Mitigating Commercial Risks in Continuous Manufacturing Drug Product

Transcription

1 Mitigating Commercial Risks in Continuous Manufacturing Drug Product Ian Leavesley Eli Lilly Indianapolis, Indiana Commercializing Continuous Processing in Pharma Boston, MA Jan 30 th Feb 1 st 2017

2 Outline Lilly Journey Comparing risks in continuous with batch manufacturing Reducing API consumption in mid and late stage development Quality by control leveraging a variety of different types of controls to assure quality Low value, high volume vs. High value, low volume strategy

3 CM isn t an Endpoint, it s a Catalyst for Changing How We Do Things there s gotta be a better way to develop / manufacture / supply, if only something changed. Workflow optimized for current process Each company needs to define the business or work process change(s) that are most beneficial for their business

4 Lilly s Journey with DP CM Business Case Simple Prototype Construct Dev Facility in Indy POC - confirm CDC replaces Batch RC Optimize Design to Apply Broadly GMP Capability Qualified in Indy GMP Capability Qualified in PR (multiple APIs) Focus on Implement ation in Dev Form. and Process Dev. Work Plans with CM 1st GMP product for clinical trials First funded project Clinical trials for two additional products Multiple funded projects on dev. unit Much faster if start recently

5 Current Lilly Strategy Accelerate timing / reduce cost of NME development / launch using CM Consider converting approved products later Focus on direct compression and maximizing capability of that platform

6 Outline Lilly Journey Comparing risks in continuous with batch manufacturing Reducing API consumption in mid and late stage development Quality by control leveraging a variety of different types of controls to assure quality Low value, high volume vs. High value, low volume strategy

7 Comparing Risks CM vs Batch - CQAs Potency Most common CM focus. More often transients than batch average. More focus on smaller sample increments v batch Expand to excipients Content Uniformity In CM, transition thinking from common cause to special cause variation detection Purity and Identify No difference Release Profile CM can help by achieving BF at lower SF

8 Improvement in Tablet Properties Affecting Release Profile (vs dry gran) Continuous process is DC ~ 6 kp stronger tablets at target tablet thickness Batch process is RC A continuous direct compression process leads to: Stronger tablets across different tablet solid fractions (tablet thickness values). Wider acceptable tablet solid fraction (tablet thickness) range with acceptable properties.

9 Comparing Risks CM to Batch - Operational Start-up more focus in CM Rejects more focus due to higher frequency samples Yield can be early issue if not planned for Batch loss less due to higher frequency samples Powder flow / segregation Much less of issue Deviations usually not CM specific Training computer proficiency, multi-skill Automation realtime monitoring, often overlooked. Predicted future growth area Still learning still some uncertainty

10 Comparing Risks CM vs Batch Organizational Fear of unknown Tie to company, not one organization, objectives Don t tie to a SINGLE non-approved molecule Regulatory US, Europe, Japan, beyond Commercial Volume predictions not reliable CM strength Cost / time of development CM strength Cost of Goods Sold not Lilly s 1st focus Material properties

11 Outline Lilly Journey Comparing risks in continuous with batch manufacturing Reducing API consumption in mid and late stage development Quality by control leveraging a variety of different types of controls to assure quality Low value, high volume vs. High value, low volume strategy

12 Scale (kg or kg/hr) Develop at scale (no scale up) Higher technical risks for scale dependent unit operations leads to: - More complex formulations - More complex manufacturing processes - Longer development timelines Launch scale Phase 3 studies Postapproval changes Develop at scale (at target commercial throughput) - Quicker development studies (~ 10 min per experiment) - Less API needed for DP dev No scale up needed prior to or after launch! - Flexibility to clinical demands - Flexibility in adjusting commercial batch sizes based on market demand Start of dev Batch processing Continuous processing

13 API and time savings promise or reality? REALITY Scaled-out from minutes to hours 1 molecule has tech transferred twice with success on first run each time Moving automated control strategy from site to site seamlessly (if planned for) Big changes, not incremental improvements

14 Outline Comparing risks in continuous with batch manufacturing Reducing API consumption in mid and late stage development Quality by control leveraging a variety of different types of controls to assure quality Low value, high volume vs. High value, low volume strategy

15 How to Deal with Material of Questionable Quality WRONG QUESTION! Question we answered: How do we not make material of questionable quality? Quality by Control

16 How to Deal with Material of Questionable Quality QUALITY BY CONTROL Design failure modes out of equipment Capable process statistical control Each feeder has sophisticated controller Ratio control of feeders Actively adjust feeder mass flow setpoints to control concentration, not total flow rate (level 1 control) Weight control loop ensures tablet weight Concentration control loop (RTD model and/or soft sensors and/or spectroscopy) Realtime analytical controls to reject disturbances

17 How Does CM Increase Assurance of Quality? Operative word ASSURANCE Multiple layers of controls BATCH CONTINUOUS Quality decisions Millions of tablets s of tablets (1 tablet for force) Sampling Frequency hours Seconds minutes (sometimes ms) Realtime accept / reject decisions No yes

18 Outline Comparing risks in continuous with batch manufacturing Reducing API consumption in mid and late stage development Quality by control leveraging a variety of different types of controls to assure quality Low value, high volume vs. High value, low volume strategy

19 CM Not just about Blockbuster Volume ONE EXAMPLE - Cancer 836 medicines and vaccines in development for 200 unique cancer types PhRMA Sept 10, 2015 IMPLICATION Low production volumes Flexible batch size to address significant growth in demand as additional indications are added Requires rapid commercialization Often short clinics Rapidly changing clinic

20 Why Not Stay Batch for low Volume? Assume 5 kg is minimum CM lot size (this # drops every year) ½ cu ft (15 liter) tumble bin Probably still too low to not require scale-up Could do semi-batch and automate filling / dispensing to enable scale-out Still have the segregation / hot-spots / flyers / tails concerns of batch processes.

21 Summary Lilly Journey Comparing risks in continuous with batch manufacturing Reducing API consumption in mid and late stage development Quality by control leveraging a variety of different types of controls to assure quality Low value, high volume vs. High value, low volume strategy