Executive Summary. A Stalwart of Collaborative and Mutually Beneficial CMO-Sponsor Partnerships CMO. 7th

Transcription

1 Executive Summary A Stalwart of Collaborative and Mutually Beneficial CMO-Sponsor Partnerships 7th CMO QUALITY OVERSIGHT & RISK MANAGEMENT SUMMIT Imbue and Protect a Culture of Quality by Ensuring the Compatibility of Sponsor and CMO Using Proven Methods and Tools

2 CONTENTS Introduction... 3 Session Summaries... 4 Resources for Information and Discussion

3 Introduction What you missed at ExL Events 7th CMO Quality Oversight and Risk Management Summit The 7th CMO Quality Oversight and Risk Management Summit focused on imbuing and protecting a culture of quality by ensuring the capability of sponsor and CMO using proven methods and tools. Held April in Boston, last year s summit brought together quality and compliance leaders and experts from pharmaceutical, medical device and biotech companies with CMOs for a unique, two-day educational and networking event. The 2017 conference disseminated best practices, shared lessons learned and conveyed information related to the latest outsourcing trends, regulatory changes and challenging issues in drug and device contract manufacturing with all-new educational spotlights, case studies, panels and more. Key outcomes for the 2017 event: safeguarding data integrity through responsible management of data and strategic contracts; identifying key metrics and measurements to standardize quality; mastering technology transfer and surmounting cultural barriers in emerging markets; turning the requirement of metrics reporting into a competitive advantage; streamlining procedures for monitoring process performance and enhancing the quality of a drug or combination product; instituting objective measures and subjective assessments to determine a CMO s capacity, capability and suitability; anticipating and mitigating risks to patients, operations and the supply chain through preemptive detection, product oversight and good governance practices; and drafting creative contracts and quality agreements that incentivize CMOs and comply with national and global requirements, among others. The following sessions are summarized in the below pages summaries and highlights from the 2017 conference. Clarify Expectations of FDA s Quality Agreements Guidance FDA s Current Thinking on Quality Agreements and Contract Manufacturing Paula Katz, Director of Manufacturing Quality Guidance and Policy, Office of Compliance, CDER, FDA Safeguard Quality by Customizing Your Audit to Accurately Assess Critical Measures Lisa Alexander, Vice President, Quality and Regulatory, BRAMMER BIO Institute Best Practices for CMO Oversight in the Emerging Tech Space Khandan Baradaran, Vice President and Global Head of Quality, DIMENSION THERAPEUTICS Select the Best CMO Using Poignant and Honed Criteria in 5 Key Areas for Evaluating Risk and Partner Suitability Robert Beall, Associate Director, Program Management, PROPHARMA GROUP Identify the Right GMP Supplier (Critical Raw Materials and Contract Manufacturers/Labs) for Emerging Technology, Niche or Start-up Companies Amnon Eylath, Head of Quality, KARYOPHARM THERAPEUTICS Learn the Implications of the FDA s Draft Document on Data Integrity and Compliance with cgmp Guidance for Industry Dale Herbranson, Vice President, Quality and Regulatory - Tech Group, Contract Manufacturing, WEST PHARMACEUTICAL SERVICES Establish Multi-Step Quality Control Procedures for Biologics During Technology Transfers to New Markets Todd Mabe, Head of Biologics, Drug Substance, GENENTECH Use Risk to Manage Oversight of a CMO Isabel Molina, Principal Technical Manager, External Quality, GENENTECH Eva Urban, Senior Manager, Global Quality Risk Management, CELGENE Case Study: Implement an Integrated Risk Management Program for External Manufacturing Susan Qu, Integrated Risk Manager, External Manufacturing, SANOFI BIOLOGICS Brid Rooney, QA Director, Genzyme External Manufacturing, SANOFI BIOLOGICS Maintain CMO Quality Oversight Through Mergers and Acquisitions Stan Russell, Head of Quality-Due Diligence, Partnerships and Integration, SHIRE Master Quality Metrics from Cognizance to Compliance Adnan Sabir, Director, Manufacturing Quality Guidance and Policy, KOWA PHARMACEUTICALS AMERICA Understand Your Process: A Key to CMO Risk Mitigation Eric W. Smart, Senior Advisor, Aseptic Manufacturing, SINGOTA SOLUTIONS Manage Risk While Working with Emerging Markets Dan Trimberger, Director QA, MOMENTA PHARMACEUTICALS This event was co-chaired by Lisa Alexander, Vice President, Quality and Regulatory, BRAMMER BIO and Stan Russell, Head of Quality-Due Diligence, Partnerships, and Integration, SHIRE. INTRODUCTION 3

4 Session Summaries Paula Katz, FDA s Director of Manufacturing Quality and Guidance for CDER s Office of Compliance, presented the FDA s Current Thinking on Quality Agreements and Contract Manufacturing She shared case studies and final guidance on contract manufacturing arrangements for drugs. The Office of Manufacturing Quality evaluates compliance with Good Manufacturing Practice for human drugs based on inspection reports, evidence gathered by FDA investigators and other sources in order to develop and implement compliance policy. QA is now expected to be part of a larger outsourcing risk management plan, with tools such as risk management strategy, process maps, supplier quality questionnaires, communications infrastructure, audit programs, quality agreements, metrics and report cards. Moreover, quality agreements can be used to define expectations and responsibilities in a contract manufacturing arrangement up front. No new rules are at play the FDA will continue to inspect against the FD&C Act and CGMP regulations, and all parties continue to be subject to the same requirements. The FDA routinely requests and reviews evidence of quality agreements. Enforcements tools include regulatory meetings, inspections, consent decrees, import alerts, seizures, warning letters, untitled letters and more. Even in a complex market, everyone is responsible for quality. Owners and contract facilities should work together proactively to characterize and control risks to product quality and patient safety. A quality agreement can help to accomplish that, but it is not the entire story. A well-drafted quality agreement can promote communication, clearly delineate responsibilities and provide for change management. What to Expect When We re InspecGng No new rules at play connnue to inspect against the FD&C Act and CGMP regulanons, and all parnes connnue to be subject to the same requirements. FDA rounnely requests and reviews evidence of Quality Agreements (or the lack of quality agreements). ImplicaNon: Compliant contract drug manufacturing without a wrifen quality agreement is difficult. 20 Lisa Alexander of Brammer Bio s Vice President of Quality and Regulatory, offered information on how to Safeguard Quality While Customizing Your Audit to Accurately Assess Critical Measures, commenting that effective audits examine both quality and technical elements. When it comes to audits, many excellent tools and training options are available. She emphasized that one size fits all does not apply and that it is important to understand what applies to your company s needs and ensure confidentiality. Considerations when auditing a CMO are: client audit history, acquisition and integration impact, site master file, relationships with FDA and regulatory authorities inspections. New technologies offer new ways to apply GMP principles. Communicate throughout the audit, giving the CMO the opportunity to resolve findings so there are no surprises when it wraps up. Flexibility and two-was transparency are key. Partnerships are of paramount importance, with an ongoing focus on relationships, communication and expectations. 4

5 Institute Best Practices for CMO Management in the Emerging Tech Space from Khandan Baradaran helped attendees identify the right CMO for their unique emerging technology and anticipate potential issues while increasing effectiveness with hands-on communication. In case studies, lessons from the emerging tech space include quality systems must be tested; limited experience and capabilities present a challenge; a focus on technology over compliance remains; and a one-stop-shop CMO is hard to find. When evaluating a CMO, it is important to seek out sufficient manufacturing experience and SME capacity for development and tech transfer, adequate facilities/equipment, operating training and knowledge, and experience of QA staff. In terms of QC testing, be prepared to bear more responsibility and provide significant QA oversight and coordination. Anticipate potential issues related to the emerging tech space such as new and non-standard release methods and processes, the need to invest in tech transfer activities, robustness issues and timeline slippages, the need for third-party vendors for non-specialty tasks, missed operating expertise and potential for high turnover, among others. Regular communication will increase effectiveness: host weekly team meetings and explore options for Person in Plant; establish one-to-one relationships with key customers and anticipate the need for unscheduled visits. Finally, let the CMO do what they do best. It is possible to preempt potential capacity issues by anticipating limited capacity due to the nature of the emerging technology and expect base case instead of best case. Explore options for staged or redundant manufacturing to reduce timelines, and explore secondary CMOs, vendors, and suppliers. Identify the right CMO for your unique emerging technology 2017 Dimension Therapeutics 6 5

6 Bob Beall, Associate Director, Program Management at the ProPharma Group, explained how to Select the Best CMO Using Poignant and Honed Criteria in Five Key Areas for Evaluating Risk and Partner Suitability, with a focus on compliance, capability, customer service and more. He recommended using two CMOs for big projects, and fully understanding product and company requirements before searching for a solution. When it comes to compliance, considerations include audit history and certifications, auditing suppliers and internal audits, management, personnel training and documentation, and warehouse, production and process controls. In terms of capability, key issues are equipment and processes, facilities and utilities, and capacity. Asking the right customer service questions is critical; this can include issues such as when the technical PM is involved in the selection process, site location, history of contract adherence, lead and turnaround time, technical transfer capabilities, reject and returns, and contingency. When examining quality issues, take a closer look at raw material testing, lab procedures, quality management, and process and cleaning validation. Finally, for cost, priorities are yields, transfer batch costs, conversion cost structure, waste disposal and event-based costing. Companies must understand and document CMO requirements and then use a weighted system best fit for those requirements. 5. Quality Questions Related to: Raw Material Testing Laboratory Procedures Quality Management Process and Cleaning Validation Example Confidential 7 6

7 Amnon Eylath, Head of Quality for Karyopharm Therapeutics, explained how to Identify the Right Suppliers (Critical Raw Materials and Contract Manufacturers/Labs) for Emerging, Niche or Start-Up Companies, including risk management guidelines, assessing suppliers, aligning with quality standards and more. Risk assessment consists of identifying hazards and analyzing/evaluating risks associated with exposure to those hazards. For risk assessment purposes, three fundamental questions are often helpful: 1) What might go wrong? 2) What is the likelihood (probability) it will go wrong? 3) What are the consequences (severity)? A supplier s competency across the expanded pharmaceutical quality system must be assessed. Leading indicators for supplier selection are: review literature published by/about the supplier; research supplier s technical capabilities; research financial stability; research supplier s regulatory history; client references; due diligence visit and perform risk assessment based on observations. It is highly advisable to have a due diligence visit and assessment by the sponsor prior to contracting with the supplier, and the due diligence team must be cross-functional. Finally, face-to-face meetings before and at the start of activities are valuable in developing relationships across functional peers and leadership teams. Pharmaceutical Quality System - ICH Q10 Key Areas: Process performance and product quality monitoring system Corrective action and preventive action (CAPA) system Change management system Management review of process performance and product quality 2017 Karyopharm Therapeutics Inc. 7 Data Integrity and Compliance With cgmp Guidance for Industry from Dale Herbranson, VP of Quality at West Contract Manufacturing, focused on good documentation practices, GMP record decision-making, storing scanned documents and more. Good documentation practices should be permanent, legible, accurate, prompt, clear, consistent, complete, direct and truthful. In terms of a manufacturing execution system, it is important to demonstrate that the workflow ensures the intended steps, specifications, calculations and so on are accurate and complete. Data integrity is now expected to be part of regular cgmp training. All records considered cgmp are subject to inspection, including audit trails, and CMOs must ensure records are managed properly as well. To that end, companies must update applicable corporate policies/procedures that impact data integrity and ensure that IT system procedures are consistent and that training programs add in electronic data integrity. Review systems currently used and add an in-depth risk review and CA plans as needed, while training internal auditors on data integrity and how to identify potential concerns. 7

8 Todd Mabe, Head of Biologics, Drug Substance Quality for Genentech, shared ideas on Establish Multi-Step Quality Control Procedures for Biologics During Technology Transfers to New Markets, including standardizing CMO controls, standards for tech transfer, strategic alliances and more. Managing CMOs over the lifecycle of the partnership begins with the buy decision, transitioning to CMO selection, tech transfer, governance/risk management, and then commercial release and retirement. CMOs vary significantly in capacity and experience, so the importance of selection cannot be overemphasized. The success of your tech transfer depends on your selection of CMO. When identifying the scope of your oversight, companies should ask: What are we outsourcing? Where do we plan to do business? Who will support the project? What level of risk are we willing to take? Governance teams can ensure quality supply to patients and the right to operate. Further, information sharing within teams is essential to ensure that all team members are informed and can present consistent, aligned communications to the CMO. CMO governance teams are responsible for resolving supply, quality or business issues that arise at the CMO. The collaboration and support of all functions within the governance team are essential components for successful resolution of such issues. The CMO governance structure should fit the needs of the relationship. The RACI model is a simple two-dimensional matrix used to help define who is Responsible, Accountable, Consulted and Informed for specific activities. Finally, seek continuous improvement through joint efforts, including strong teamwork and collaboration, metric and annual product reviews, greater CMO accountability, workshops with joint teams, mitigating risks and more. Managing CMOs over the lifecycle of the partnership CMO Lifecycle Buy Decision CMO Selection Tech Transfer Commercial Release Retire Site Selected Supply and Quality Agreement approved Licensure PPQ Batches Released Make, Assess, Release Performance (Metrics) Governance/ Risk Management Stage Gate Reviews Review detailed plans, resources and costs GMP Readiness for PPQ runs Submission readiness 8

9 Eva Urban, Celgene s Senior Manager, Global Quality Risk Management, and Isabel Molina, Genentech s Principal Technical Manager, External Quality of copresented Use Risk Management for CMO Oversight. Isabel Molina led off with an overview of Quality Risk Management in which she detailed key considerations of how quality risk management should be applied at a CMO. The primary principles of quality risk management are the evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient, and the level of effort, formality, and documentation of the quality risk management process should be commensurate with the level of risk. Eva Urban led highlighting the importance of exposure, hazard, consequence, probability and harm in terms of risk. Organizations can engage quality risk management throughout the CMO lifecycle, using risk factors to establish optimal oversight. Benefits including process mapping, knowledge of risks, science-based/fast decision-making, avoiding duplication oversight PO/CMO, and ensuring a common language and understanding of risks. Applying quality risk management throughout the product lifecycle provides a proactive approach to identifying, scientifically evaluating and controlling potential risks to quality as well as a framework for increasingly targeted and effective risk control. It also facilitates continual improvement of process performance and product quality via ties to PQS. Key considerations in contract manufacturing are quality risk management triggers are defined throughout the CMO life cycle, however, implement, manage and decommission activities may vary; the CMO must have a quality risk management program in accordance with applicable regulations; QRM requirements are defined in the Quality Agreement and ownership must be established. When integrating quality risk management with quality systems, PQS elements inform and provide triggers for reassessment and evaluation as to the effectiveness of QRAs and controls. In summary, companies must recognize how important it is to evaluate existing controls: Risk is an enabling process that must interface with PQS as well as an input into quality decision-making. Eva Urban noted that challenges, on the other hand, are defining and aligning on quality risk management, one PO and very different CMOs, CMOs serving different clients, ongoing risk review and the escalation process. Effective risk communication between product owners and CMOs is critical. Goals today include transparency, continuous improvement, a greater focus on data and a patient-driven process. Now, formal risk assessments for individual applications lead to greater risk management and communication. Five Key Terms to Know Exposure Hazard Links the hazardous properties of biological, physical, chemical or events to the chance of consequence Act or phenomenon posing potential harm to some person or thing and its potential consequence (not directed) Consequence Degree of damage or loss from some failure (event, incident, or occurrence) Probability Numerical value assigned to a random event Harm Damage to health, including the damage that can result from loss of product quality or availability (ICHQ9) Global Quality Risk Management & Compliance - For Celgene Internal Use Only 9

10 Brid Rooney, Integrated Risk Manager External Manufacturing (EM) and Susan Qu, QA Director, Genzyme EM, at Sanofi Biologics presented Implementing an Integrated Risk Management Program for External Manufacturing, highlighting the company s biologics external manufacturing as a strategic asset within industrial operations. External manufacturers are involved in some aspect of production for the majority of Sanofi Biologics products. To effectively manage these relationships and meet the needs of the business and patients, the Biologics EM team oversees the external network as if it were a multi-product site, effectively managed and fully integrated into Sanofi Industrial Affairs. The external manufacturing governance model ensures that the external manufacturing network consistently delivers on balanced scorecard objectives through effective governance and relationship management, applying appropriate risk management principles and tools to mitigate quality, contractual, financial, supply chain, regulatory and legal risks. Integrated risk management helps to set strategy and make decisions. Program deliverables include awareness of the overall risk profile of external manufacturers, buy-in of risk mitigation plans by the EM Site Leadership Team, identification of risks for escalation within Sanofi and/or communication to external manufacturers, and an overall risk assessment report. External Manufacturing (EM) EM Integrated Risk Management Program Operates as a virtual multi-product site in the global manufacturing network of Sanofi Industrial Affairs Biologics. 7th CMO QUALITY OVERSIGHT & RISK MANAGEMENT SUMMIT DATE 10 7th CMO QUALITY OVERSIGHT & RISK MANAGEMENT SUMMIT DATE 14 10

11 Stanley Russell of Shire s Head of Quality-Due Diligence, Partnerships, and Integration facilitated Maintain CMO Quality Oversight Through Mergers and Acquisitions, encouraging companies to ensure transferability and interim execution of formal agreements while creating and implementing comprehensive transition plans. A successful merger is successful for all key stakeholder groups, and CMO oversight throughout the process can ensure supply continuity for patients and seamless merging of processes/systems satisfaction for suppliers/ partners. While CMO oversight during a merger is simple, it is not necessarily easy. The three keys are: 1) strategy and governance (guiding principles, formal agreements, stakeholder roles, and responsibilities); 2) planning and execution (detailed project plan, process maps, individual transition plans, reporting/escalation mechanisms); and 3) communication and adaptation (formal communication plan, two-way communication in a matrix environment, channels of information for every stakeholder). Common areas of risk include maintaining knowledge with employee changes, moving targets, critical issue communication and resolution timelines, ongoing redundancy and the unknown. Adnan Sabir of Kowa Pharmaceuticals explained how to Master Quality Metrics From Cognizance to Compliance, covering topics such as old and new quality metrics, FDA expectations, establishing a coherent metrics program and customizing metrics. Quality metrics follow on the heels of other significant FDA initiatives formulated to proactively build quality into products. After modifying initial guidance, the FDA reduced its scope to three primary metrics: lot acceptance rate, product quality compliant rate and invalidated out-of-specification rate. The FDA expects quality goals to encourage pharma to improve and sustain better product quality via continuous improvement, conduct risk-based field inspections, mitigate drug shortages, inspire for continuous manufacturing, and measure senior management engagement in QMS. Pharma s goals include: the ability to produce high-quality drugs and biologics on a regular basis, reducing plant inspections, decreasing reporting of post-approval changes, determining more objective measures to reflect realistic performance goals, and leading or motivating going for CM. Establishing quality metrics begins with assessing quality culture within an organization to help in identifying gaps in quality, and then identifying metrics that align with company targets. The most important metric is gauging a quality culture within the organization by questioning senior management during audits. Understanding and managing quality culture are critical to effective risk management and strategy development and assessment. There is a major shift towards innovation and continuous improvement with the Pharmaceutical cgmps in the 21st century, and the FDA is trying to inspire continuous manufacturing. 11

12 Eric Smart, Senior Advisor, Aseptic Manufacturing at Singota Solutions, provided guidance on how to Understand Your Process: A Key to CMO Risk Mitigation, sharing details on determining critical process parameters, reducing process variables, and bridging the gap from lab to plant. The company focused on methods to reduce project risks when moving from the laboratory to a GMP, CMO manufacturing setting. Setting the stage for success entailed establishing project objectives centered on deliverables, quality, and timelines. It is important to identify critical project parameters or key variables that affect a production process prior to manufacturing. Triage process variables and eliminate those that cannot be changed or are unlikely to impact process, then develop a plan to explore critical process parameters, being realistic about what time and budget will allow you to evaluate. Ultimately, having fewer variables equals less variability. Humans are the number-one source of errors in manufacturing, thus increasing automation greatly reduces opportunities for mistakes. Following production, take a critical look at how the process behaved: Did you remain within established parameters? Did critical process parameters predict a successful outcome? Did you discover any you had not anticipated? What further lab work can you do to improve your process before it is used again? By carefully evaluating critical process parameters in advance of scale-up, the risks inherent to GMP manufacturing can be better understood and reduced. Moreover, a well-conceived and -executed study can improve CMO performance, reduce the chance of an unexpected outcome, better prepare you for regulatory submission, and improve a process through its development and commercial life cycle. Setting the Stage for Success Deliverables Establish Project Objectives Quality Timeline 4 BioConvergence d/b/a Singota Solutions Dan Trimberger, Senior Director of Quality Assurance for Momenta Pharmaceuticals, delivered on how to Manage Risk While Working with Emerging Markets, reminding attendees that not all CMOs are the same and each CMO needs to be managed differently, especially in emerging markets. Risk management starts with due diligence visits and initial quality audits. He suggested that owners: learn about the culture and norms within the market, stay highly engaged and be willing to adjust your thinking. Evaluating risk takes time and effort, including conference calls and research into company policies as well as FDA and EU expectations. Ensure that communications are clear and regular (both internally and externally) and put effort into building relationships. The biggest risks are GMPs/GMP thinking are new, the potential for significant cultural/work norm difference, turnover and data integrity. Ultimately, managing risks in emerging markets takes time, travel, sharing and understanding. Sponsors should be willing to throw all of the risk analysis tools away, ask a lot of questions and dig below the surface because items we think are risk are often just the tip of the iceberg. 12

13 Resources for Information and Discussion 8th CMO March 21-22, 2018 Hilton Boston Back Bay Boston, MA QUALITY OVERSIGHT & RISK MANAGEMENT SUMMIT Fortify Quality and Ensure Compliance Through Robust Conversations About Cultural Implications and Transference ADDITIONAL RESOURCES 13