Best Practices for Selection and Oversight of CMOs for Manufacturing of Potent Products Polina Rapoport, M.S., MBA Principal Site Manager External Manufacturing Collaborations Genentech, Member of the Roche Group
Topics Roche/Genentech processes for CMO selection and management Challenges and best practices in managing a potent CMO supply chain What about in-licensed products? Challenges of managing SHE gaps with CMOs inherited through in-license and acquisitions Case Studies
Roche Facts Founded in 1896 Headquartered in Basel, Switzerland Founding families still hold majority stake 88,500 employees worldwide Active in 150 countries and on every continent Global Roche Group 2014 sales: 47.5 billion Swiss Francs World s largest biotech company Top five global leader in pharmaceuticals Number one leader in in vitro diagnostics Genentech Facts Founded in 1976 Became a member of the Roche Group in March 2009 Headquartered in South San Francisco, California Approximately 14,000 employees Headquarters for all Roche pharmaceutical operations in the U.S. - 35 medicines approved for people with various serious or life-threatening diseases - US Pharmaceutical 2014 sales: $17.4 billion* - Genentech s Research and Early Development group (gred) has more than 30 potential new medicines in development
Roche/Genentech Pipeline Commercial: We make 35 medicines for people with serious diseases. Development Pipeline Phase I (33 NMEs + 11 AIs) Phase II (9 NMEs + 21 Als) Phase III (9 NMEs + 21AIs) Registration (1 NME + 3 Ais*) Cancer 19 NMEs, 10 Ais Immunology 2 NMEs Infectious diseases 3 NMEs Cardiometabolism 1 NME Neuroscience 7 NMEs Ophthalmology 1 NME, 1 AI Cancer 10 NMEs, 9 Ais Immunology 1 NME, 3 Ais Infectious diseases 4 NMEs Cardiometabolism 2 NMEs Neuroscience 6 NMEs Cancer 3 NMEs, 18 Ais Immunology 3 NMEs, 2 Ais Neuroscience 2 NMEs, 1 AI Ophthalmology 1 NME Cancer 1 NME (US) (cobimetinib + Zeloboraf, metastatic melanoma) 3 AIs* (ex-us) (MabThera subcutaneous, CLL, Avastin, recurrent cervical cancer, Perjeta, HER2+ BC Neoadj) NME: New Molecular Entity, or potential new medicines AI: Additional Indication, or new use for a medicine
External Manufacturing Reliably deliver the pipeline and ensure uninterrupted supply. Provide strategic, outsourced manufacturing solutions, delivering quality medicines to patients by enabling network flexibility, broadening technical capabilities, and minimizing risk. Minimize Risk Capacity Strategic, Outsourced Manufacturing Solutions Financial Management An integral part of the operations strategy Technology Access Network Flexibility
External Manufacturing Scope Broad coverage of products; supported across the life cycle Development Commercial Early Stage Late Stage Drug Substance Drug Product Warehouse and Distribution Clinical Packaging and Distribution Local CMOs Redressing Suppliers Biologics Small Molecules Device & Combination Products ADCs
CMO Sites Supporting Drug Manufacturing For the commercial market and the development pipeline
CMO Lifecycle Business Processes Managing CMOs over the lifecycle of the partnership Buy Decision Category Management Select Implement Manage Decommission Site Selected and Contract Signed Project Implementation Supply to Patients and Performance Management Decommissioning Complete Risk Management Multi function teams enable success
CMO Selection Basis Audits: SHE Quality/GMP Roche SHE Requirements GMP/Quality Business and Technical Compound & Process aspects Passing Roche SHE audit is often a requirement to continue with further evaluation CMO Fit for Roche Network or Specific Project
SHE and Quality Audits Expectations for CMO Audit scheduled and led by Roche SHE and GMP Compliance groups These audits are scheduled separately Focus on CMO compliance with Roche SHE and QA requirements CMO s function and its programs Industrial hygiene capabilities Ø Hazard assessment process and HHC evaluation for client material Ø Control must be supported by air monitoring data. Ø Exposure control methodologies Ø Engineering controls Ø Personal Protective Equipment (PPE) - CMO Cleaning and Cleaning Verification approach - CMO cross-contamination prevention controls
Roche Directives for Safety and Environmental Protection Directive K1: Performing a Workplace Health Risk Assessment Risk = Hazard X Exposure Directive K15: Social and Environmental Performance Evaluation of Third Party Manufacturers and Service Providers The overall aim is to ensure that third parties doing business with Roche meet not only all relevant legal requirements, but Roche standards as well Directives K1 and K15 provide Roche requirements of CMOs for containment during manufacture and impact CMO selection decisions
Roche Health Hazard Category (HHC) As Basis For Containment Requirements HHC = Health Hazard Category ; ioel = internal Occupational Exposure Limit ; ADE = Acceptable Daily Exposure Roche industrial hygiene committee (RIHC) assigns HHC based on available data which is often limited for new compounds entering clinical space For new compounds where OEL is not defined, must control to the bottom of the band in each category
SHE Audits Can Not Give Blanket Approval Audits evaluate equipment and containment with respect to a specific molecule Process, scale, drug load (in the case of DP) can impact suitability from SHE perspective Highly potent molecules need to be reviewed and evaluated against existing equipment and facility audits before the they are placed at the site Frequent and well coordinated communication between CMO management group and Roche SHE is required to ensure that projects are placed at the CMOs in compliance with Roche directive requirements
Client vs CMO practices Reliance on Engineering controls vs PPE Differences in assessment from Client toxicologist vs CMO toxicologist ADE of client A product, made immediately before client B product,..etc What is the responsibility of the CMO to harmonize ADEs approaches of client A and B etc. to get consistent cleaning approach Ø Roche position: Ø Ø Ø Notify CMO of exposure and cleaning limit that must be met Up to the CMO what engineering controls are used to achieve that exposure limit. Engineering controls are to be confirmed by air monitoring data. Adequacy of product change cleaning procedures is to be confirmed with data from suitable analytical methods.
Global Organization Impact Roche and Genentech are a global organization which means multiple external collaboration and sourcing groups are working with overlapping CMO networks Global Category Management Commercial External Collaborations Clinical External Collaborations Non-GMP Sourcing Need to ensure a single voice when communicating Roche requirements to CMOs
SHE Audit and Follow-up Management Process To PTDMX SPOC and Site Managers CMO Questionnaire (template and info evaluation Audit scheduling Audit memos CMO PTDMX Site Manager Group SHE Auditor CMO PTDMX Site Manager PTDMX SPOC SHE SPOC Group SHE Auditor CMO PTDMX Site Manager Group SHE Auditor To CMOs Questionnaires to CMO Audit scheduling Audit memo communication Follow-up on audit observations: closure of compliance gaps
CMO Joint Governance Structure ESC: Executive Steering Committee Flexible and collaborative framework and process Levels utilized based on project and/or CMO need JSC: Joint Steering Committee Joint Leaders Decisions Escalation Process ESC and/or JSC implemented less frequently or not at all if: early phase low complexity, volume and/ or value CMOs JMT: Joint Management Team Recommendations Accelerates problem-solving & conflict resolution Empowers team to drive program forward Minimizes surprises across the collaboration Sub-Teams Quality (QA) Technical Engineering Leaders Joint Team Leaders Leaders Leaders Core Team Extended Team (ad hoc) Leaders Leaders Roche/GNE representation ESC = Head of OU or Function Head JSC = Function Head JMT = CMO Site Managers Supply Chain QC, etc. Project and management teams Milestone/stage review processes
What About CMOs Inherited Through Acquisition?
What About CMOs Inherited Through Acquisition? Genentech has approximately 50 active collaborations with companies and institutions from around the world. In 2014, Genentech signed 55 agreements, including: CMOs are often inherited as part of supply chain during acquisitions, in-license deals, and collaborations Often not enough flexibility in the timeline to transfer to pre-approved CMOs in the network CMOs not familiar with Roche requirements and often not in compliance Compounds are often not assigned HHC prior to acquisition or basis for assignment of HHC are different from Roche practice Gaps in SHE compliance need to be managed while maintaining supply and project timelines
Case Study #1 Acquisition with two projects and a network of 4 CMOs of which 3 are not part of Roche clinical CMO network Both molecules classified by Roche as HHC 3A, containment must be < 1 μg/m 3 API manufacturing sites are in compliance with Roche requirements at the current scale but not for scale-up DP manufacturing CMOs are not in compliance with Roche requirements
Case Study #2 In-license of a new molecule where all clinical supply manufacturing is at a single CMO (both API and DP) Roche assigned HHC 2, but CMO used is not in compliance to meet Roche containment requirements even for this category Immediate API and DP re-supplies required to avoid clinical stockout
Case Study #3 Acquisition of a new molecule where all clinical supply manufacturing is at CMOs not in Roche approved network (both API and DP) Roche assigned HHC 1, but CMO used for DP is not in compliance to meet Roche QA requirements with respect to equipment cleaning and cleaning verification Very fast timeline to Phase I start
Case Study #4 Due diligence for a potential acquisition of two compounds with no assigned HHC Three of the CMOs used are not in Roche network and have not been audited by Roche One of the CMOs has been audited by Roche SHE and is known to not be in compliance with Roche containment requirements Current timelines will not allow for transfer to Roche pre-approved suppliers
How to Manage the Gaps? Schedule audits as soon as possible and evaluate gaps Risk based approach Work with CMOs on interim solutions to reduce risk Long term solutions for compliance Consider transfers to preapproved CMOs that are in compliance with Roche requirements
Doing now what patients need next
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Roche Industrial Hygiene Committee (RIHC) Derives compound ADE Clinical data Nonclinical data Epidemiological data Data from other sources E V A L U A T I O N Critical effects A SS ES S M E N T Limit value(s)
Summary of ADE aspects All ADEs are safe All ADEs uniquely substance-specific, and may be exposure route specific All ADEs have different data bases; Ø Early ADEs for APIs have a weaker data base -> tend to have higher built-in adjustment factors -> lower ADEs Ø Late stage API ADEs have a broader database: ADEs tend to be higher Ø ADEs for intermediates and cleaning agents often based on limited data Ø Roche target: hit the correct category at the first assessment, then only correction within the category (= refinement ) with database growth