Overview Internal review Presentation title: QRM, It s not all about the assessment Track title: Day 1, Session 2 Speaker: Seamus Orr Date / Time: 10 August 2015, 14.30 15.00 Time allotted: 30 minutes Dot point overview (no more than 10 points): Definition of Quality Risk Management (QRM) Importance of QRM Regulatory expectations Reactive QRM Proactive QRM Practical QbD approaches for QRM Conclusions Slide 1 of 37 PharmOut 2015
QRM Not all about the Assessment Presented by Seamus Orr 10 th August 2015
Overview Definition of Quality Risk Management (QRM) Importance of QRM Regulatory expectation Reactive QRM Proactive QRM Practical QbD approaches for QRM Conclusions Slide 3 of 37 PharmOut 2015
Quality Risk Management PIC/S code of GMP, PE 009-11, March 2014 Slide 4 of 37 PharmOut 2015
Benefits of QRM for Manufacturers Better understanding of processes and controls. Increased awareness by staff of risk concepts, leading to better compliance with GMP and product safety, quality and efficacy. Cost savings from reduction in defects and poor quality. Greater likelihood of passing regulatory GMP inspections. Slide 5 of 37 PharmOut 2015
Using Risk Based Decisions Opportunity to scale validation and project activities Be prepared to use risk assessments to justify including or omitting any activity Number and detail of design reviews Need and scope of source code review Rigor of supplier assessment...companies Level and scope of should testing not invest more effort and time into the risk management process than is commensurate with the potential impact on the system or business. Slide 6 of 37 PharmOut 2015
International Conference on Harmonisation ICH Q8 ICH Q9 ICH Q10 ICH Q11 Pharmaceutical Development Quality Risk Management Pharmaceutical Quality System Development and Manufacture of Drug Substances The US FDA influence includes the FDA Process Validation Guidelines Slide 7 of 37 PharmOut 2015
Quality Risk Management (QRM) in Part 1 of the PIC/S GMP Guide Clauses 1.5 and 1.6 of Part 1 of the PIC/S GMP Guide requires QRM to be an integral part of a manufacturer s Quality System. These clauses make QRM mandatory for manufacturers. That is, the manufacturer is responsible for assessing risks to medicinal products and managing these risks to an acceptable level. Slide 8 of 37 PharmOut 2015
Annex 20 corresponds to ICH Q9 is voluntary but QRM is not; provides tools for how to comply with the expectation that QRM is applied. For coherence and completeness, the whole of ICH Q9 has been copied into Annex 20. i.e. they are identical Slide 9 of 37 PharmOut 2015
What is Risk? Retrospectively: Making decisions around product and quality risk for deviations/issues/complaints Pro-actively: Facility Design Qualification & Validation Change Management - Impact assessments PM Programs and Calibration Audit Frequencies Materials Management Training Optimisation Slide 10 of 37 PharmOut 2015
Quality Risk Management (QRM) The QRM process must be systematic with defined policies and procedures Must operate across the lifecycle Principles and methodologies should be clear Criteria and decisions from assessments should be documented Slide 11 of 37 PharmOut 2015
Quality Risk Management (QRM) Begin the QRM Process Risk Assessment Risk Identification Risk Analysis Product & Process Development Risk Evaluation Risk Communication Risk Control Risk Reduction Risk Acceptance QRM Tools Control Strategy Development Output of the QRM Process Risk Review Review Events Continual Improvement Slide 12 of 37 PharmOut 2015
The ICH Q9 Risk Management Model Initiate the Risk Management Process Risk Assessment consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards. The steps include risk identification, risk analysis and risk evaluation. Risk Control includes decision making to reduce and/or accept risks. The purpose of risk control is to reduce the risk to an acceptable level. Risk Communication is the exchange or sharing of information about risk and its management between the decision makers and others. Risk Review requires the output/results of the risk management process be reviewed to take into account new knowledge and experience, i.e. not a once only event QRM processes subject to periodic and triggered review Initiate Risk Management Process Risk Assessment Risk Control unacceptable Risk Communication Risk Review acceptable 13 Slide 13 of 37 PharmOut 2015
Quality Risk Management (QRM) Begin the QRM Process QRM critical at several stages of Process Development Risk Communication Risk Assessment Risk Identification Risk Analysis Risk Evaluation Risk Control Risk Reduction Risk Acceptance QRM Tools Product & Process Development Output of the QRM Process Risk Review Review Events ICH Q9 Slide 14 of 37 PharmOut 2015
Quality Risk Management (QRM) Begin the QRM Process Risk Assessment Risk Identification Risk Analysis Risk Evaluation Risk Communication Risk Control Risk Reduction Risk Acceptance QRM Tools Control Strategy Development Output of the QRM Process Risk Review Review Events ICH Q9 Slide 15 of 37 PharmOut 2015
Quality Risk Management (QRM) Begin the QRM Process Risk Assessment Risk Identification Risk Analysis Risk Evaluation Risk Communication Risk Control Risk Reduction Risk Acceptance QRM Tools Output of the QRM Process Risk Review Review Events Continual Improvement Slide 16 of 37 PharmOut 2015
Risk Management Methodology Supporting statistical tools Acceptance Control Charts (see ISO 7966) Control Charts (for example) Control Charts with Arithmetic Average and Warning Limits (see ISO 7873) Cumulative Sum Charts; CuSum (see ISO 7871) Control Charts (see ISO 8258) Weighted Moving Average Design of Experiments (DOE) Pareto Charts Process Capability Analysis Histograms Use others that you are familiar with. Slide 17 of 37 PharmOut 2015
QbD a systematic approach Ishikawa Capability TOOLS FMEA Pareto DOE Slide 18 of 37 PharmOut 2015
QbD a systematic approach Target the product profile Determine Critical Quality Attributes (CQAs) Link input material attributes and process parameters to CQAs and perform risk assessment Develop a design space Design and implement a control strategy Manage product lifecycle, including continual improvement Slide 19 of 37 PharmOut 2015
Q8(R1) Pharmaceutical Development Revision 1 from the Guidelines 2.3 Linking Material Attributes and Process Parameters to CQAs Risk Assessment Risk assessment is a valuable science-based process used in quality risk management (see ICH Q9) that can aid in identifying which material attributes and process parameters have an effect on product CQAs. While the risk assessment is typically performed early in the pharmaceutical development, it can be helpful to repeat the risk assessment as information and greater knowledge become available. Slide 20 of 37 PharmOut 2015
Q8(R1) Pharmaceutical Development Revision 1 from the Guidelines 2.3 Linking Material Attributes and Process Parameters to CQAs Risk Assessment continued Risk assessment tools can be used to identify and rank parameters (e.g., operational, equipment, input material) with potential to have an impact on product quality based on prior knowledge and initial experimental data. For an illustrative example, see Appendix 2. The initial list of potential parameters can be quite extensive, but is likely to be narrowed as process understanding is increased. The list can be refined further through experimentation to determine the significance of individual variables and potential interactions. Once the significant parameters are identified, they can be further studied (e.g., through a combination of design of experiments, mathematical models, or studies that lead to mechanistic understanding) to achieve a higher level of process understanding. Slide 21 of 37 PharmOut 2015
Q8(R1) Pharmaceutical Development Revision 1 from the Guidelines 2.4 Design Space The linkage between the process inputs (input variables and process parameters) and the critical quality attributes can be described in the design space. Is Key for claiming Process Understanding Process understanding is Key for Quality Risk Management QRM is the base for any Control Strategy Slide 22 of 37 PharmOut 2015
Q8(R1) Pharmaceutical Development Revision 1 from the Guidelines 2.4.1 Selection of variables. The risk assessment and process development experiments can not only lead to an understanding of the linkage and effect of process inputs on product CQAs, but also help identify the variables and their ranges within which consistent quality can be achieved. An explanation should be provided in the application to describe what variables were considered, how they affect the process and product quality, and which parameters were included or excluded in the design space. An input variable or process parameter need not be included in the design space if it has no effect on delivering CQAs when the input variable or parameter is varied over the full potential range of operation. The control of these variables would be under good manufacturing practices (GMP). However, the knowledge gained from studies should be described in the submission. Slide 23 of 37 PharmOut 2015
Cause and Effect Process Drying Analytical Temp RH Operator Temp/RH Operator Training Plant Factors Precompressing Main Compressing Feeder Speed Press Speed Punch Penetration Depth Tooling Feed Frame Compressing Endpoint Power Time Air Flow Shock Cycle Spray Rate Spray Pattern Scrape Down Chopper Speed Mixer Speed P.S. Granulation Water Binder Temp Other Lubricant Disintegrant Binder Drug Substance P.S. Process Conditions LOD Diluents P.S. LOD Age Raw Materials Sampling Method Water Content Slide 24 of 37 PharmOut 2015
QRM Tools: Failure Mode Effects Analysis (FMEA) Risk Assessment Sub-Step Event (Failure mode) Effect Severity (S) [1<2<3] Probability (P) [1<2<3<4] Detectability (D) [1<2<3] Risk factor (S*P*D) Granulation Drying water content not meet specification of degradation 2 3 1 6 Risk Reduction Actions: Risk reduction strategy Severity (S) [1<2<3] Probability (P) [1<2<3<4] Detectability (D) [1<2<3] Risk factor (S*P*D) Risk reduction Comments introduce online NIR 2 1 1 2 4 indirect measurment introduce IPC analytic 2 2 1 4 2 Mass Spectrometry of exhaust gases 2 1 2 4 3 direct measurement; time consuming indirect measurment; unspecific Slide 25 of 37 PharmOut 2015
Summary and PIC/s GMP Regulatory expectations? 1 2 3 4 5 6 A documented procedure/plan for Quality Risk Management. Application of QRM to all relevant areas, including key QA activities and manufacturing steps. Integration of QRM into normal business systems. Use of systematic approach, relevant scientific knowledge and expertise in risk assessment, evaluation and mitigation. Documenting QRM processes. Reviewed on a periodic basis. Slide 26 of 37 PharmOut 2015
Regulators and risk management What can go wrong? Identify and clarify the events considered undesirable Why? Qualify or quantify the likelihood and consequence of the risk What can be done? Evaluate each risk and decide if they are acceptable or require action Slide 27 of 37 PharmOut 2015
Regulators and risk management Risk Management is the overall and continuing process of risk minimisation through a product s lifecycle to optimise the benefit/risk balance... risk information continuously emerges. Slide 28 of 37 PharmOut 2015
QRM and regulators What do PIC/s regulators expect regarding QRM? A documented procedure/plan for Quality Risk Management. Application of QRM to all relevant areas, including key QA activities and manufacturing steps. Integration of QRM into normal business systems. Use of systematic approach, relevant scientific knowledge and expertise in risk assessment, evaluation and mitigation. Documenting QRM processes. Reviewed on a periodic basis. Slide 29 of 37 PharmOut 2015
QRM & other Regulators (from GMP Frequently Asked Questions, MHRA, UK, June 2010) All manufacturing authorisation holders... must have a system for QRM. Inspectors will review the QRM system as part of the Quality System section of the inspection. (from Pre-approval Inspections Guidance Manual, US FDA, Dec 2010) It is critical that a robust quality system incorporate a scientific and risk based approach.... (from WHO GMP for pharmaceutical products, main principles, 2011) The concept of QA, GMP, QC & QRM are interrelated aspects of quality management & should be the responsibility of all personnel. Slide 30 of 37 PharmOut 2015
Some Typical Inspection Observations related to QRM There were no formal SOP for QRM and impact assessment. The SOP relating to QRM did not provide specific information about how QRM was to be performed and implemented. The SOP for QRM did not include coverage of supplier qualification, deviation management, complaints and defects. There was no risk register to facilitate the management, monitoring and review of formal risk assessments. Slide 31 of 37 PharmOut 2015
Key messages Reduce subjectivity of implementing QRM by making sure the right people are at the table (SME and accountable personnel) Use QRM methods appropriately and present the conclusions and justifications clearly Use QRM proactively for increasing the knowledge of your product and processes Risks to Data Integrity also expected to be reviewed regularly Slide 32 of 37 PharmOut 2015
Thank you for your time. Questions? Seamus Orr Senior Consultant seamus.orr@pharmout.net www.pharmout.net Slide 33 of 37 PharmOut 2015