CMO-Innovator partnerships to improve Quality and reduce Risk.

Transcription

1 Pharma&Biotech CMO-Innovator partnerships to improve Quality and reduce Risk. CASSS - CMC Strategy Forum, Gaithersburg, 21 st July 2014 Jesús Zurdo, Lonza Pharma&Biotech

2 Disclaimer Certain matters discussed in this presentation may constitute forward-looking statements. These statements are based on current expectations and estimates of Lonza Group Ltd, although Lonza Group Ltd can give no assurance that these expectations and estimates will be achieved. The actual results may differ materially in the future from the forward-looking statements included in this presentation due to various factors. Furthermore, Lonza Group Ltd has no obligation to update the statements contained in this presentation. Statements included in this presentation do not necessarily reflect Lonza Group Ltd s views on the subject presented Note: All slides are incomplete without verbal comments. 2 Aug-14

3 Mission Impossible: How (not-to) develop a new drug DISCOVERY MANUFACTURING CLINIC The Result

4 The Almost Impossible Business of Developing Drugs: Attrition Evolution Pammolli et al. (2011) Nature Rev Drug Dis 10, Mounting Pressure from Payers Of all registered anti-cancer drugs evaluated by NICE 43% were approved in 2012 vs 65% in (0% approved in 2013, Jan-Dec 6 agents)* * NICE: UK National Centre for Health & Clinical Excellence

5 Big Quality as a Continuum: PLM, QbD and other buzzwords. Retirement Follow-on New formulations Etc. Design Concept Target validation Drug design / discovery Development Prototype optimisation Manufacturing devel Clinical validation Efficacy / safety Utilisation Disease condition Regime / dosing Patient segmentation Commercialisation Marketing Sales Distribution Reimbursement Manufacturing Supply chain Costs Quality Regulatory

6 The Quality Trilogy (Juran) Quality Planning [QbD*] Quality Control Quality Improvement Establish quality goals Evaluate actual performance Prove the need Identify who the customers are Determine the needs of the customers Develop product features that respond to customers' needs Develop processes able to produce the product features Establish process controls; transfer the plans to the operating forces Compare actual performance with quality goals Act on the difference Establish the infrastructure Identify the improvement project Establish project teams Provide the teams with resources, training and motivation to: Diagnose the causes Stimulate remedies Establish controls to hold the gains Juran, J.M. (1989). The Quality Trilogy: A Universal Approach to Managing for Quality 6 Aug-14

7 Juran s Big Q : A re-appraisal Topic Content 'small Q' Content 'Big Q' Expansion 'Big Q*' (Pharma) Products Manufactured goods All products, goods and services, whether for sale or not Processes Processes directly related to manufacture of goods All process manufacturing support; business, etc. From 'product' design to healthcare provision (incl. quality in supply chain) Industries Manufacturing All industries, manufacturing, service, government, etc., whether for profit or not From discovery, to manufacturing, distribution, administration, healthcare provision, disease and patient management, etc. Quality is viewed as: A technological problem A business problem An 'industry' problem Customer Clients who buy the products All who are affected, external and internal How to think about quality Based on culture of functional departments Based on the 'universal trilogy' of quality (planning, control & improvement) Quality goals are included: Among factory goals In company business plan Cost of poor quality Evaluation of quality is based mainly on: Costs associated with deficient manufactured goods Conformance to factory specifications, procedures, standards All costs that would disappear if everything were perfect Responsiveness to customer needs (current and future) Patients, payers, clinicians, contractors, health commissioners, etc. Costs related to product failure no longer absorbed in drug prices Responsiveness to medical and societal needs Improvement is directed at: Departmental performance Company performance Healthcare performance & sustainability Training in managing for Concentrated in the quality Companywide quality is: department Coordination is by: the quality manager A quality council of upper managers Modified from: Planning for Quality, 2d ed. (1990). Juran Institute Inc. Wilton, CT, pp 1-12 Company and Partners

8 Big Quality* in Biopharma: Some Challenges Processes Old & Rigid: Not easy to modify / optimize once approved Unpredictable: "The product is the process Long & Cumbersome: Resistance to change Slow in adopting innovation Not fit for purpose: Commercial process for prototype testing & validation Hierarchical & linear development: Lack of a holistic approach to development Silos Fragmented Disconnection discovery-development: Product / process interdependence [External CROs / CMOs] 8 Aug-14

9 Partnerships for Quality* Integrating Supply Chain & Workflows 1. Early De-risking (Bridging Discovery & Development) Manufacturability Productivity Stability Formulability 2. Fast Transition to Clinic (Prototype Validation) DISCOVERY Developability: Risk Assessment / Product Design Safety Immunogenicity Immunotoxicology Simpler Process Development DEVELOPMENT Effectiveness Biological Activity RoA & Delivery Pharmacology Innovator CMO / CRO 3. Delivery (Design Drug, not just API) PoC IN HUMAN Admin / Pharmacology Patients 9 Aug-14

10 The Importance of Formulation & Delivery

11 Concentration (mg/ml) No. Registrations Concentration (mg/ml) Subcutaneous delivery: Aggregation & Viscosity Challenges i.v. s.c./i.m A C i.v. B Novel formulations: - Roche IBM / Halozyme - Controlled release formulations 50 0 Formulation an IP / marketing strategy - Follow on / biobetters (biosimilars?) - Tracing the footsteps of insulin

12 The Payers Perspective Patient self-administration as the Holy Grail Treatment of Children with Crohn Disease Home infliximab infusion program [Avg Costs treatment of patient (50Kg)] Home Infusion Infliximab Nursing services / care Supplies Laboratory samples Duration of infusion Total avg. cost $3,744 Hospital Infusion Infliximab Nursing services / care Supplies Laboratory samples Length of hospitalization Physician visit Total avg. cost $7,776 $ 4,032 Savings Strategies to improve delivery s.c. / i.m. formulations (formulability) controlled release / extended half-life Source: Condino et al. (2005) J Pediatr Gastroenterol Nutr, 40: Aug-14

13 Developability: Starting with the end in mind Beyond ICH Q8: Bridging Product & Process Design

14 The 3 Pillars of Developability Developability Manufacturability Productivity Quality ochemical stability (e.g. oxidation, degradation) ophysical stability (aggregation) opost Translational Modifications Formulability Safety Immunogenicity ot-cell epitopes ocellular responses ImmunoToxicology ocytokine release syndrome Specificity ooff-target interactions Pharmacology & Mode of Action PK/PD - Bioavailability odelivery / RoA ohalf life oformulability Mode of Action oimmunomodulation odosing & patient segmentation oefficacy

15 Lead Selection & Design: Developability: Aggregation & Stability

16 Developability Mindset: HT, Low Cost, Qualitative Information 1- Computational Tools 2- Adapted Analytics Reduce material fold Representative product: Pooled / Transient SSI Proxy / Surrogate analytics Yes-No / Better-Worse Increase throughput fold 16 Aug-14

17 Developability Risk Assessment & Mitigation Strategy In Silico Analysis Risk Identification Potential Problem Highlighted Aggregation Potential Deamidation, PTM, clipping Risks Early Stage Intervention Select Alternative Sequence Select Alternative Sequence Reengineering Reengineering Late Stage Intervention Process Optimisation Process Optimisation 17 Aug-14

18 Risk Assessment. Early QbD Application of FME(C)A to Developability Risk Deamidation VH CDR3 Deamidation CH2 Oxidation VL FW2 Aggregation Potential Effects Loss of activity, degradation, aggregation Different charged species, potential degradation Loss of activity, aggregation Loss of activity, process yields, failing specifications, safety / immunogenicity Severity (S) Occurrence * (O) High Risk to Process Low Risk to Process Low Risk to Process High Risk to Process Criticality Risk Risk Mitigation Action Required Assessing Criticality = Prob. Occurrence x Impact Re-engineer product Additional analytics detect / mitigate excursions that could affect activity. Etc Re-engineer product Screen larger number of clones during CLC Introduce additional purification steps to remove aggregates Etc Risk Parameters: 1 = Low risk; 5 = Intermediate risk; 10 = High risk * Occurrence here equates to Probability of occurrence as predicted (in silico)

19 Reengineering mabs to Improve Developability. A Case Study

20 Immunogenicity & Immunotoxicology

21 Epibase in silico immunoprofiling Method Predictive tool driven by structural bioinformatics in conjunction with experimental data Peptide/HLA binding necessary condition for T-cell activation Uses structural characteristics of the HLA receptor Statistical layer based on experimentally determined binding affinities of peptides Usage Ranking of lead candidates Lead characterisation

22 In Vitro Immunogenicity Assessment Test Product Human PBMC B-cell Receptor repertoire B cell epitopes T cell epitopes HLA allotypes (MHC class I/II) Formulation Contaminants Aggregates T-Cell Receptor repertoire (CD4/CD8) Pre-existing memory In Vitro assay to assess the immunogenicity of Biotherapeutics & Vaccines

23 Viventia Case Study: De-immunization of VB6-845 Objective Minimize the potential immunogenicity risk of the fusion protein VB6-845 by de-immunizing the Fab portion In silico De-immunization Screening for T-cell epitopes using Epibase Antibody structure modeling Substitutions to eliminate T-cell epitopes based on structure integrity In Vitro Verification & Testing of De-immunized Protein Screening for T-helper cell responses using PBMCs from healthy donors Individual and population responses 23 Aug-14

24 # responsive donors SI>2 Viventia Case Study: In vitro Testing Single Donor and Population Level De-immunized Fab shows a substantial and significant reduction in its ability to raise T-cell responses Single Donor In vitro testing: # positive donors (53 tested) Population Relative Response within the test population WT Fab De-immunized Fab WT Fab De-immunized Fab 24 Aug-14

25 Maximizing Success Ex-vivo Immunotoxicity & Immunomodulation Challenge: Human immunopharmacology cannot be replicated properly in animal models Ex-vivo systems to assess some of the aspects of immunotoxicology of therapeutic candidates Immunotoxicity / hypersensitivity / Inflammation Modulation of immune response Cytokine Release Syndrome (CRS) modelling Clinical trial protocols changed after Anti-CD28 superagonistic antibody TGN1412 Modelling a (cytokine) storm in a test tube Possibility of testing different genetic make-ups / disease background HLA allotypes Ethnicity Disease background Dosage Paul Ehrlich Institute 25 Aug-14

26 Time is GOLD

27 The Future of Process Development: Prototype Processes for True Translational Medicine? Present Standard Process Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year STANDARD PROCESS / GMP mat TOX PHASE 1 PHASE 2 PHASE 3 New Processes / SSI ABRIDGED PROCESS TOX PHASE 1 PHASE 2 PHASE 3 Two Tier process: Prototype & Commercial Future Non Clonal TOX PHASE 1 PHASE 2 PHASE 3 Clonal Proc. Dev. Feedback Loop (back to bench) 27 Aug-14

28 A new paradigm for biopharmaceutical development

29 Summary Research & Development working in Partnership Not just activity / titre (to select / optimize lead) Introduce Quality in design / screening. Design product for success!! Less of the right (& clean) product is better Facing the risk early on Killing the trolls while they re still small (Fail early) Or rather select / design Quality Lead Candidates Reduce attrition in later preclinical and clinical development Delivering biologics is more than simply injecting them!! Keep in mind the final treatment at the outset Biology of disease P 3 : Payers!! HC Professionals and Patients Get quickly to the patient Translational medicine needs to be facilitated Current processes too long D R 29 Aug-14

30 Any Questions? Zurdo, J. (2013) Pharmaceutical Bioprocessing. 1(1), Zurdo, J. (2013) European Biopharmaceutical Review. 195, The Cell Culture Dish Blog 30 Aug-14