Virtual Company & Supply Chain – Challenges of CMO QP Forum 12 April 2018 - PowerPoint Presentation

Virtual Company & Supply Chain – Challenges of CMO QP Forum 12 April 2018 TCD School of Pharmacy & Pharmaceutical Sciences Based on “The complexity and challenges of the management of global product release scenarios ” - Dissertation submitted to Trinity College Dublin for the degree of Masters in Pharmaceutical Manufacturing Technology By Deirdre Dunne, B. Sc. ( Applied Science)

2 Committed to improving patients’ lives by identifying, developing and commercializing meaningful products that address unmet medical needs

Growing Global Network ~ 1150 employees worldwide | Multiple offices in EU and US | Headquarters in Dublin, IrelandProducts reach patients in over 80 countries | Manufacturing operations in Ireland and Italy 3 Partner Market 2 Jazz Direct Market 1 Headquarters Office Locations 1 Reflects market in which Jazz directly commercializes one or more products, 2 Reflects market in which Jazz commercializes one or more products through a distributor or other representative but does not directly commercialize any product

Focus for 2015 QP Forum “The Challenges with managing CMOs” 4

Focus for 2018 QP Forum Virtual Company & Supply Chain – Challenges of CMO oversight5

Increased Regulatory focus on Sponsor and CMO relationshipAt the Parenteral Drug Association (PDA)/FDA Regulatory Conference in September 2017, Washington. Francis Goodwin Division Director CDER FDA presented ‘CDER Regulatory Perspective Compliance and Enforcement trends’. He particularly addressed warning letters, import alerts and regulatory discretion activities. 6 Top Concerns Barbara Unger. Unger Consulting Inc. Data Integrity & Your Contract Manufacturer – Common Pitfalls to Avoid. Outsourced Pharma, 03rd November, 2017.

Number of warning letters issued by FDA in 2017 7 The question could be asked by the Regulators why these issues were not highlighted earlier by the Sponsors who contracted the services of these facilities. The requirements are clear in respect to oversight of contract facilities, is this a failure in the Sponsors supplier management program ? FDA Data Dashboard Warning letters and Responses

Importance of Regulatory Intelligence Evaluation of Health Authority inspections or other enforcement actionsMonitoring warning letters alone is not sufficient. Firms should seek to obtain form 483s from all FDA Inspections, including sites of the contract manufacturer where they do not have product. Frequently, problems are systematic and evaluation of all inspections conducted at the firm’s sites can provide an early warning that something is amiss . Firms should monitor FDA import alerts and recalls . Firms should be informed of all health agency inspections of the contract site and be informed of their findings, outcomes, and recommendations.8Barbara Unger. Unger Consulting Inc. Best Practices for Data Integrity Oversight at your Contract Manufacturer. Bioprocess Online , 04th December, 2017.

Data Integrity EU GMP Chapter 7 / EMA guidanceData Integrity requirements should be incorporated into the company’s contractor/vendor qualification/assurance program and associated procedures In addition to having their own data governance systems, companies outsourcing activities should verify the adequacy of comparable systems at the contract acceptor. The contract acceptor should apply equivalent levels of control to those applied by the contract giver . Formal assessment of the contract acceptor’s competency and compliance in this regard should be conducted in the first instance prior to the approval of a contractor, and therefore verified on a periodic basis at an appropriate frequency based on risk.9Barbara Unger. Unger Consulting Inc. Best Practices for Data Integrity Oversight at your Contract Manufacturer. Bioprocess Online , 04th December, 2017.

Data Integrity How can the sponsor make lot release decisions with confidence based on data from their contracted partner?Effective on-site evaluation of contract manufacture (initial and ongoing) On site auditing by auditors with significant expertise or training and experience of how health authorities are currently evaluating data governance within the GMP system Identify and justify information required to support a lot release decision – which data and why Create secure means of data transmission between CMO and SponsorQTA10Barbara Unger. Unger Consulting Inc. Best Practices for Data Integrity Oversight at your Contract Manufacturer. Bioprocess Online , 04th December, 2017..

Management of change is critical to ensure MA compliance in a virtual company like Jazz 11

Quality Technical Agreement defines the management of changes CMO is qualified as per Jazz Pharmaceuticals’ supplier management program CMO is required to have established written procedures for control of changes that include Jazz notification, Jazz approval of changes, follow-up, and closure of changes as they relate to manufacture, testing, storage, assembly, labelling and distribution of the ProductCMO notifies Jazz in accordance with QTA and written proceduresSupplier QualificationQuality AgreementNotification of ChangesJazz has the opportunity to acknowledge and/or approve changes made to procedures, processes, materials, including the specifications thereof, used in the execution of Services which may impact upon the quality of the Product prior to the execution of those changes Jazz Review CMO Review Written Procedures The CMO reviews and/or approves changes made to any procedures that impact on the assembly, labelling or distribution of the Product Jazz Quality Oversight of CMOs Change control

13 Challenges in External Manufacturing

Challenges for Jazz14

Challenges for Jazz 15

Communication c an be a challenge for a virtual CompanyCan be hard to maintain cohesion in virtual teams C o-located teams working in multiple time zones Need to establish clear processes for communicationOn how people react during virtual meetings – rules for good virtual meeting habitsDealing with different quality cultures and time-zones Jazz has clearly defined team support roles – ‘virtual plant teams’ for each product that ‘mirrors’ the structure of teams in a manufacturing plant16Tips for virtual teams Chapter 7. Build your Team ‘The First 90 Days’ by Michael D. Watkins

Jazz conducts regular visits of contract facilities to foster Partnership and Oversight 17

18 Management of significant cGMP compliance problems (is there a “warning system”?)

Jazz monitors Suppliers for compliance by three main activities 19 Communication is critical and is achieved by way of regular quality to quality meetings, business review meetings and partnership meetings Communication

Establishing a formal Quality Technical Agreement (QTA) 20

Establishing a formal Quality Technical Agreement (QTA) Training and awareness of a new quality agreement or changes to a quality agreement is a key activity as part of the supplier oversight program. QTAs are stored in an central electronic location for cross functional access; to ensure deliverables within the agreement are understood. Non conformance to the Quality A greement between Jazz and contract facility is monitored and trended in the deviation management system.A specific drop down code is selected in the deviation system for an event related to the quality agreement. This is used as a tool used for trending conformance to the QTA within the PQS.21

Limitations of the QTA? 22 Deirdre Dunne (2016). The Complexity and Challenges of Management of Global P roduct Release Scenarios – Quality Oversight of CMOs. EQPA News issue 5 Dec 2016

Auditing the contractor’s facilities 23 FDA, US Food and Drug Administration (2015) Request for Quality Metrics, Guidance for the Industry draft, July 2015.

Assessing the Quality Culture of the CMO24 Top five quality attributes that can serve as substitutes for quality culture Management communication that quality is everyone’s responsibility Site has formal quality improvement objectives and targets Clear performance criteria for feedback and coaching Quality topics included in at least half of all-hands meetingsCollecting error prevention metricsPritesh Patel, Denyse Baker, Rick Burdick, et al. (2015) Quality Culture Survey Report. PDA Journal of Pharmaceutical Science and Technology 2015, 69 631-642. September-October 2015. PDA Quality Culture Survey report suggested that certain characteristics are driving good behaviours This is a useful tool that can be incorporated in audit programs

25 Maintenance and monitoring

Maintenance and Monitoring 26 SRB = Supplier Review Board

Maintenance and Monitoring 27

CMO Scorecards We utilise CMO scorecards as a tool to support supplier performance management. If the scorecard flags red we know there is an issue. The score card attributes are built on the requirements set out in the quality agreement e.g. stability reporting on time, notification of changes, batch acceptance rate. 28

Person in Plant Benefits •Validation campaign presence •Campaign-based manufacturing •Faster visibility to issues •Immediate decision making and approvals •Liaison between sponsor and CMO departments •Can build a strong long term partnership with CMO  Risks •May not make sense for low volume products •Does not prevent deviation events (reactive) •On site presence may not result in quicker visibility of issues •Must have authority to make product related decisions •Must involve QA at sponsor 29 Barbara Unger. Unger Consulting Inc. Best Practices for Data Integrity Oversight at your Contract Manufacturer. Bioprocess Online , 04th December, 2017.

Workshop Discussion How big of a challenge is it for the MA holder to keep actual activities in the CMO and Suppliers aligned with registrations?For virtual company what approaches have others taken to data integrity? What are key Competencies of Person-In-Plant? Management of primary packaging component deficiency leading to parenteral finished product inspection action limit excursion The value of regulatory surveillance as an indicator of CMO performance30

Audits & Inspections – Audit Mind Map 31

Person in Plant – Key Competencies •Effectiveness depends on skills and experience of individual –cultural fit with CMO –credentials and technical expertise –ability to influence without authority –trusted by sponsor and CMO –ability to build and balance relationships with sponsor and CMO –ability to facilitate resolution of issues –has authority to make decisions on behalf of sponsor –know which side of the fence they are on 32 Barbara Unger. Unger Consulting Inc. Best Practices for Data Integrity Oversight at your Contract Manufacturer. Bioprocess Online , 04th December, 2017.