Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 How to Combine the Efforts on the New Initiatives – QbD, PAT, QRM, and Validation/Continuous Verification ISPE Nordic PAT COP meeting Malmö 2007-10-25 Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Background – Regulatory initiatives Slide no 2 ” This industry wastes $50 billion each year because of lack of manufacturing efficiency” Source: George Washington and Washington Universities report (presented 2006) Th e Cr iti ca lP at h FDA CG M P fo r ICH Q8 th e 21 Pharmaceutical Development st Ce nt ur y ICH Q10 Quality Systems Process Analytical Technology FUTURE DESIRED STATE ICH Q9 Quality Risk Management Development & Manufacturing Costs Cost and Benefit of QbD Increased Resources (e.g., development costs, organizational planning) Current State Dr Jan Gustafsson, Novo Nordisk A/S Decreased Expenses (e.g. manufacturing costs, compliance costs) • Empirical development approach • Quality by testing & inspection • Frozen process with reactive changes Desired State • Quality by design development • Flexible process & continual improvement Initiate QbD Efforts QbD Fully Realized QbD Implementation Progress 2007-10-14 Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 4 The New Initiatives • The vision • Continuous product and process improvement • Transparent, science and risk based dossier submission, review, and approval as well as operations • Empowerment to manufacturers re. continuous improvement throughout product and process life-cycles and supply chain • More efficient and effective regulatory oversight • The new initiatives contain issues such as: • Focus on design (ICH Q8; QbD) • Focus on doing the right things (ICH Q9; QRM) • Focus on understanding and control of the manufacturing process (FDA; PAT) • Focus on more efficient use of resources re. V&Q (ASTM; quality verification • Regulatory Flexibility (FDA, EMEA) • The new initiatives lead to: • • • • Better (mechanistic) Process understanding Better product/process/facility knowledge Better use of resources Regulatory flexibility Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 5 The new initiatives, Novo Nordisk way Quality by Design QRM PAT QbD & Design space V&Q Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 6 Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 7 The QbD process ”Start with the end in mind” Needs of the patient Product design Process design Equipment design Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 ICH Q8 – Introduces new Concepts • Regulatory Flexibility • Quality by Design • Design Space Slide no 8 Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 9 ICH Q8 - Regulatory Flexibility • Proposed by applicant and approved by regulator, based on demonstrated product knowledge and process understanding • Degree of regulatory flexibility is predicated on the level of relevant scientific knowledge provided • Opportunities to facilitate • risk-based regulatory decisions (reviews and inspections) • manufacturing process improvements, within the approved design space described in the dossier, without further regulatory review • reduction of post-approval submissions • real-time quality control, leading to a reduction of end-product release testing Source: Moheb Nasr, ONDQA CDER, FDA Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 10 Regulatory Flexibility • Regulatory flexibility is proposed for: • • • • Process validation Scale and equipment change Site changes Real time release No additional batch wise end product testing is needed 3 batch validation will be replaced by a continuous process verification Changes of scale will be made immediately without notifying authorities Operation within developed design space, a transfer (site A to site B) could be made immediately without authorities being notified in advance Source: Mock P2 Submission presentation by the EFPIA PAT Topic Group Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 11 Quality by Design (QbD) • Product designed to meet patient needs and performance requirements • Process designed to consistently meet product critical quality attributes • Impact of starting raw materials and process parameters on product quality is understood • Process continually monitored, evaluated and updated to allow for consistent quality over time • Critical sources of process variability are identified and controlled • PAT tools is critical to realisation of QbD. PAT enables a high level of process understanding and process control ICH Q8 provides clarity to facilitate implementation !!! Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 12 Design Space changes within DS is not a change and is Process variable 2 not subject to post approval regulatory changes Traditional Specifications ce a e Sp c e g pa d S le n g w i no es K D Normal Operating Ranges Operating range Process variable 1 Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 13 Dr Jan Gustafsson, Novo Nordisk A/S 4. A General Quality Risk Management Process Slide no 14 Initiate Quality Risk Management Process Risk Assessment Risk Identification Risk Analysis Risk Communication Risk Evaluation unacceptable Risk Control Risk Reduction Risk Acceptance Risk Management tools Team approach 2007-10-14 Output / Result of the Quality Risk Management Process Risk Review Review Events ICH Q9 Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 15 The ”Influence” and “QRM” Chains ¾ ¾ ¾ ¾ ¾ The facilities influence the processes The processes influence the product The product influences the patient In addition there are other factors influencing each step QRM is done top down Patient QRM Product Process Other influences Facilities Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 16 Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 17 FDA on PAT • The goal of PAT is to understand and control the manufacturing process, which is consistent with our current drug quality system: quality cannot be tested into products; it should be built-in or should be by design. (from www.fda.gov) FDA wants to use the quality concept of PAT to improve quality and enhance efficiency. PAT is considered a win-win strategy for industry and customers. Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 18 Current state End product testing Variable input Variable output Process Fixed process OOS or Reject unacceptable products Quality by Inspection Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 19 Desired future state Real time monitoring and control Variable input Constant output Process Robust and Adjustable Process Facilitated e.g. by PAT / DS Quality by Design Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 The feedback mechanisms of PAT Slide no 20 Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 21 Dr Jan Gustafsson, Novo Nordisk A/S Current situation • 3 batches • Science? • Generally accepted 2007-10-14 Slide no 22 Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 23 Continuous Verification • ICH Q8 • Glossary: “Continuous Quality Verification”: “An alternative approach to process validation in which manufacturing process performance is continuously monitored and evaluated” • EMEA, Mock P2 submission • Assurance is given that each step is routinely and reproducibly producing material for the next step through consequent manufacturing within established Design Spaces • Process verification in compliance with the design space • Application by the control strategy • Conclusion: “Therefore the 3 batch validation will be replaced by a continuous process verification Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 24 Continuous Verification • ASTM E55, WK9935 • Describes Continuous Quality Verification • Continuous Quality Verification (CQV) is an approach to verify that a process will consistently produce product meeting its pre-determined critical quality attributes in which manufacturing process performance is continuously monitored and evaluated. • The use of various Process Analytical Technology Principles and Tools will provide the means for Continuous Quality Verification • A review of the process control strategy, acceptance criteria and process monitoring requirements, manufacturing documentation, and an evaluation and documentation of the Continuous Quality Verification data should be conducted at a predefined stage of a process or batch to make an assessment and conclusion of the process validity. Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 25 Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 26 Organisation of QbD – Novo Nordisk EA Board Steering Group Focus Group Quality by Design QbD & DS Work Group QbD & DS Coordination Group EA PAT Work Group Val. & Qual. Work Group PAT Coordination Group Val. & Qual. Coordination Group =Forming =Not yet set up – on hold Implementation Project Quality RM Work Group QRM Coordination Group Quality byby Design – Future Desired State Quality Design – Future Desired State Quality by Design Dr Jan Gustafsson, Novo Nordisk A/S Development core Process Manufacturing Development & Verification Core Process Development Core Process, Product Transfer From Discovery Product Development & Design 2007-10-14 Manufacturing Core Process Transfer to Production Scale QRM1 QRM4 Development Core Process, Process Transfer from Discovery Process Development Technology Transfer to Production Scale QRM2 Manufacturing & Quality Verification Technology Transfer Engineering Facility Design & Verification QRM = Quality Risk Management Activities Project Quality Planning Design Reviews Define Facility Design Testing Commissioning plans and reports Qualification Plans and Reports QRM3 Project Change Management Corporate Change Control Configuration Management Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 28 QbD – Proposed Document Structure General FG QbD QRM WG Applic´s C&Q WG Applic´s + Flow PAT WG QbD/DS WG Applic´s Process Development & Design Procedures (When to apply what) Application Procedures (How to apply) Product Development & Design Flow Applic´s Facility Design & Verification Manufacturing & Quality Verification Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 29 Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 PQLI PQLI = Product Quality Lifecycle Implementation • Builds on: • ICH Q8, Q9, and potentially on Q10 • QbD • Design Space • Regulatory flexibility within Design Space • • • • • 21st cGMPs • PAT guidance Supported by EMEA It is a five year programme Outputs – White Papers, Articles, Documents Embraces Regions that use ICH Guidelines Slide no 30 Dr Jan Gustafsson, Novo Nordisk A/S 2007-10-14 Slide no 31 ISPE´s Industry Driven Transparent Forum • • • • • • Common understanding of QbD Pragmatic approach to QbD implementation Enhance quality of QbD submissions Reduce need for post approval submissions Enable focused GMP inspections by regulators Pragmatic solutions to manage product development and quality throughout product life cycle • Process and product understanding • Science and risk based Dr Jan Gustafsson, Novo Nordisk A/S Task Teams • • • • TT TT TT TT Design Space DP/API Critical vs. Non-Critical DP/API Control Strategies DP/API Legacy Products DP/API (new) 2007-10-14 Slide no 32 Dr Jan Gustafsson, Novo Nordisk A/S Meetings in Europe • Latest: • Berlin, September 2007 • Next • Copenhagen, April 2008 2007-10-14 Slide no 33