Quality Risk Assessment: a Lifecycle Approach in Evaluating Quality Attributes for Bioproducts 2009 MBSW, May Suntara Cahya, PhD

Outline “Biomolecule Diversity” Molecule Risk Assessments Risk Scoring Relation with CQA’s Concluding Remarks Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company 2

Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company Gemzar MW 300 Da Insulin MW 5808 Da MAb MW 150 kDa Fusion Molecule MW 65kDa Molecular Size & Higher Order Structure 3

Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company Potential to Impact: Manufacturing consistency (lot-to- lot variability) Stability Toxicity Efficacy Safety Immunogenicity PK/PD Translational Events Splicing Frame shifts Intron read-through Post-Translational Modifications Glycosylation (N- & O-linked) –Site occupancy –Glycan structures Phosphorylation Chemical & Enzymatic Modifications Aggregation Proteolytic clipping Deamidation Isomerization Oxidation Glycation Pyruvylation Pyroglutamatation CM&C Toxicology Clinical ADME Molecular Heterogeneity 4

Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company Monoclonal Antibody Variants Predominant pyroglutamation of Gln1 Predominant loss of Lys447 Heterogeneous glycosylation of Asn297 Partial oxidation of Met252 Partial glycation of several lysines Partial succinimide & isomerization of Asp56 (CDR) Partial deamidation of Asn315, Asn384 & Asn389 Partial succinimide & isomerization of Asp401 Partial loss of Gln1 Incomplete disulfide Partial cleavage at Pro329-Ser330 (2x2x2x2 2 x2x8x2x3 3 x2x2x2) 2 /2 = >10 10 variants 5

Molecule Risk Assessments Complexity in managing the risks (Safety & Efficacy) Impact on control strategies Had historically been part of dev process –Assessments more subjective –Opinions could vary depending on the individuals Motivation:  More standard & objective ways of performing the risk assessment Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company 6

Molecule Risk Assessments Motivation cont’d Consistent approach that works for multiple molecules (Antibodies, Fusion Proteins, Peptides) Phase appropriate assessments Documentations at key points during molecule development Consistent with ICH guidance on risk assessments and QbD (ICH Q9 and ICH Q8) Focused on molecule quality attributes and analytical control strategy Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company 7

Risk Components Broken down into three risk components Severity : The impact of the particular quality attribute on the pharmacological properties of the biomolecule, including toxicity, safety, efficacy, PK/PD profile, and immunogenicity – Location of modification – is it in a region critical to molecule’s activity – Documented evidence of impact Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company 8

Risk Components Detectability : The capability of the analytical methods to detect and quantify the particular quality attribute (i.e., specific vs. non-specific method) as well as the use of the method in the analytical control strategy (i.e., routine vs. non-routine method) – Routine method developed – Non-routine developed – Attribute is not currently monitored Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company 9

Risk Components Occurrence : The likelihood of the particular quality attribute to exceed a specified level of concern (“Exposure Limit”), based upon API and drug product manufacturing process variability as well as the stability of the API and drug product throughout their respective shelf-lives – Stage of development – Platform modification – Data that is available – Growth on stability Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company 10

Risk Scoring Each risk component has different levels of risk scoring Overall risk scored based on Risk Priority Number (RPN) = Severity X Occurrence X Detectability Flowcharts to facilitate scoring evaluation Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company 11

Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company Risk Assessment Flow Chart - Severity 12

Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company Detectability “1”: Modification is detected and accurately quantified by a specific, routine test method OR Modification is detected by a non-specific, routine test method AND accurately quantified by a specific, non-routine test method, “3”: Modification is detected by a non-specific, routine method OR Modification is detected and accurately quantified by a specific, non- routine test method “9”: Appropriate methods are not currently available or used for detection and accurate quantification of the modification. 13

Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company Occurrence – Part 1 14

Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company Occurrence – Qualitative Non- Stability 15

Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company Occurrence – Qualitative Stability 16

Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company Occurrence – Quantitative 17

Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company k = 0.5 k = 0.8 Occurrence – Quantitative n<6 Init Shelf-life Limit U “Nominal” x x x Growth over shelf-life 18

Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company Occurrence – Quantitative n≥6 Init Shelf-life Limit U x x x x x x Growth over shelf-life 19

Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company RPN Scoring RPN = Severity x Occurrence x Detectability Overall risk: High Two components are rated high Minimum RPN = 63 Overall risk: Low Method exists AND either severity/occurrence rated low Highest RPN = 27 20

Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company RPN Scoring Degree of “Harm” Chance of “Harm” 21

Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company Relation with CQA’s Tool to assess criticality of molecule attributes and identify potential CQA’s List of potential CQA’s are broader than just molecule modifications Some quality attributes are likely to always be “critical” due to their known potential to impact patient safety and product efficacy. Examples Include: Host Cell Proteins, DNA, Endotoxin, Bioburden, Sterility, Viruses, Content/Protein Concentration, etc 22

Concluding Remarks Risk Mitigations Gaining additional information (more data: literature, in-vivo, additional lots, etc) Better detection methods Improved mfg process (level and/or variability) Improved analytical method precision “Exposure limit” vs Specification limit Commercial specifications has been historically set based on process capability, may be tighter than the exposure limit May re-assess the occurrence risk  risk of OOS Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company 23

Concluding Remarks “Lifecycle” approach Deliverables at gate reviews throughout development cycle Documentations at key gate reviews Guidance on roles and responsibilities: RACI diagram Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company 24

Summary The approach provides the basic framework to perform risk assessment of biomolecules Consistency and objectivity across molecules Phase appropriate evaluations Continual revisions are expected as more experience is gained overtime Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company 25

Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company Risk Assessment Team Mike DeFelippis Bryan Harmon Cathy Srebalus Barnes Sarah Demmon Suntara Cahya 26

Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company Acknowledgments Susan JanesMatt Hilton Melody GossageBruce Meiklejohn Juliana KretsingerJill Olinger Mandy DorseyOwen Van Cauwenberghe Jeff SchwartzenhauerKristi Griffiths Kamal EgodageGary Sullivan Sacha Storms Chi Nguyen Agatha Feltus 27

Questions? Suntara Cahya, 2009 MBSWCompany Confidential Copyright © 2009 Eli Lilly and Company 28