Biotherapeutic product characterization to support accelerated process development Kyle Zingaro, Ph.D. Alexion Pharmaceuticals 2015 Biomanufacturing Technology Summit June 25, 2015
Our Mission: Treating Patients with Severe & Devastating Diseases Alexion is focused on developing lifetransforming treatments for patients with severe and life-threatening diseases Severe Transformative Clinical Benefit Devastating Life-Threatening No Effective Treatments 2
Toronto, Canada Brussels, Belgium Government Affairs, EMEA Stockholm, Sweden Nordic Tokyo, Japan Japan Regional HQ Smithfield, RI Manufacturing Operations London, UK Munich, Germany Cambridge, MA Translational Medicine Group Cheshire, CT Global Headquarters North America Regional HQ Washington DC Global Government Affairs Dublin, Ireland Global Supply Chain and Distribution Paris, France European Service Center Barcelona, Spain Moscow, Russia Lausanne, Switzerland EMEA Operations Center Milan, Italy Istanbul, Turkey Shanghai, China Miami, FL Latin America Regional HQ Dubai, UAE Middle East Operations Mumbai, India Global Business Services Sydney, Australia Asia-Pacific Regional HQ Mexico City, Mexico Bogotá, Colombia São Paulo, Brazil Buenos Aires, Argentina Our Global Footprint ~2,400 dedicated employees serving patients in almost 50 countries 3
Biologic Process Development Connecting process inputs with product output
Development of a Biologic Manufacturing Process The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. -ICH Guideline Q8 (R2) 5
Process Development Goals Definition and characterization of a robust process to generate quality therapeutic products Assessment of risk in design of new processes and change to existing processes Implementation of new technologies to improve those processes Support of clinical and commercial manufacturing efforts 6
Analytical Method Lifecycle Roadmap
Development and Characterization: Who supports whom? Clone selection, process definition, and process changes can not happen without analytical data Analytical methods exist to support manufacturing process definition and operation http://programmedevelopment.com/what-is-ability- /ability-and-methods 8
Defining a Biologic Fingerprint What level of characterization defines a product?
Critical Quality Attributes (CQA) A CQA is a physical, chemical, biological, or microbiological property that should be within an appropriate limit, range, or distribution to ensure the desired product quality. -ICH Q8 (R2) Biologics Include primary, secondary, tertiary, and quaternary protein structure and post-translational modifications 10
A Biological Fingerprint Primary and higher order structure with posttranslational and chemical modifications which uniquely describe a protein Fingerprint-like: integrated, multi-parameter approaches that are extremely sensitive in identifying analytical differences 1 No clear consensus definition Challenged by constantly evolving analytical methods https://www.mdsp.org/organization/fieldoperationsbureau/barracks/barracknro ckville/fingerprintingservices.aspx 1 Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product, FDA Guidance for Industry, 2014 11
Biologic Fingerprints & Innovator Companies Clearer connections between biophysical quality and clinical safety and efficacy Development of robust processes requires an understanding of the impact of process inputs on the biologic fingerprint Implementation of process changes require demonstration of comparability in critical quality attributes 12
Approval of Zarxio (Neupogen Biosimilar) methionyl-granulocyte Colony Stimulating Factor (G-CSF) http://www.fda.gov/downloads/advisorycommittees/committee smeetingmaterials/drugs/oncologicdrugsadvisorycommittee/u CM428780.pdf 13
Clinical Phase Relevant Testing & Characterization How much do we learn as a product & process develop?
When do we really need to know all that? Process improvement and optimization is completed throughout clinical development timeframes Process knowledge is expected to be limited for early filings Complete information must be available for commercial filing Phase 1 Phase 2 Phase 3 Approval Commercial Product 15
Product Safety and Efficacy Studies Different phases of clinical trials require different standards: Phase 1 (Safety) Simple efficacy assay (eg. ELISA), limited method understanding, and method qualification Phase 3 (Efficacy) Established and well characterized methods, method validation, cell-based efficacy assays Method understanding improves throughout development process 16
Process Changes Manufacturing process changes will happen! Clinical Manufacturing vs. Commercial Manufacturing Changes must produce highly similar material Clinical Development Significant Changes Approved Application Major, Moderate, or Minor Changes 17
Accelerated Process Development Faster from clinic to market
Why do we need to develop processes faster? Patient Benefit Provide beneficial therapies to patients faster Regulatory Changes Breakthrough designation shortens clinical and CMC timelines Commercial Benefits 19
Isn t faster a good thing? All stages of process and method development still need to be completed We have less time to develop and less time to respond to regulatory inquiries How can we get it all done? 20
Strategies for Faster CMC Development Reconciling shorter timelines and better characterization
Management Strategies Detailed Quality Target Product Profile (QTPP) Cross-Functional Communication Clinical and CMC Collaboration Strategic Planning Templates 22
Technical Strategies Predictive Modeling Process and product predictions throughout development and product lifecycle Real Time Monitoring More data produced at and online Platform Processes 23
Platform Processes Defining an evolving standard
Why do we need a platform? Data derived from relevant prior knowledge, including platform manufacturing, can be leveraged to support development of the commercial process and expedite scientific understanding. -ICH Guideline Q11 25
What makes a good platform? Quality Robustness Raw Material Supply Chain Scalability Productivity Cost Effective Quality Analytics Purification Cell Bank Production Bioreactor Seed Train 26
Why do we change a platform process? Technology Continues to Evolve Quality Robustness Productivity Patient Safety Removal of animal derived components Raw Materials Biomanufacturing Flexibility, Bio-G, Bioproduction Group, http://www.bio-g.com/whitepapers/download/3 27
How & when do we change a platform process? Incremental improvement can be identified but are difficult to implement Step-wise improvements when sufficient progress has been made in a new platform What is the clinical or commercial need? Platform qualification evaluations using our biologic fingerprint How close is close enough? 28
Conclusions and Future Challenges
Conclusions Process development timelines are always shortening CMC development efforts including process and method development need to keep pace Both method and process should be expected to evolve to meet the clinical and commercial applications of a product 30
Future Challenges Analytical and manufacturing technologies continue to evolve Standards and expectations will evolve with those technologies Timelines will always be shortened where possible while the expectations do not change Organization, communication, and efficient management are required to meet those expectations 31
Acknowledgements Process Development Pratik Jaluria Hunter Malanson Matt Rimbey Ina Alickolli Krishanu Mathur Loray Paul Luke Loftus Analytical Sciences Zhenyu Gu & Jack Yu Product Characterization Adriana Kita 32