1. Risk Assessment in QbD David R. González Barreto 1 QbD Risk Assessment in QbD Introduction and Few Tools David R. González Barreto

2. Risk Assessment in QbD David R. González Barreto 2 QbD QbD – a systematic approach TOOLS Ishikawa Capability FMEA Pareto DOE

3. Risk Assessment in QbD David R. González Barreto 3 QbD 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

4. Risk Assessment in QbD David R. González Barreto 4 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. Q8(R1) Pharmaceutical Development Revision 1 – from the Guidelines

5. Risk Assessment in QbD David R. González Barreto 5 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.

6. Risk Assessment in QbD David R. González Barreto 6 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.

7. Risk Assessment in QbD David R. González Barreto 7 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.

8. Risk Assessment in QbD David R. González Barreto 8 FMEA - Objectives Failure Mode and Effects Analysis (FMEA) and Failure Modes, Effects identify potential failure modes for a product or process, –to assess the risk associated with those failure modes, –to rank the issues in terms of importance and –to identify and carry out corrective actions to address the most serious concerns.

9. Risk Assessment in QbD David R. González Barreto 9 FMEA Overview In general, Failure Modes, Effects Analysis (FMEA) requires the identification of the following basic information: –Item(s) –Function(s) –Failure(s) –Effect(s) of Failure –Cause(s) of Failure –Current Control(s) –Recommended Action(s) –Plus other relevant details

10. Risk Assessment in QbD David R. González Barreto 10 FMEA Overview Basic Analysis Procedure for FMEA The basic steps for performing an Failure Mode and Effects Analysis (FMEA) or Failure Modes, Effects Analysis include: –Assemble the team. –Establish the ground rules. –Gather and review relevant information. –Identify the item(s) or process(es) to be analyzed. –Identify the function(s), failure(s), effect(s), cause(s) and control(s) for each item or process to be analyzed. –Evaluate the risk associated with the issues identified by the analysis. –Prioritize and assign corrective actions. –Perform corrective actions and re-evaluate risk. –Distribute, review and update the analysis, as appropriate.

11. Risk Assessment in QbD David R. González Barreto 11 Ishikawa Diagram

12. Risk Assessment in QbD David R. González Barreto 12 Ishikawa Diagram – Minitab Procedure Worksheet Window – Data Structure

13. Risk Assessment in QbD David R. González Barreto 13 Ishikawa Diagram – Minitab Procedure Input - Menu Selection

14. Risk Assessment in QbD David R. González Barreto 14 Ishikawa Diagram – Minitab Procedure Input Window

15. Risk Assessment in QbD David R. González Barreto 15 Ishikawa Diagram – Minitab Procedure Output Window

16. Risk Assessment in QbD David R. González Barreto 16 Group Exercise - Ishikawa Select a process or sub-process and draw an Ishikawa diagram considering the correspondent, input parameters (Cpp’s or not) and their relationship with CQA’s

17. Risk Assessment in QbD David R. González Barreto 17 Pareto Diagram

18. Risk Assessment in QbD David R. González Barreto 18 Pareto Diagram – Minitab Procedure Worksheet Window – Data Structure

19. Risk Assessment in QbD David R. González Barreto 19 Pareto Diagram – Minitab Procedure Input - Menu Selection

20. Risk Assessment in QbD David R. González Barreto 20 Pareto Diagram – Minitab Procedure Input Window

21. Risk Assessment in QbD David R. González Barreto 21 Pareto Diagram – Minitab Procedure Output Window Issues: -Weighted Paretos - Nested Paretos Issues: -Weighted Paretos - Nested Paretos

22. Risk Assessment in QbD David R. González Barreto 22 Risk Priority Numbers Most analyses of this type also include some method to assess the risk associated with the issues identified during the analysis and to prioritize corrective actions. A common method is to calculate: Risk Priority Numbers (RPNs)

23. Risk Assessment in QbD David R. González Barreto 23 Risk Priority Numbers Risk Evaluation Methods A typical failure modes and effects analysis incorporates some method to evaluate the risk associated with the potential problems identified through the analysis. Many variations of Risk Priority are used. The most typical one follows. –Risk Priority Numbers To use the Risk Priority Number (RPN) method to assess risk, the analysis team must: –Rate the severity of each effect of failure. –Rate the likelihood of occurrence for each cause of failure. –Rate the likelihood of prior detection for each cause of failure (i.e. the likelihood of detecting the problem before it reaches the end user or customer). –RPN = Severity x Occurrence x Detection –The RPN can then be used to compare issues within the analysis and to prioritize problems for corrective action. This risk assessment method is commonly associated with Failure Mode and Effects Analysis (FMEA).

24. Risk Assessment in QbD David R. González Barreto 24 Guidelines for Ocurrence PROBABILITY of FailureFailure ProbRanking Very High: Failure is almost inevitable>1 in 210 1 in 39 High: Repeated failures1 in 88 1 in 207 Moderate: Occasional failures1 in 806 1 in 4005 1 in 2,0004 Low: Relatively few failures1 in 15,0003 1 in 150,0002 Remote: Failure is unlikely<1 in 1,500,0001 Probability

25. Risk Assessment in QbD David R. González Barreto 25 Guidelines for Severity Hazardous without warning Very high severity ranking when a potential failure mode effects safe system operation without warning 10 Hazardous with warning Very high severity ranking when a potential failure mode affects safe system operation with warning 9 Very HighSystem inoperable with destructive failure without compromising safety8 HighSystem inoperable with equipment damage7 ModerateSystem inoperable with minor damage6 LowSystem inoperable without damage5 Very LowSystem operable with significant degradation of performance4 MinorSystem operable with some degradation of performance3 Very MinorSystem operable with minimal interference2 NoneNo effect1 Severity

26. Risk Assessment in QbD David R. González Barreto 26 Guidelines for Detectability DetectionLikelihood of DETECTION by Design ControlRanking Absolute UncertaintyDesign control cannot detect potential cause/mechanism and subsequent failure mode10 Very Remote Very remote chance the design control will detect potential cause/mechanism and subsequent failure mode 9 RemoteRemote chance the design control will detect potential cause/mechanism and subsequent failure mode8 Very Low Very low chance the design control will detect potential cause/mechanism and subsequent failure mode 7 LowLow chance the design control will detect potential cause/mechanism and subsequent failure mode6 Moderate Moderate chance the design control will detect potential cause/mechanism and subsequent failure mode 5 Moderately High Moderately High chance the design control will detect potential cause/mechanism and subsequent failure mode 4 HighHigh chance the design control will detect potential cause/mechanism and subsequent failure mode3 Very High Very high chance the design control will detect potential cause/mechanism and subsequent failure mode 2 Almost CertainDesign control will detect potential cause/mechanism and subsequent failure mode1 Detectability

27. Risk Assessment in QbD David R. González Barreto 27 FMEA Example - 1

28. Risk Assessment in QbD David R. González Barreto 28 FMEA Example - 2

29. Risk Assessment in QbD David R. González Barreto 29 Group Exercise - FMEA Using the previously drawn Ishikawa diagram from the selected process or sub- process, and the guidelines for O, S, and D, include several items on the FMEA table and calculate the RPN

30. Risk Assessment in QbD David R. González Barreto 30 Guidelines for Defining CCP’s

31. Risk Assessment in QbD David R. González Barreto 31 Using the Criticality Matrix To use the qualitative criticality analysis method to evaluate risk and prioritize corrective actions, the analysis team must: Rate the severity of the potential effects of failure. Rate the likelihood of occurrence for each potential failure mode. Compare failure modes via a Criticality Matrix, which identifies severity on the horizontal axis and occurrence on the vertical axis. These risk assessment methods are commonly associated with Failure Modes.

32. Risk Assessment in QbD David R. González Barreto 32 Criticality Matrix

33. Risk Assessment in QbD David R. González Barreto 33 FMEA - Applications and Benefits The Failure Modes, Effects and Analysis (FMEA) procedure is a tool that has been adapted in many different ways for many different purposes. It can contribute to improved designs for products and processes, resulting in higher reliability, better quality, increased safety, enhanced customer satisfaction and reduced costs. The tool can also be used to establish and optimize maintenance plans for repairable systems and/or contribute to control plans and other quality assurance procedures. It provides a knowledge base of failure mode and corrective action information that can be used as a resource in future troubleshooting efforts and as a training tool for new engineers.

34. Risk Assessment in QbD David R. González Barreto 34 Control Plan – for CQA’s

35. Risk Assessment in QbD David R. González Barreto 35 Capability Analysis for CQA Esp. Inf. Esp. Sup.

36. Risk Assessment in QbD David R. González Barreto 36 Capability Analysis for CQA Process Bandwith Tolerance Bandwith LTLNominalUTL

37. Risk Assessment in QbD David R. González Barreto 37 LEILESCpk = 1 Capability Analysis for CQA LEILESCpk = 2LEILESCpk = 1

38. Risk Assessment in QbD David R. González Barreto 38 Capability Analysis – Minitab Procedure Worksheet Window – Data Structure

39. Risk Assessment in QbD David R. González Barreto 39 Capability Analysis – Minitab Procedure Input - Menu Selection

40. Risk Assessment in QbD David R. González Barreto 40 Capability Analysis – Minitab Procedure Input Window

41. Risk Assessment in QbD David R. González Barreto 41 Capability Analysis – Minitab Procedure Output Window

42. Risk Assessment in QbD David R. González Barreto 42 Experimentación Proceso o Sistema Variables de Entrada Variables Controlables Factores Recursos Personal Equipo de Medidas Otros X y Variables de Salida Variables de Respuesta En DOE las variables X’s son manipuladas sistemáticamente. Típicamente resulta en una matriz de variables no correlacionadas CPP’s CQA’s

43. Risk Assessment in QbD David R. González Barreto 43 Experimentación y = f ( X ) +  Aspiramos a obtener un modelo matemático de la forma:

44. Risk Assessment in QbD David R. González Barreto 44 1 2 3 4 5 6 7 8 Low High Time Low High Time Low High Rotational Speed No Yes Homogeneity No Yes Homogeneity No Yes Homogeneity Particle Size Time Rotational Speed Particle Size Time Step 3 Step 1 Step 2 – 2 k Factorial Experiment Low Rotational Speed High Rotational Speed Low Particle Size High Particle Size Low Particle Size k=3 Experimental Space Design Space Process VariablesOutput Case Number Time Rotationa l Speed Particle Size Homogeneity 1High Yes 2High LowYes 3HighLowHighYes 4HighLow No 5LowHigh No 6LowHighLowYes 7Low HighNo 8Low No Particle Size Rotational Speed Rotational Speed Time Rotational Speed Particle Size Design Space Control Space Step 4 Copyright © IBS Caribe, Inc. 2008

45. Risk Assessment in QbD David R. González Barreto 45 QbD QbD – a systematic approach TOOLS Ishikawa Capability FMEA Pareto DOE

46. Risk Assessment in QbD David R. González Barreto 46 GLOSSARY Control Strategy: A planned set of controls, derived from current product and process understanding, that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. (ICH Q10) Critical Quality Attribute (CQA): A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. Critical Process Parameter: A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.

47. Risk Assessment in QbD David R. González Barreto 47 GLOSSARY Edge of Failure: The boundary to a variable or parameter, beyond which the relevant quality attributes or specification cannot be met. Proven Acceptable Range: A characterized range of a process parameter for which operation within this range, while keeping other parameters constant, will result in producing a material meeting relevant quality criteria. Quality by Design: A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management. Real-time release: The ability to evaluate and ensure the acceptable quality of in-process and/or final product based on process data, which typically include a valid combination of assessed material attributes and process controls.