Integrated Continuous B iomanufacturing: Quality and Regulatory C onsiderations

1. Integrated Continuous Biomanufacturing: Quality and Regulatory Considerations Chantal CazeaultExecutive Director, Product Quality Integrated Continuous Biomanufacturing, Castelldefels, Spain October 20-24, 2013

2. Presentation Outline • Drivers for Innovation • Enablers of Continuous Manufacturing • Integrated Continuous Manufacturing: Key Quality and Regulatory Considerations • Continuous Manufacturing and Single-use Technologies: Opportunities and Challenges • Conclusion .

3. Innovation in Manufacturing: What are the Drivers from a Regulator’s Perspective? • Speed to clinic/market, especially in areas of unmet medical needs • Cost of drugs • Manufacturing flexibility (maintaining production capacity) • Increased focus on Product Quality and Quality by Design/PAT • e.g. FDA’s 2011 Strategic Plan Overarching goal is patient safety, uninterrupted drug supply and lowering drug costs.

4. Enablers of Continuous Manufacturing • Increased use of disposable, single-use technologies • Bioreactors • Ready-to-use chromatography columns • Viral filters • TFF • Increased titers using improved media formulations, feed strategies, higher producing clones, etc. • New recovery/purification methods being developed (moving bed and counter current chromatography) • Control system sophistication

5. Enablers of Continuous Manufacturing • Innovation in real-time measurement and control technologies • Deeper process knowledge; just-in-time product disposition • Increased interest in continuous manufacturing process from beginning to end: less equipment, smaller portable equipment, fewer steps, faster cycle times • FDA looking at effects of continuous manufacturing on product quality (2011 Strategic Plan)

6. Continuous Manufacturing: Key Quality and Regulatory Considerations • No guidance specific to continuous manufacturing • Strong encouragement from regulators to use QbD principles. Why? • Provides a more systematic approach to product development, based on sound science, Quality Risk Management, patient safety • Emphasizes product/process understanding and process control • It all comes down to understanding your product and establishing a commercial manufacturing process capable of consistently producing a product of the intended quality • How? • Identifying CQAs of the product • Identifying potential sources that lead to variability in the CQAs • Establishing a control strategy to ensure that the CQAs remain consistent and within acceptable limits over the lifecycle of the product

7. Operational Concepts will Challenge Existing Paradigms • Manufacturing facilities with modular design: standardized, portable and flexible designs • Modular/reconfigurable manufacturing systems • Need for process oversight due to reduced segregation (i.e. ballroom) • Minimally disruptive reconfiguration for NPI • Area classification • Increased use of closed systems • Concurrent Multi-product Production • Segregation through technology • Predominantly single-use systems upstream • Limited CIP/SIP

8. Operational Concepts will Challenge Existing Paradigms • Reduced size and volume of equipment • “Scale-up” by adding more production lines or extending time as opposed to increasing size of bioreactor • Continuous Harvesting and Purification • Sampling: finding the right balance in sampling frequency, on-line/in-line monitoring, rapid assays • Reduced residence time and process holds • Less opportunity for bioburden proliferation

9. Connected Purification Process Reduces the Need for Large Hold Tanks FVIP Feed Column 3 Clean Column 3 Wash Column 3 Load Column 3 Equil Surge Tank CEX FT Column 2 Load Column 2 Wash Column 2 Clean Column 2 Elution FT – Viral Filtration Elapsed Time: 1.5-4 hrs. Elapsed Time: 3-7 hrs. Overall Time with Cleaning UF/DF Ultrafiltration Diafiltration Total Process Time: ~10-14 hrs. Elapsed Time: 7-11 hrs Viral Filtration

10. Continuous Manufacturing: Key Quality and Regulatory Considerations • Continuous processes have to be validated to demonstrate that the process is consistently making product of intended quality • Steady-state: Is the process stable? • Control strategy: Continuous processes are more complex to design and require a higher level of control • Continuous process verification • Continuous fermentation: • Typically done at smaller scale but longer culture time • Focus on in vitro cell age (genetic stability), end-of-production cells (susceptibility to contamination, viral safety) • Use of physical, analytical barriers for prevention and early detection of contamination (e.g. HTST, PCR)

11. Continuous Manufacturing: Key Quality and Regulatory Considerations • Implementation of a fully continuous process: • Enhanced process understanding, including raw material variability • Understanding of potential interactions between unit operations • Need to build in flexibility; • If a unit operation fails, does the entire process go down? • Process upset conditions: do you discard the portion of the batch affected by the upset? • Can process adjustments be made real-time? • Challenge is achieving control of the overall integrated process not just by unit operations • Batch definition

12. Implications of PAT strategy • Integration of operational quality control with manufacturing • Facility design should allow for at-line testing • Scaling data-based decision making capabilities • PAT will increase relevant, actionable data acquired • Need for sophisticated data management systems • Increasing real-time quality assurance on the floor

13. Single-use Technologies: Opportunities and Challenges • Innovation and improvements in single-use technology have led to broader acceptance by industry and regulators • Single-use technology is no longer limited to upstream processing • Emergence of ready-to-use, disposable purification systems • Overall robustness and functionality of single-use systems has improved

14. Single-use Technologies: Opportunities and Challenges • Single-use technology offers many advantages over traditional stainless steel systems such as: • Increased flexibility • Quicker turnaround between batches, campaigns • Reduced cleaning burden (CIP, SIP, cleaning validation) • Reduced risk of cross-contamination between products (multi-use facilities) • Reduced risk of contamination and less down time • Improved sterile connections and sample handling

15. Single-use Technologies: Opportunities and Challenges • The main concerns over the use of single-use technology pertain to extractables/leachables and vendor dependency • More information is now available on extractables and leachables to support risk assessments • Many disposables are now available from multiple vendors • Single-use systems from different vendors are not necessarily interchangeable; still have to demonstrate fitness-for-use • Lot to lot variability should also be assessed

16. Comprehensive Leachables and Extractables Strategy Component Evaluation Process Assessment Analytical Confirmation • L&E profile major component of vendor selection • Vendor documentation evaluation • Compiled in format of risk assessment for many factors: • Temperature • Exposure duration • Surface area • Process step • Total L&E calculated based on cumulative assessment • Clearances for specific compounds of concern determined • Spiking studies to confirm clearance capability • Testing at full scale to confirm clearance Summary Report

17. Conclusion • Continuous manufacturing clearly presents significant opportunities, not only from a business perspective but from a regulatory compliance perspective. • Product, process understanding and a robust control strategy will be key to successful implementations. • Regulators are open to new approaches in manufacturing and control strategies, however, there is a lack of experience with continuous manufacturing models in biotech. It will be critical to engage regulators early and keep an open dialogue during the development phase.

18. Acknowledgments • Tony Mire-Sluis • Darrin Cowley • Barry Cherney • Brandon Persinger • Emanuela Lacana • Mark Heintzelman