneficial Removal of reaction inhibitors Improved ability/benefit of applying PAT controls Feed-back and feed-forward Larger number of data points for evaluation of product No hold times of product in between unit operations Reduced potential for chemical or physical degradation, settling/aging/curing of material 12

13 Continuous Processing Case study/data examples 13

14 Continuous blending/tableting system Loss in weight powder feeders Continuous blender Tablet press 14

15 Continuous blending/tableting system Detail view Number of feeders will be dependent on formulation PAT-enabled process throughout Opportunity for advanced process models 15

16 10:26:54 10:39:41 10:41:43 10:43:46 10:45:49 10:47:52 10:49:54 10:51:57 10:54:00 10:56:02 10:58:05 11:00:09 11:02:12 11:04:14 11:06:17 11:08:20 11:10:22 11:12:25 11:14:33 11:16:36 11:18:38 11:20:41 11:22:44 11:24:46 11:26:49 11:28:52 11:30:54 11:32:57 11:34:59 11:37:02 Predicted component B concentration Real-time predictions of Active on in-line NIR: System characterization (residence time distribution) Continuous blending DOE Component B wt% Process note ComponentB was spiked as a tracer at a blending condition to show RTD (Residence Distribution Time) for process development. Data showed different RTD at two blending conditions. 0 Time 16

17 10:26:54 10:43:11 10:48:44 10:54:17 10:59:52 11:05:24 11:10:57 11:16:36 11:22:09 11:27:41 11:33:14 11:38:47 11:44:37 11:50:10 11:55:46 12:01:19 12:06:52 12:12:24 12:18:07 12:23:39 12:29:14 12:35:04 14:20:44 14:26:26 14:31:59 14:37:37 14:43:10 14:48:44 14:54:19 15:00:10 15:05:44 Predicted Component A wt% Real-time predictions of Active on in-line NIR: Change-over dynamics Continuous blending DOE Condition C PAT real-time predictions for: Concentration of active. A different lot of active charged at Condition C than Condition A and B. 40 Steady state of blending condition A Steady state of blending condition B Component A wt% Process notes Blending uniformity using moving block RSD. Condition A showed lower RSD than that of Condition B. Real-time release?? Time 17

18 Challenges of Continuous Processing Real and potential challenges include: 1. Technical/engineering challenges 2. Quality definition/regulatory challenges 3. Commercial Reality 18

19 1. Technical/Engineering Challenges Powder processing is often poorly characterized to begin with; running continuous vs. batch can add further challenges: Feeding accuracy and precision In-line blender efficiency blend uniformity Managing Start-up and Shutdown Balancing system throughput PAT applications development Control strategy- Perturbations Integration/automation 19

20 2. Quality Definition/Regulatory Challenges Single-most discussed Quality/Regulatory Topic? Definition of a batch in a continuous process Discussion points: Batch definition based on unit time vs. material dispensed in batch equipment Requires process monitoring in periodic intervals to allow segregation of material in case of atypicals Validation of flexible batch sizes validate every potential size separately? Increased complexity of overlapping raw material and excipient lots Rodin The Thinker Rodin Museum, Philadelphia USA 20

21 2. Quality Definition/Regulatory Challenges, cont. Other hot topics: No easy way to pause batch in case of issues Very difficult to quarantine in-process material PAT real-time control strategies can be complex PAT method analytical aspects, including regulatory acceptance More involved automation/process control loops than in conventional batch processing Generally continuous processing is very innovative approach risk of regulatory non-acceptance in global marketplace Discussion still very actively ongoing even in US and Europe 21

22 3. Commercial Reality Obvious benefit for high-volume products How many in pharma future? Pharmaceutical industry in general has excess capacity While less capital than batch processing, initial investment still high due to complexity of equipment/control system Potential value for multi-product, platform technologies Continuous dry granulation (CDG), high shear wet granulation (HSWG), fluid bed granulation/drying (FBGD), tablet coating Currently limited interest for small volume, high value products Startup/shutdown losses Use existing capacity 22

23 Continuous Manufacturing Processes: A Technological Reality A Realization Challenge? Company A (large scale global pharma) has developed: 3 continuous drug substance manufacturing lines 3 continuous drug product manufacturing lines All top 10 pharma companies have development programs on continuous manufacturing Only 1 out of 6 lines operational Very careful and deliberate speed and capital investment 23

24 Conclusions Continuous manufacturing holds many technological and operational promises Many projects underway, by diverse set of players, in various stages of completion We will see more of this in the future However actual manufacturing lines running very few (or none) Jury is still out on realized benefits 24

25 Acknowledgements Bob Meyer, Fan Zhang-Plasket ERC-SOP GEA Pharma Systems 25