ICH Q8 & Q9. Presented by John Montalto 13 May, 2013

Transcription

1 ICH Q8 & Q9 Presented by John Montalto 13 May, 2013

2 Guidelines Please contribute Please stopme to ask a question Please relax and enjoy yourself Phone on silent Slide 2 PharmOut 2013

3 ICH Q8 01 Introduction 02 ICH Quality paradigm 03 Pharmaceutical development 04 QbD 04a QbDcase study 05 Control strategy 06 QTPP 07 DoE 08 Process capability 09 Outcomes of Pharmaceutical development Slide 3 PharmOut 2013

4 ICH Q9 10 QRM overview 11 History of QRM 12 QRM resources 13 QRM Regulatory implementation 14 QRM multi-disciplinary teams 16 Risk registers 17 Risk management models 18 Risk management summary Activity 9-10 Activity Risk justifications Slide 4 PharmOut 2013

5 Assessment Open book assessment 30 minutes Hand in Assessment and Feedback form. Thank-you! Slide 5 PharmOut 2013

6 Introduction to Pharmaceutical Development and Quality Risk Management Presented by John Montalto 13 May, 2013

7 John Montalto I hold a Bachelor of Science degree and a Diploma in Management 16 years industry experience in a variety of roles Facilitator and consultant to various government agencies, regulators and the United Nations Slide 7 PharmOut 2013

8 Lei Hao This activity is a getting to know you exercise: Introduce yourself What is one interesting fact about you? 5 min/? Slide 8 PharmOut 2013

9 Course structure ICH Q8 Day 1 Pharmaceutical development Design space ICH Q9 Day 2 Implementation of Quality Risk Management (QRM) ICH Q9 Day 3 QRM models Slide 9 PharmOut 2013

10 Course objectives ICH Q8 ICH Q9 Understand the basic concepts and requirements of Pharmaceutical Development Understand the concepts and requirements of Quality by Design (QbD) Identify critical quality attributes and critical process parameters in a manufacturing process Integrate QRM into quality management systems Understand different risk assessment tools Slide 10 PharmOut 2013

11 Activity 1 Pharmaceutical development With the person next to you, discuss and document the following: Define the term pharmaceutical development What does pharmaceutical development mean to you? What do you expect within pharmaceutical development? Contribute to the group discussion WB 1/ 10 mins Slide 11 PharmOut 2013

12 Activity 2 Quality Risk Management (QRM) With the person next to you, discuss and document the following: Define the term Quality risk management What does Quality risk management mean to you? What do you expect from a QRM system? Contribute to the group discussion WB 2/ 10 mins Slide 12 PharmOut 2013

13 Influences on pharmaceutical development and risk management first factory mutual insurer was created ISO Medical devices Application of risk management to medical devices published ICH Q9 ICH Q10 ICH Q s Failure Modes ICH Effects established ICH Analyses Q8 were used to improve efficiency and run time of equipment from a Slide 13 reliability PharmOut 2013 perspective ASTM ASTM E2500- E ISO Risk management principles and guidelines

14 Top 10 Most Frequently Cited GMP Deficiencies (PIC/S Member Authorities) (July 2010 June 2011) 1. Documentation on manufacturing 2. Design & maintenance of premises 3. Documentation quality systems elements/procedures 4. Personnel issues training 5. Design & maintenance of equipment 6. Cleaning validation 7. Process validation 8. Product Quality Review 9. Supplier & contractor audit 10. Calibration of measuring & testing equipment Slide 14 PharmOut 2013

15 Top 10 Most Severe GMP Deficiencies (PIC/S Member Authorities) (July 2010 June 2011) 1. Design & maintenance of premises 2. Contamination, potential for (chemical, physical, microbial) 3. Design & maintenance of equipment 4. Sterility assurance 5. Batch release procedures 6. Process validation 7. Cleaning validation 8. Investigation of anomalies 9. Documentation quality systems elements/procedures 10.Regulatory issues noncompliance with marketing authorisation Slide 15 PharmOut 2013

16 Top Ten GMP Deficiencies found by MHRA (UK) (from MHRA web site Aug 2011) 1. Investigation of Anomalies 2. Quality management 3. Quality management (Change Control) 4. Validation Master Plan & Documentation 5. Corrective Action/Preventative Action (CAPA) 6. Complaints and Product Recall 7. Documentation 8. Equipment Validation 9. Quality Management Product Quality Review 10. Investigation of Anomalies - OOS Slide 16 PharmOut 2013

17 Pharmaceutical development and risk management in the future A greater emphasis on risk registers is one anticipated focus of regulatory agencies Integration of risk management into the wider quality systems Slide 17 PharmOut 2013

18 The ongoing impact of ICH Quality Guidelines Within the GMP guides expect an ongoing alignment with: ICH Q8 Pharmaceutical Development ICH Q9 Quality Risk Management ICH Q10 Pharmaceutical Quality System Slide 18 PharmOut 2013

19 EU GMP updates short term GMP chapter 1 GMP chapter 7 GMP Annex 2 PharmaceuticalQuality System Q10 alignment Outsourced Activities Q9 and Q10 alignment The MHRA has expressed its desire to better regulate and control biological products, and sees this industry as one of sustained growth and increasing proliferation in the market place Slide 19 PharmOut 2013

20 EU GMP updates mid term GMP chapter 2 GMP chapter 5 Q9 and Q10 alignment - Continuous verification of training The term pedigree and verifyingthe pedigree of starter materials - Location - Suppliers - Integrity of supplied product - Inspection and compliance of suppliers - Raw materials and starter materials controls - Certification of suppliers Slide 20 PharmOut 2013

21 EU GMP updates long term GMP chapters 3 and 5 Q9 alignment GMP chapter 6 GMP chapter 8 GMP Annex 16 Q9 and Q10 alignment Q9 alignment Qualified Persons Segregated facilities Formal considerationsfor Out Of Specification resultsand trending guidance Reporting strategies, product shortages, Corrective and Preventative Action systems and root cause analysis Harmonisation and mechanisms for ensuring consistent approaches for Qualified Persons and batch release Slide 21 PharmOut 2013

22 EU GMP proposals Ongoing regulatory focus The MHRA anticipate an ongoing adoption of ISO14644 Cleanrooms and associated controlled environments into Annex 1 Manufacture of Sterile Medicinal Products requirements Blood and tissues The creation of a Good Practice code for blood and tissues is seen as critical to public safety Improved clarification on collection and testing stages Slide 22 PharmOut 2013

23 EU GMP proposals Concept papers Annex 15 Qualification and Validation Continuous Process Verification will become a formal requirement of validation methodologies Annex 17 Parametric Release The rise of new technologies and on line testing technology will shape annex 17 in the future Slide 23 PharmOut 2013

24 EU GMP proposals Concept papers Good Distribution Practice for Active substances QRM guidelines for excipients handling Slide 24 PharmOut 2013

25 Pharmaceutical development an opportunity to present the knowledge gained through the application of scientific approaches and quality risk management to the development of a product and its manufacturing process. Slide 25 PharmOut 2013

26 Why adopt a risk management approach? "Two 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 Slide 26 PharmOut 2013

27 Laying the foundations Understanding the principles of QRM is the foundation for ensuring the process consistently produces a quality product. Slide 27 PharmOut 2013

28 Activity 3 What could go wrong? WB 3/ 10 mins Slide 28 PharmOut 2013

29 The quality paradigm Presented by John Montalto 13 May, 2013

30 ICH -20 year process The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) The ICH was initiated in 1990 Objective of ICH: Technical and scientific harmonisation between Japan, Europe and US. This objective has evolved significantly. Slide 30 PharmOut 2013

31 Quality Paradigm Paradigm a framework containing the basic assumptions, ways of thinking and methodology that are commonly accepted by members of a scientific community Slide 31 PharmOut 2013

32 Quality paradigm Develop a harmonised pharmaceutical quality system applicable across the lifecycle of the product emphasizing an integrated approach to quality risk management and science. Pharmaceutical Quality System ICH, 2003 Quality risk management Science and knowledge Slide 32 PharmOut 2013

33 Quality paradigm ICH Q8 Pharmaceutical Development ICH Q11 Development and Manufacture of Drug Substances ICH Q9 Quality Risk Management ICH Q10 Pharmaceutical Quality System Slide 33 PharmOut 2013

34 Quality paradigm Science and knowledge should not be isolated, but are dynamic across the lifecycle of the product and process and implemented throughout the quality management systems Slide 34 PharmOut 2013

35 Quality paradigm Key points 1 Quality must be built in. Quality cannot be tested in. 2 Utilise and rely on science throughout the product lifecycle 3 QRM is a key enabler to be applied acrossthe product lifecycle 4 Toassure product quality, a robust pharmaceutical quality system and knowledge management must be in place 5 An integrated approach to quality; including development, manufacturing and quality Slide 35 PharmOut 2013

36 Quality paradigm Quality must be built in. Quality cannot be tested in. In process and end product testing are only indicators of product quality What must be considered: In process and end product testing Process reliability and robustness Controlling variables More comprehensive assurance of product quality Slide 36 PharmOut 2013

37 Quality paradigm Utilise and rely on science throughout the product lifecycle What are the Critical Quality Attributes (CQAs) of a bottle of water? Slide 37 PharmOut 2013

38 Quality paradigm Slide 38 PharmOut 2013

39 Quality paradigm QRM is a key enabler to be applied across the product lifecycle Utilise QRM to formalise knowledge and establish more reliable communication mechanisms Utilise QRM to assess and evaluate the impact of variables to the product and process QRM is a dynamic process that continually evolves Slide 39 PharmOut 2013

40 Quality paradigm To assure product quality, a robust pharmaceutical quality system and knowledge management system must be in place: QRM must be integrated into the quality management system Knowledge must be: Acquired Captured Managed Slide 40 PharmOut 2013

41 Quality paradigm An integrated approach to quality, including: Development Manufacturing Quality Stand alone systems will not adequately incorporate knowledge Information and knowledge from all phases of the product lifecycle must feedback into the quality management system Slide 41 PharmOut 2013

42 ICH Q8 Empirical, minimal approach Considers only the essential product development requirements Enhanced approach Quality by Design (QbD) Comprehensive understanding of product and process Slide 42 PharmOut 2013

43 Approaches & Outcomes Minimal Enhanced Conducted one variable at a time minimum product knowledge Focus on optimization and reproducibility of process End product testing Primary control through FPP specifications FPP quality controlled by in-process and end product testing Multivariate experiments extensive product knowledge Focus on control strategy and robustness of process On line (PAT) tools utilized FPP specifications part of overall control strategy FPP quality ensured through risk based control strategy since product and process are well understood. Real time release testing with possible reduction of end product testing Quality over product life cycle managed through problem solving and corrective action Quality over product life cycle managed through preventive action and continuous improvement Satish Mallya, World Health Organisation, 2011 Slide 43 PharmOut 2013

44 Quality paradigm The ultimate aim of quality is to improve patient outcomes Slide 44 PharmOut 2013

45 Pharmaceutical Quality System Pharmaceutical Development Technology Transfer Commercial Manufacturing Product Discontinuation Good Manufacturing Practice Management Responsibilities PQS elements Process Performance & Product Quality Monitoring System Corrective Action / Preventative Action System Change Managements System Management review Knowledge Management Enablers Quality Risk Management Slide 45 PharmOut 2013

46 Influences on pharmaceutical development and risk management first factory mutual insurer was created ISO Medical devices Application of risk management to medical devices published ICH Q9 ICH Q10 ICH Q s Failure Modes ICH Effects established ICH Analyses Q8 were used to improve efficiency and run time of equipment from a Slide 46 reliability PharmOut 2013 perspective ASTM ASTM E2500- E ISO Risk management principles and guidelines

47 ICH Q8 Pharmaceutical Development Presented by John Montalto 13 May, 2013

48 Quality In Brussels, 2008, the ICH made the following statement: develop a harmonisedpharmaceutical quality system applicable across the lifecycleof the product emphasizing an integrated approach to quality risk management and science. Slide 48 PharmOut 2013

49 Pharmaceutical development The aims of pharmaceutical development include: The design of a quality product and its manufacturing process Slide 49 PharmOut 2013

50 Pharmaceutical development Design a quality product and its manufacturing process Build quality in to the design of the product and its manufacturing process Consistently deliver the intended performance of the product Slide 50 PharmOut 2013

51 Pharmaceutical development Research and Development (R&D) activities should not be isolated from the wider business. R&D provides an excellent opportunity to learn about the product and its manufacturing process. This learning and knowledge must be translated into the subsequent life cycle phases. Slide 51 PharmOut 2013

52 Pharmaceutical development R&D is no longer restricted to developing a pharmaceutical product, it must include the development of a manufacturing process. One of the greatest variables any product will face is the up scale of a manufacturing process. Slide 52 PharmOut 2013

53 Pharmaceutical development What can be done with all of this information gained from pharmaceutical development? 1 Establish quality risk management program for the product and its manufacturing process 2 Gain knowledge and establish parameters (design space) where you can verify the consistent manufacture of a product that fulfils its intended purpose Slide 53 PharmOut 2013

54 ICH Q8 ICH Q8 Pharmaceutical Development, is split into two sections: Part I Pharmaceutical Development details what regulatory submissions need to include for compliance Part II Annex to Pharmaceutical Development considers an approach to realising Pharmaceutical Development Slide 54 PharmOut 2013

55 Pharmaceutical development Slide 55 PharmOut 2013

56 Pharmaceutical development How does a lack of information impact your business right now? How does a lack of knowledge impact your quality decisions right now? Do you know why your product is in the dosage from that it is in? Slide 56 PharmOut 2013

57 Pharmaceutical development Quality by Design (QbD) is one component of pharmaceutical development: Manufacturing processes and formulation Product quality Process control strategies Risk based regulatory scrutiny Patient safety Slide 57 PharmOut 2013

58 Pharmaceutical development While design space is optional, Control Strategy is never optional Jacques Morenas, former PIC/S Chair, April Slide 58 PharmOut 2013

59 US FDA Process Validation stages Stage 1 Process Design Stage 3 Continued Process Verification Stage 2 Process Qualification Slide 59 PharmOut 2013

60 US FDA Stage 1 Identify sources of variability Stage 3 Statistical evaluation of data Stage 2 Control of variability Slide 60 PharmOut 2013

61 Pharmaceutical development Quality by Design Design space Establishing product and process performance parameters Testing, Design of Experiments, verification of product and process performance parameters Stress testing Understanding the impact of variables on your product and process Slide 61 PharmOut 2013

62 Pharmaceutical development Understanding the impact of variables on your product and process. Quality risk management approach Understanding and controlling variability to deliver consistent products that fulfil their label claims Slide 62 PharmOut 2013

63 What drives your process? Product Product understanding is required to design the process. Process Critical Quality Attributes define the process. Slide 63 PharmOut 2013

64 CQA and CPP Critical Quality Attribute A CQA is 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 Drug substance, excipients, intermediates Slide 64 PharmOut 2013

65 CQA and CPP 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 Slide 65 PharmOut 2013

66 Pharmaceutical development Slide 66 PharmOut 2013

67 Pharmaceutical development Risk Assessment Slide 67 PharmOut 2013

68 Activity 4 ICH Q8 Pharmaceutical development Activity 4.1 Read and review section 2 to section Summarise the main points in your workbook Work in pairs or individually Contribute to group discussion WB 4.1/ 45 mins Slide 68 PharmOut 2013

69 Pharmaceutical development Considerations should include: Drug substances Excipients Container closure Manufacturing processes Slide 69 PharmOut 2013

70 Pharmaceutical development Organisations may want to fulfil the minimum requirements for product development. This may be a false economy because enhanced science based knowledge may result in more flexibility from regulators. Slide 70 PharmOut 2013

71 Drug product components Drug substance considerations: Physiochemical and biological properties Consider pharmacopeia requirements manufacturability Slide 71 PharmOut 2013

72 Characterisation What are the potential impurities of the drug substance? What are the sources of each impurity? Are impurities a result of degradation or process failure? Slide 72 PharmOut 2013

73 Drug product components Drug substance considerations: What is the drug substance specification? For each test in the specification, what is the justification for the acceptance criteria? For each test in the specification, provide a summary of analytical methods. Slide 73 PharmOut 2013

74 Drug product components What are the storage conditions and the retest/expiry period for the drug substance? The structure of stability studies must be considered Slide 74 PharmOut 2013

75 Drug product components Excipients: The excipients chosen and the justification for selection Compatibility with the drug substance and other excipients must be considered manufacturability Slide 75 PharmOut 2013

76 Drug product components Excipients: What are the components and composition of the final drug product on both a per unit dose and %w/w basis? How does each excipient work in the product? For example, does any excipient exceed the FDA inactive ingredient database limit for this route of administration Slide 76 PharmOut 2013

77 Drug product Formulation development: Which attributes are critical to the quality of the drug product? What is the therapeutic benefit of the product? Slide 77 PharmOut 2013

78 Drug product Overages: The preference is to eliminate overages due to degradation of the product over time. This in itself is an excellent demonstration of pharmaceutical development where a key attribute must be designed to be robust and repeatable and not have to compensate for lack of capability. Slide 78 PharmOut 2013

79 Drug product Physiochemical and biological properties: What impacts safety, performance and manufacturability of the product? Aseptic products will pose different challenges and greater attention on process capability may be required. Slide 79 PharmOut 2013

80 Manufacturing process development What is the manufacturing process utilised and how will the process be controlled? What manufacturing processes are available and what adaptation is required? Slide 80 PharmOut 2013

81 Manufacturing process development The manufacturing process development programme or process improvement programme should identify any critical process parameters that should be monitored or controlled (e.g., granulation end point) to ensure that the product is of the desired quality. Slide 81 PharmOut 2013

82 Methods of manufacture (MoM) The EU guide to Process Validation provides some detail relevant to methods of manufacture. Non-standard MoM Specialised dose forms New technology in conventional processes Highly specialised or highly complex processes Non-standard methods of sterilisation Highly specialised or highly complex Includes processes such as lyophilizationand aseptic manufacture, real time release (parametric release) Slide 82 PharmOut 2013

83 Standard or Non-standard MoM: Needs to be justified on a case-by-case basis considering the appropriate development data or by reference to similar products. Slide 83 PharmOut 2013

84 Manufacturing process development What is the existing or proposed control strategy for the manufacturing process? How are critical attributes monitored? How will data gathered during development studies be analysed? Slide 84 PharmOut 2013

85 Manufacturing process development considerations What is the rationale for selecting this manufacturing process for the drug product? What process development studies, were conducted and at what scale? (the EMA Guideline on Process Validation refers to a scale up factor of less than 10) Slide 85 PharmOut 2013

86 Manufacturing process development What is the process map listing input material attributes, process parameters, and output material quality attributes for all of the unit operations in the manufacturing process? How will the robustness of the process be measured? Slide 86 PharmOut 2013

87 Container closure system Based on the intended use of the product, the container closure system should be justified. Considerations should include: Primary packaging materials Consideration of the product supply chain Materials of construction and product compatibility Slide 87 PharmOut 2013

88 Container closure system Dosing devices must be able to consistently deliver the required dose. Repeated use verification may should consider real life product conditions Slide 88 PharmOut 2013

89 Microbiological attributes Microbiological attributes may include: Microbial limits testing and the relevance of this Preservative systems and the justification for these systems For aseptic products, maintaining integrity of the container closure system Antimicrobial preservative effectiveness Slide 89 PharmOut 2013

90 Novel product considerations Use pharmaceutical development studies to supplement clinical trial information: Pharmaceutical development advantages Know what your product and process can tolerate Understand how various parameters influence product quality Knowing and not guessing, what s important to patient safety and product quality Slide 90 PharmOut 2013

91 Legacy product considerations Design space is considered optional, but control strategy is not optional. Advantages Formal product and process knowledge Clear communication from product development through to manufacture of what impacts product and process quality Regulatory flexibility Disadvantages The cost of establishing a non compulsory item The payback is too difficult to quantify Slide 91 PharmOut 2013

92 ICH tripartite integration Q8 Q9 Q10 Quality Target Product Profile (QTPP) Clinicaland non clinical studies on drug substance Risk efforts to evaluate patientneeds and product risks Knowledge management; previous knowledge and experiments Slide 92 PharmOut 2013

93 ICH tripartite integration Q8 Q9 Q10 Process development Characterisation of process Design of Experiments (DoE) Determine failure modes Identify potential product parameters that impact quality Batch records Technical transfer Supplier identification and selection Slide 93 PharmOut 2013

94 ICH tripartite integration Q8 Q9 Q10 Commercial manufacture Commercial process design On line technology implementation Develop control strategy Manage risks Standard Operating Procedures Validation Process Analysis and trending of data Monitoring and establishing alert and action limits Slide 94 PharmOut 2013

95 Acknowledgements Jennifer A. Maguire, Ph.D& Karen A. Bernard, Ph.DCMC Reviewers, Office of Generic Drugs, US Food and Drug Administration US FDA Process Validation Guidance for Industry, 2011 EMA Guideline on Process Validation, 2012 ICH Slide 95 PharmOut 2013

96 Quality by Design Presented by John Montalto 13 May, 2013

97 Quality by Design (QbD) 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 Slide 97 PharmOut 2013

98 QbD The company that fails is the company that comes to us and says Just tell us what to do and we will do it. The company that succeeds is the company that says to us Here is what we did and why we think it is appropriate. Dr. Phillip Minor National Institute of Biological Standards and Control Slide 98 PharmOut 2013

99 FDA Pharmaceutical GMPs for the 21st Century Science & Risk based regulation FDA s New Initiative on Drug Product Quality Janet Woodcock, MD Director, Center for Drug Evaluation and Research Food and Drug Administration October 25, 2002 Slide 99 PharmOut 2013

100 Impact of Risk Slide 100 PharmOut 2013

101 The impact of Science ICH Tripartite Risk Quality Targeted Product Profiles QTPP Other documents Case studies PDA & FDA GMP s EU US FDA PIC/S ICH Q8, Q9 Q10 and Q11 Critical Quality Attributes (CQA) Critical Process Parameters CPP Design of experiments DOE Product Lifecycle QbD Design EU - Voluntary space Control EU - Mandatory strategy Slide 101 PharmOut 2013

102 Who is driving QbD? As we ve said many, many times, FDA Office of Generic Drugs expects QbDapplications starting January US FDA s Lawrence Yu, Deputy Director for science and chemistry in the You Office heard of Generic right, full Drugs implementation of QbDin January Slide 102 PharmOut 2013

103 Where does QbD start? QbD is a lifecycle concept FDA Process Validation -3 stages 1. Process Design = Quality by Design 2. Process Qualification 3. Continued Process Verification Slide 103 PharmOut 2013

104 What is QbD? The quality by design (QbD) principle can be simply stated as follows: Once a system has been tested to the extent that the test results are predictable, further testing can be replaced by establishing that the system was operating within a defined design space. Slide 104 PharmOut 2013

105 What is the goal? Focus of FDA PV Guideline Variable or variability- Mentioned 19 times Control- Mentioned 62 times Statistics- Mentioned 15 times Inputs and Outputs Slide 105 PharmOut 2013

106 FDA PV Stages Stage 1 Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities. Identify Variability Stage 2 Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing. Control of Variability Stage 3 Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control. [FDA Guidance for Industry Process Validation: General Principles and Practices, Jan 2011] Statistics Slide 106 PharmOut 2013

107 Design space The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval (ICH Q8). Slide 107 PharmOut 2013

108 Design space A design space can be dynamic and updated as knowledge and experience with the process are acquired. Operating within the design space is part of the control strategy. Design space is generally part of R&D and the risks associated with scale up must be identified and controlled. Slide 108 PharmOut 2013

109 Design space Consider the design space for a single unit operation i.eget participants to design an ideal packing line. Link to CQAs Upstream and downstream interfaces Slide 109 PharmOut 2013

110 Design space Slide 110 PharmOut 2013

111 Design space In developing design spaces for existing products, multivariate models can be used for retrospective evaluation of historical production data. The level of variability present in the historical data will influence the ability to develop a design space, and additional studies might be appropriate. Slide 111 PharmOut 2013

112 Design space Capturing development knowledge and understanding contributes to design space implementation and continual improvement. Slide 112 PharmOut 2013

113 Slide 113 PharmOut 2013

114 Control strategy table DrugSubstance CQA (3.2.S.2.6) / Limit In Drug Substance In process Controls (IncludingIn-process testing and process parameters) Controls on material attributes (raw materials / starting materials / intermediates) Impact of Manufacturing Process Design Is CQA tested on drug substance / Included in Drug Substance specification (3.2.S.4.1) Organic Purity Impurity X NMT 0.15% Designspace of the reflux unit operation composed of a combination of % water in Intermediate E and the reflux time in step 5 that delivers Intermediate F with Hydrolysis Impurity 0.30% (3.2.S.2.2) Yes/Yes Impurity Y NMT 0.20% Any individual unspecified impurity NMT 0.10% Process parameters step 4 (3.2.S.2.2) P(H2) 2 barg T <50 C In-process test step 4 (3.2.S.2.4) Impurity Y 0.50% Specs for starting material D (3.2.S.2.3) Yes/Yes Yes/Yes Total impurities Yes/Yes NMT 0.50% Enantiomeric purity S-enantiomer NMT 0.50% Specsfor starting material D (3.2.S.2.3) S-enantiomer 0.50% Stereocentreis shown not to racemize; (3.2.S.2.6) No/No Residual Solvent In-process test during drying after final purification step Ethanol (3.2.S.2.4) NMT 5000 Slide ppm 114 LOD 0.40% PharmOut 2013 In-processresults correlated to test results on drug substance No/Yes

115 Activity 4 ICH Q8 Pharmaceutical development Activity 4.2 Read and review section 2.3 to section 2.6 Summarise the main points in your workbook Work in pairs or individually Contribute to group discussion WB 4.2/ 45 mins Slide 115 PharmOut 2013

116 Extracted from the FDA IM release worked example dnewdrugapplicationandagenerics/ucm pdf Slide 116 PharmOut 2013

117 Lifecycle Approach Example Process Design PV (PPQ) Commercial Manufacturing Level of QC Lab Testing Could vary based on approach Variability Estimate Established Post Periodic Review Signal Change introduced / CAPA PAT Implemented Monitoring QC Testing Time / Process Knowledge Control Strategy is dynamic over the lifecycle Slide 117 PharmOut 2013

118 Quality By QC Sampling Sampling Errors Introduction of variables through sampling interventions Testing How accurate is the test method? Is the sensitivity of the test known What is the incidence of false positives Slide 118 PharmOut 2013

119 Sampling n = 6 Slide 119 PharmOut 2013

120 Sampling First 6 Slide 120 PharmOut 2013

121 Sampling Random 6 Slide 121 PharmOut 2013

122 Sampling Stratified Slide 122 PharmOut 2013

123 Sampling Systematic Slide 123 PharmOut 2013

124 Sampling First Last Targeted Slide 124 PharmOut 2013

125 Sampling Morning Tea First Lunch Shift Change Afternoon Tea Last Knowledge / Risk Slide 125 PharmOut 2013

126 Holistic Approach Continued Process Verification Process Qualification Process Design Continued Process Verification Process Qualification Process Design Continued Process Verification Process Qualification Process Design Extensive product and process design efforts can lead to streamlined efforts in later stages of product lifecycle Slide 126 PharmOut 2013

127 Lifecycle Approach Example Process Design PV (PPQ) Commercial Manufacturing Level of QC Lab Testing Could vary based on approach Variability Estimate Established Post Periodic Review Signal Change introduced / CAPA PAT Implemented Monitoring QC Testing Time / Process Knowledge Control Strategy is dynamic over the lifecycle Slide 127 PharmOut 2013

128 What is the Process Validation Shift in Emphasis? Old definition: Process validation is defined as the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products. New definition: Objective understand and control input variability impact and manufacturing process to assure consistent product quality and reliable supply Concern about recent quality issues and drug shortages FDA Guidance for Industry, Process Validation: General Principles and Practices, January Slide 128 PharmOut 2013

129 Quality by Design case study Presented by John Montalto 13 May, 2013

130 Activity 5.1- The perfect Cappuccino! Inputs Outputs Raw Materials Milk Sugar Water Chocolate Powder Coffee Beans QTPP Taste Temperature Equipment Cup-saucer-spoon Grinder Espresso Machine Barista Appearance Aroma Texture WB 5.1/ 5 mins Slide 130 PharmOut 2013

131 Activity 5.2 -QbDCase Study The perfect cappuccino Complete a risk assessment for making a cappuccino Risk rate each process stage against the inputs Low (L), Medium (M), High (H) Work in groups E.g. Raw Material WB 5.2/ 40 mins Slide 131 PharmOut 2013

132 Risk Assessment Processing stage Milk Sugar Water Chocolate Coffee beans Cup, Saucer, Spoon Grinder RM QC & QA Grinding Brewing Frothing Low Low Low Low High Low Low Low Low Low Low High Low Low Low Low High Low Low Low Low Med. Low Low Low Low Low Low Slide 132 PharmOut 2013

133 Design of Experiment (DOE) Extent of coffee grind is critical to quality, but how much is enough? What other variables need to be considered in the DOE process? Grinder, Grinding time, Fineness. How can these variables be tested? Slide 133 PharmOut 2013

134 Activity 5.3 -QbDCase Study The perfect cappuccino What controls would you put in place in order to reduce the risk? (Establish a control strategy) WB 5.3/ 5 mins Slide 134 PharmOut 2013

135 The perfect Cappuccino! Inputs Controls Outputs Raw Materials Milk Sugar Water Chocolate Powder Coffee Beans Equipment Cup-saucer-spoon Grinder Espresso Machine Barista Vendor Assurance Screening Thermometer CQA Taste Temperature QA Appearance Aroma Texture Slide 135 PharmOut 2013

136 Activity 5.4 -QbDCase Study The perfect cappuccino Repeat the risk assessment for making a cappuccino assuming the control strategy is in place. Risk rate each process stage against the inputs Low (L), Medium (M), High (H) Work in groups E.g. Raw Material WB 5.4/ 10 mins Slide 136 PharmOut 2013

137 Risk Assessment Processing stage Milk Sugar Water Chocolate Coffee beans Cup, Saucer, Spoon Grinder RM QC & QA Grinding Brewing Frothing Low Low Low Low Low Low Low Low Low Low Low Med. Low Low Low Low Low Low Low Low Low Med. Low Low Low Low Low Low Slide 137 PharmOut 2013

138 Identifying variables Quality Target Product Profile (QTPP) Appearance Temperature Aroma Texture Taste Sweetness Bitterness Aftertaste Critical Quality Attributes (CQA) Taste Temperature (Safety) Slide 138 PharmOut 2013

139 Controlling Variables Critical Quality Attributes (CQA) Temperature Critical Process Parameters (CPP) Thermometer Acceptance criteria Taste Coffee beans Source control Auditing Acceptance criteria Grinding How much grinding Slide 139 PharmOut 2013

140 Control Strategy Inputs Outputs Raw Materials Milk Sugar Water Chocolate Powder Coffee Beans Equipment Cup Spoon Coffee Machine Barista CQA Taste Temperature QA Appearance Aroma Texture Slide 140 PharmOut 2013

141 Control Strategy Planned set of controls, derived from current product and process understanding that assures process performance and product quality A control strategy can include, but is not limited to the following: Material attributes (raw materials, starting materials, intermediates, reagents, primary packaging materials) Controls are implicit in the design of the manufacturing process In-process controls Controls on drug substance Slide 141 PharmOut 2013

142 Control Strategy Presented by John Montalto 13 May, 2013

143 Control strategy A planned set of controls, derived from current product and process understanding that ensures 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, inprocess controls, finished product specifications, and the associated methods and frequency of monitoring and control. (ICH Q10) Slide 143 PharmOut 2013

144 Control strategy Control strategies are designed to ensure product quality, consistently. Some considerations for control strategies include: In process controls Input material control Container closure controls Slide 144 PharmOut 2013

145 Control strategy The focus of control strategies must be, initially on critical process parameters. Remember, critical process parameters are translated from critical quality attributes. Critical process parameters must be measurable and quantifiable. Slide 145 PharmOut 2013

146 Control strategy The aims of pharmaceutical development are to minimise sources of variability and to build knowledge of product and process. Understanding your product, process and variables facilitates the development of adequate control strategies. Slide 146 PharmOut 2013

147 Control strategy Risk transfer is an appropriate control strategy: Can you implement controls at another stage of the process? Is there an opportunity to minimise the reliance on end product testing? Slide 147 PharmOut 2013

148 Control strategy ICH diagramatic example of real time feed back loop NEEDS A DIAGRAM FROM JOHN Slide 148 PharmOut 2013

149 Control strategy Control strategy inclusions: Control of input materials and attributes Product specifications Controls for unit operations Monitoring and measuring CQAs during processing An ongoing monitoring program Slide 149 PharmOut 2013

150 Control strategy Control strategy is a continuum of controls, as opposed to one discrete control for one parameter Slide 150 PharmOut 2013

151 Linking ICH Q8, Q9 and Q10 to develop a control strategy Identify all quality attributes based on current process and product understanding Risk assessments identify Critical Quality Attributes (CQAs) Control Strategy design, develop and implement Dynamic process as product knowledge and process understanding increase Continual improvement Slide 151 PharmOut 2013

152 Control strategy Slide 152 PharmOut 2013

153 Risk assessment identify Critical Quality Attributes (CQAs) Appearance Performance Comfort Stopping Heating /Cooling Transmission Severity (impact on quality) Probability (risk likelihood) L H L H L L L M M M L M Detectability H M H M H H Total L H L H L L Slide 153 PharmOut 2013

154 Risk assessment identify CQAs Appearance Performance Comfort Stopping Heating/ Cooling Transmission Colour Brake assembly Acceleration Suspension Seat covering Tyres Fuel type Slide 154 PharmOut 2013

155 Developing Control Strategy Stopping Brake assembly Stopping Vehicle gradually stops by application of a foot peddle at 10m/s/s Control Strategy Qualification of manufacturing equipment Assembly Process Validation Control Strategy Raw materials, lubricants and oils Feedback Maintenance Life Plans -Brake pressure switch calibration, inspection regime Slide 155 PharmOut 2013

156 An ongoing process How would you use control strategies to verify your validation efforts? Slide 156 PharmOut 2013

157 An ongoing process While design space is optional, Control Strategy is never optional Jacques Morenas, PIC/S Chair, April 2011 Slide 157 PharmOut 2013

158 CQA and CPP Critical Quality Attribute A CQA is 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 Drug substance, excipients, intermediates 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 Slide 158 PharmOut 2013

159 CQA and CPP In-process control Checks performed during production to monitor and if appropriate, adjust the process In-process tests Tests which may be performed during the manufacture of either the drug substance or drug product, that may be outside of routine inprocess tests Slide 159 PharmOut 2013

160 Quality Risk Management Product knowledge drives Process development Develop Control Strategy Continual improvement Slide 160 PharmOut 2013

161 An ongoing process It is a requirement of GMP that manufacturers identify what validation work is needed to prove control of the critical aspects of their particular operations. Annex 15, PIC/S Guide to Good Manufacturing Practice for Medicinal Products Annexes, January, 2013 Slide 161 PharmOut 2013

162 Control strategy The controls may include parameters that apply to: Drug substance Drug product materials Components Facilities and equipment parameters In process controls Finished product specifications Slide 162 PharmOut 2013

163 Control Strategy is not Is not a new concept Your products and processes already have control strategies Is not just a list of specifications for QC testing requirements Is NOT optional Slide 163 PharmOut 2013

164 Implement Control Strategy Every process and product has an associated control strategy: Overall strategy for a product Discrete control strategy for an operation Slide 164 PharmOut 2013

165 Various approaches Control strategy approaches: In-process testing Real time release testing End-product testing Localised Control strategy approaches Controls on raw and starting material attributes, intermediates and reagents Sequence of purification steps Order of addition of reagents Training and personnel matters Gowning and clean room behaviours Slide 165 PharmOut 2013

166 Batch release Control Strategy and batch release decisions are separate Control Strategy is not the only consideration when batch release decisions are determined Slide 166 PharmOut 2013

167 Defining the control strategy What are the quality criteria (QTPP)? Rely on knowledge - including the design of the product and process Risk based approach to identify critical process parameters Ongoing knowledge and continual improvement Slide 167 PharmOut 2013

168 Control strategy within the lifecycle The control strategy requires continual improvement. How can you build knowledge? The more you know about your product and performance the more ability you will have to control. Slide 168 PharmOut 2013

169 Traditional approach Emphasis on end-product testing Operating ranges set on observed process data Generally narrow target range Process capability (or lack of capability) Slide 169 PharmOut 2013

170 In process approach In process determination that a CQA is within an appropriate range or limit. Remember validation requires a high degree of assurance. Documented evidence In the not so distant future technology will change control strategies. Process Analytical Technologies (PAT) Real Time Release Testing (RTRT) Slide 170 PharmOut 2013

171 Different points of view Industry Analytical testingsensitivity Equipment limitations Regulators Has risk been adequatelyidentified and controlled? Quality Management Systemadequacyto support the Control Strategy Cost Compliance with Annex 15? Slide 171 PharmOut 2013

172 Summary Product Quality and Process Performance Monitoring: Ensure a state of control is maintained (control inter and intra batch variability) Plan and execute a system for monitoring CQAs and CPPs Slide 172 PharmOut 2013

173 Summary Use QRM to establish Control Strategy Control Strategy facilitates timely feedback/feed forward and appropriate CAPA Provide tools for measurement and analysis of parameters and attributes within Control Strategy Identify sources of variation affecting process performance and product quality focus continuous improvement here Use internal and external feedback Provide and manage knowledge to enhance process understanding Slide 173 PharmOut 2013

174 Quality Target Product Profile (QTPP) Presented by John Montalto 13 May, 2013

175 QTPP A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product. ICH Q8 Slide 175 PharmOut 2013

176 QTPP Establish Quality Target Product Profile (QTPP) Identify Critical Quality Attributes (CQA) of the FPP Investigate quality attributes of the API and formulation ingredients Outline control strategies Select an appropriate manufacturing process and establish the Critical Process Parameters (CPP) Slide 176 PharmOut 2013

177 QTPP The QTPP is a cornerstone of design for the development of the product QTPP considerations Intended clinical use of the product Dosage and dosage forms Container closure systems Therapeutic indication, release and delivery Drug product quality criteria Slide 177 PharmOut 2013

178 QTPP Slide 178 PharmOut 2013

179 QTPP considerations Paracetamol Quality Target Profile (QTPP) Requirements Translation into Critical Quality Attributes (CQAs) Dose 500 mg tablet Identity, Assay, Content Uniformity Container Plastic blister, foil backing All blisters filled, correct number of strips in pack, Unit Integrity and other characteristics Subjective properties Identity, Appearance, colour, uniformity Taste, odour Appearance and other characteristics Absence of defects Patient safety chemical purity Patient safety biological purity Chemical and drug product stability : 3 year shelf life Impurities and / or degradation products below ICH or to be qualified Free from pathogens, Free from yeast or moulds or below the specified limit Degradation products below ICH or to be qualified and no changes in bioperformance over expiry period Pharmacopoeial Compliance Meets pharmacopoeial requirements for tablet dosage forms Meets requirements of TGO 78 (Aust.) Acceptable degradation product levels at release, appropriate manufacturing environment controls Input raw material quality Degradation controlled by packaging, protected from light & heat & oxygen Input raw material quality Quality of direct impact services and utilities Clean manufacturing environment and equipment Acceptable impurity levels at release appropriate manufacturing & environmental controls Pharmacopoeial tests and specifications Slide 179 PharmOut 2013

180 Activity 4 ICH Q8 Pharmaceutical development Activity 4.3 Read and review Part II: Pharmaceutical development Annex Section 2 to 2.3 Summarise the main points in your workbook Work in pairs or individually Contribute to group discussion WB 4.3/ 45 mins Slide 180 PharmOut 2013

181 Quality by Design considerations Presented by John Montalto 13 May, 2013

182 Quality by Design Establishing quality by design can take many different forms: Consider single or multi-variate analysis Usually some time of experimentation will feature to establish product and process tolerances Slide 182 PharmOut 2013

183 Design of Experiments (DoE) Quality Risk Management recognises that formal efforts are not always appropriate and that informal justifications can provide adequate information. Consider a summary table of factors and ranges reviewed and the conclusions drawn Slide 183 PharmOut 2013

184 Design of Experiments (DoE) DoE can be utilised to establish design space considerations: What was the criteria used to select variables? How were ranges for the variables established? The interaction of variables may also need careful attention Slide 184 PharmOut 2013

185 Design of Experiments (DoE) Raw material variability may have an impact on DoE. The handover of information from process development to commercial manufacture may include raw material suppliers Slide 185 PharmOut 2013

186 Design of Experiments (DoE) Constants: Listing of the parameters that would be kept constant during the DoEsand their respective values, including predictions on the impact of scale on these parameters Slide 186 PharmOut 2013

187 Design of Experiments (DoE) The type of experimental design: People may use predictive models to anticipate outcomes Models can provide great value but the models chosen must be analysed and evaluated for potential weaknesses in data Slide 187 PharmOut 2013

188 Design of Experiments (DoE) Scale dependant factors: Scale up is a great source of variability for any process and the control of scale up work and the impact of scale up must be adequately managed Slide 188 PharmOut 2013

189 Design of Experiments (DoE) Results and statistical analysis of DoE data showing the statistical significance of the factors and their interactions, including predictions made from DoE studies relevant to scale and equipment differences Considerations need to include statistically significant data sizes Multiplication and extrapolation of data is complex and may demand subject matter expertise Slide 189 PharmOut 2013

190 Design of Experiments (DoE) For organisations with QMS, design of experiments should be based on data: Perform an analysis on the available data Allow the date to guide your single variate and multi-variate experiments Slide 190 PharmOut 2013

191 Process Capability Presented by John Montalto 13 May, 2013

192 Process Capability Medicinal products are consistentlyproduced and controlledto the quality standards appropriateto their intended use and as required by the marketing authorisation or product specification. Slide 192 PharmOut 2013

193 A Capable Process? Sufficient knowledge & understanding about critical product and process parameters and quality attributes Control Strategy in place Process in a State of Control Knowledge & understanding gained over time Continued Process Verification Process Design Process Qualification Slide 193 PharmOut 2013

194 US FDA stance on Process Capability We recommend that a statistician or person with adequate training in statistical process control techniques develop the data collection plan and statistical methods and procedures used in measuring and evaluating process stability and process capability. Slide 194 PharmOut 2013

195 US FDA stance Production data should be collected to evaluate process stabilityand capability. If properly carried out, these efforts can identify variabilityin the process and/or signal potential process improvements. Both quality and business benefits Slide 195 PharmOut 2013

196 Process Capability Two Assumptions: The process is in statistical control. The distribution of the process considered is Normal. Sources of variation well understood and detectable The impact of variation on the process and on product attributes clearly defined The variation must be controlledin a manner commensurate with the riskit represents to the process and product Slide 196 PharmOut 2013

197 What is normal? Normal distributions are symmetrical with a single central peak at the mean (average) of the data. The shape of the curve is described asbell-shaped (Gaussian)with the graph falling off evenly on either side of the mean. 50% of the distribution lies to the left of the mean and 50% lies to the right of the mean. Slide 197 PharmOut 2013

198 Normal distribution Area under the curve =100% ~68% of the area falls within 1 StDev. ~ 95% of the area falls within 2 StDev. ~ 99.7% of the area falls within 3 StDev. Slide 198 PharmOut 2013

199 Process Capability Analysis Process capability analysis compares the performance of a process against its specifications. Two parts of Process Capability: 1) Measure the variability of the output of a process 2) Compare that variability to its specification (USL and LSL) Slide 199 PharmOut 2013

200 Process Capability Index Process Capability IndexorProcess Capability Ratiois a statistical measure ofprocess capability: the ability of a process to produce output within specification limits. Process capability indices measure how much"natural variation"a process experiences relative to its specification limits and allows different processes to be compared with respect to how well they are controlled. There are several statistics that can be used to measure the capability of a process. We will look at Cpand Cpk. Generally, need 50 independent data values. Slide 200 PharmOut 2013

201 Process Capability Index (Cp) Cp= Estimates what the process is capable of producing if the process mean were to be centred between the specification limits. Assumes process output is approximately normally distributed Slide 201 PharmOut 2013

202 Process Capability Index (Cpk) Cpk= Estimates what the process is capable of producing, considering that the process mean may not be centred between the specification limits (2-sided specification) Slide 202 PharmOut 2013

203 Process Capability Indices If group of darts off the bullseye, but grouped tightly= good Cp, or good process capability, but not good Cpk. If the group of darts are closer to the bullseye, that is good Cpk. If Cp=Cpkthe process is centred at the midpoint of the specification limits. If Cp>Cpk the process is off-centre. Slide 203 PharmOut 2013

204 Process in control & capable? Need to evaluate overall process variation over time Slide 204 PharmOut 2013

205 A more realistic process Intra and inter batch variation over time Slide 205 PharmOut 2013

206 Special Cause Variation Slide 206 PharmOut 2013

207 Data analysis Control Charts used to assess whether or not a process is in statistical control These charts (e.g. Xbar R, Xbar-S, I-MR) are sensitive to detecting shifts in the process. Numerous statistical packages (standalone and embedded in automation software) that assist with these calculations If the Normal distribution assumption is not appropriate, yet capability indices are recorded, one may seriously misrepresent the true capability of a process. Slide 207 PharmOut 2013

208 Data gathering Select the critical parameters to measure Understand the sources of variation and their magnitudes-special or common cause? Collect the correct data-needs to be reliable source, to the correct number of significant digits and in the correct time order Clear procedures and instructions in place-a systematic procedure for determining the capability of the process Slide 208 PharmOut 2013

209 Process Capability Analysis-Minitab Slide 209 PharmOut 2013

210 Process Capability Analysis-Minitab Anderson-Darling (AD) Normality test shows that data does not follow a Normal distribution. This is due to the fact that the p-value for the A-D test is <0.005 Reason for data shift? Outlier? Slide 210 PharmOut 2013

211 Process Capability Analysis-Minitab Histogram indicates spread of data and the USL and LSL In this case, all samples met specification, but if the target is a result of 99, the process is running high. May drift above USL in future? A number of results could be outliers and may prompt an investigation? Results close to the USL Slide 211 PharmOut 2013

212 Process Capability Analysis-Minitab Cpof 1.56 indicates that the data is within the LSL and USL Cpkof 0.62 indicates that the process is not centred or off target The plot also shows that the process is off-target Within and Overall results shown Slide 212 PharmOut 2013

213 Process Capability Analysis-Minitab Xbar-R or Xbar-S charts are used when data is collected in subgroups. Individuals and Moving Range (I-MR) chart is used when there are no subgroups. The I chart is sensitive to non-normal data. The moving range (MR) chart shows variability between one data point and the next. Reason for data shift? Outlier? Slide 213 PharmOut 2013

214 Process Capability Analysis-Minitab Graph detailing the Last 25 Observations or results. Can visually show if data is trending any particular direction Can be useful, in addition to the other tools previously discussed Slide 214 PharmOut 2013

215 Process Capability Analysis Many more useful statistical tools available Non-normal data can be transformed before calculating the process capability indices using the transformed datarequires knowledge to use the correct method of transformation Slide 215 PharmOut 2013

216 Activity 4 ICH Q8 Pharmaceutical development Activity 4.4 Read and review Part II: Pharmaceutical development Annex Section 2.4 to Summarise the main points in your workbook Work in pairs or individually Contribute to group discussion WB 4.4/ 45 mins Slide 216 PharmOut 2013

217 The outcomes of Pharmaceutical Development Presented by John Montalto 13 May, 2013

218 Continual improvement of the product InputsInputs Manufacturing experience Deviations/CAPA Performance monitoring Complaints Management reviews Variability Continual improvement Product lifecycle adjustment Adjustments based on routine feedback loops Ongoing process and facility design to improve on the original models Knowledge library expands Feed forward/back Control strategy Slide 218 PharmOut 2013

219 Continual improvement of the process Inputs Inputs PQS processes Outsourced activities Self inspection External inspection Regulatory considerations Your business Continual improvement PQS adjustment Allocation of resources Learning and training Updates to quality policies and objectives Documentation Communication Knowledge library expands Feed forward/back PQS Management Slide 219 PharmOut 2013

220 What should regulators be looking for? How does senior management demonstrate pharmaceutical quality system commitment? Ensuring adequate resourcing Pharmaceutical Quality System (PQS) importance is communicated Strong interfaces and relationships with all externals Management reviews process performance, product quality reviews and the PQS performance Slide 220 PharmOut 2013

221 Quality Of particular importance Quality must be built in and will not only improve by further testing and inspection Better use of modern science through the lifecycle Quality risk management is a key tool throughout the lifecycle A strong quality system with appropriate knowledge management builds quality in throughout the lifecycle An integrated approach to product development, manufacturing and quality Slide 221 PharmOut 2013

222 ICH tripartite integration Q8 Q9 Q10 Process development Characterisation of process Design of Experiments (DoE) Determine failure modes Identify potential product parameters that impact quality Batch records Technical transfer Supplier identification and selection Slide 222 PharmOut 2013

223 ICH tripartite integration Q8 Q9 Q10 Commercial manufacture Commercial process design On line technology implementation Develop control strategy Manage risks Standard Operating Procedures Validation Process Analysis and trending of data Monitoring and establishing alert and action limits Slide 223 PharmOut 2013

224 Activity 4 ICH Q8 Pharmaceutical development Activity 4.5 Read and review Part II: Pharmaceutical development Annex Section 2.6 Summarise the main points in your workbook Work in pairs or individually Contribute to group discussion WB 4.5/ 30 mins Slide 224 PharmOut 2013

225 ICH Q9 Quality Risk Management Presented by John Montalto 13 May, 2013

226 Quality Risk Management If everything is critical, nothing is critical Slide 226 PharmOut 2013

227 Quality Risk Management overview Slide 227 PharmOut 2013

228 Initiating a QRM process A policy and procedure must be in place before initiating QRM Establish the QRM criteria and detail the scope of the process This requires discipline and structure Slide 228 PharmOut 2013

229 Initiating a QRM process What is the problem, process or scenario being reviewed? Be specific to define the problem and detail assumptions made QRM is about communication, so if people are aware of assumptions they are better able to respond Slide 229 PharmOut 2013

230 ICH Q9 Initiating a QRM process Be prepared with as much relevant information as possible and be conscious of time Wherever possible have verifiable data available relevant to the process under review Slide 230 PharmOut 2013

231 ICH Q9 Initiating a QRM process Establish a multi disciplinary team Manage the process by establishing outcomes and expectations and ensure predetermined acceptance criteria are established Slide 231 PharmOut 2013

232 Risk assessment 1 What might go wrong? 2 What is the likelihood it will go wrong? 3 What are the consequences? Slide 232 PharmOut 2013

233 Risk assessment Risk identification Inputs to risk identification may be varied is your QMS able to support your data requirements? Slide 233 PharmOut 2013

234 Risk assessment Risk analysis Qualitative and quantitative process to comprehend the severity, likelihood and detectability of harm. Slide 234 PharmOut 2013

235 Risk assessment Risk evaluation Compare your quantitative outcome with the predetermined criteria to prioritise your efforts and identify what is not acceptable. The reliability of the data used is critical. Slide 235 PharmOut 2013

236 Risk control 1 Is the risk above your predetermined criteria/threshold? 2 What can be done to reduce or eliminate risks? 3 Are new risks introduced with risk controls? Slide 236 PharmOut 2013

237 Risk control Ultimately, there is one decision to be made: is the risk acceptable or does the risk require further control? Performing a risk assessment with a pre-determined outcome in mind is non compliant and will not add value to your business Slide 237 PharmOut 2013

238 Risk communication Risk is all about facilitated communication -Have you identified all of the parties that need to be part of the communication process? How do you communicate with internal stakeholders? How do you communicate with patients? Are your communication strategies formalised? Slide 238 PharmOut 2013

239 Risk communication Slide 239 PharmOut 2013

240 Risk review QRM is a dynamic process that starts but does not necessarily end. Outline what will trigger a review of your QRM processes Consider feedback and how you will handle information and knowledge and ensure that as you acquire knowledge that the QRM system is maintained Slide 240 PharmOut 2013

241 Informal and formal efforts It is not appropriate to have a formal risk effort for all processes and questions that arise. Irrespective of the mechanism used, all outcomes should be formalised and justified Slide 241 PharmOut 2013

242 Risk management tools Slide 242 PharmOut 2013

243 Risk management tools The risk management tool is of secondary importance: Select a method that your people are comfortable with. Use the most appropriate model for the process under review. Consider the QRM exposure within your organisation and use an appropriate model. Slide 243 PharmOut 2013

244 The history of Quality Risk Management Presented by John Montalto 13 May, 2013

245 Influences on pharmaceutical development and risk management first factory mutual insurer was created ISO Medical devices Application of risk management to medical devices published ICH Q9 ICH Q10 ICH Q s Failure Modes ICH Effects established ICH Analyses Q8 were used to improve efficiency and run time of equipment from a Slide 245 reliability PharmOut 2013 perspective ASTM ASTM E2500- E ISO Risk management principles and guidelines

246 Slide 246 PharmOut 2013

247 Slide 247 PharmOut 2013

248 We all have different risk tolerances Personal perceptions need to be managed, if data available did not support your perception would you be able to adjust? Personal tolerances should be put aside rely on the acceptance criteria established by management Embrace the reality that we all think in different ways Slide 248 PharmOut 2013

249 Why are we here? The establishment and maintenance of a satisfactory system of quality assurance and the correct manufacture of medicinal products relies upon people. PIC/S Guide to Good Manufacturing Practice for Medicinal Products Part I - January, 2013 Slide 249 PharmOut 2013

250 A risk management history 1940 s and 1950 s Military and Aerospace (MIL STDs) 1960 s reliability, engineering approaches; FMECA, HACCP 1980 s ISO Risk Management for Medical Devices Other industry standards ICH Q9 Quality Risk Management Slide 250 PharmOut 2013

251 PIC/S GMP The term risk is mentioned 370 times in the PIC/S GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS PART I, II and the annexes Slide 251 PharmOut 2013

252 Risk Management QRM has evolved over an extended period of time: Initially risk management was focussed on asset protection Now risk management is used to profile and estimate an organisation s exposure to various failure modes Slide 252 PharmOut 2013

253 Quality Risk Management QRM has revolutionised GMP compliance: Some organisations have not realised this revolution All decisions in a GMP regulated environment should be based on QRM criteria Slide 253 PharmOut 2013

254 Definitions Harm physical injury or damage to the health of people, or damage to property or the environment Hazard potential source of harm Slide 254 PharmOut 2013

255 Definitions Risk combination of the probability of occurrence of harm and the severity of that harm Risk Management systematic application of management policies, procedures and practices to analyse, evaluate and control risk across the product lifecycle Slide 255 PharmOut 2013

256 Definitions Risk combination of the probability of occurrence of harm, the severity of that harm and the detectability of that harm Risk Management systematic application of management policies, procedures and practices to analyse, evaluate and control risk across the product lifecycle Slide 256 PharmOut 2013

257 Definitions Risk can be categorised as SOD Severity Opportunity Detection Slide 257 PharmOut 2013

258 Quality Risk Management Relevant resources Presented by John Montalto 13 May, 2013

259 ISO Risk Management ISO considers two themes that risk management in the regulated industries does not consider. The risk culture of an organisation External and internal risk that organisations need to manage Slide 259 PharmOut 2013

260 ISO The risk management framework within ISO Slide 260 PharmOut 2013

261 Risk management creates value Risk management Critical organisational process Is the basis for making decisions Directly addresses uncertainty Systematic and structured system Tailored People and cultures are considered Transparent and dynamic Enables Continual improvement Slide 261 PharmOut 2013

262 Risk management Management commitment: The internal and external context of the organisation How is an organisation perceived? Management must commit to risk management Slide 262 PharmOut 2013

263 Risk management A policy must be established Internal communication and reporting processes People must be accountable for their decisions Establishing a common risk criteria allows for transparency in decision making Adequate resources must be available Slide 263 PharmOut 2013

264 Risk management The risk management process and system must be monitored and reviewed Communication and consultation is fundamental to risk management Risk criteria must be considered and established Slide 264 PharmOut 2013

265 NAB Slide 265 PharmOut 2013

266 NAB Slide 266 PharmOut 2013

267 Risk Magazine, September 2010 David Lewis, who headed the Australian Prudential Regulation Authority s (APRA s) probe, said as the investigation unfolded it became clear that the problems were not confined to the trading desk. During our investigation, we interviewed a lot of people involved including the four traders, he said. The traders were young; highly motivated; and very gung-ho as traders tend to be. One thing became clear immediately: they didn t think that they had done anything wrong. They didn t think that they were stealing anything; they thought it was their job to make money for the bank and in their minds this is what they were doing. Yes, they knew that they were breaking the bank s rules. But, to them, these were just bureaucracy that got in the way of what the bank really expected them to do. Slide 267 PharmOut 2013

268 Risk Magazine, September 2010 Lewis added that the investigation revealed widespread issues within NAB, despite sophisticated controls system, and most were connected with cultural and human elements, as opposed to system breakdowns. Despite several probes, NAB s internal audit department was warned off when it queried what was happening on the FX options desk. Internal auditors were told the traders were untouchable. Meanwhile, risk managers failed to properly challenge the traders and the executive risk Committees managed to miss the early warning signs of the coming scandal, despite regular breaches of daily excess limits being reported. Most seriously, Lewis said, the organisational culture at the bank was a far cry from its stated Policy and procedure. Slide 268 PharmOut 2013

269 NAB Billions of dollars traded annually Massive, lucrative bonuses were awarded Young, highly educated professionals What does this say about the culture of the organisation? Slide 269 PharmOut 2013

270 NAB Activity List 3 mechanisms you would implement to reduce risks for currency traders Slide 270 PharmOut 2013

271 GMP says... Slide 271 PharmOut 2013

272 ISO Quality Standards ISO Medical devices -- Quality management systems -- Requirements for regulatory purposes ISO Medical devices -- Application of risk management to medical devices Slide 272 PharmOut 2013

273 ISO says... Slide 273 PharmOut 2013

274 ISO says... Slide 274 PharmOut 2013

275 ISO components 1. Scope 2. Terms and definitions 3. General requirements for risk management 4. Risk analysis 5. Risk evaluation 6. Risk control 7. Evaluation of overall residual risk acceptability 8. Risk management report 9. Production and post-production information Slide 275 PharmOut 2013

276 Risk Management Process The manufacturer shall establish and maintain risk management policies Integrate and review as part of the Quality Management System Hazard identification Monitor the effectiveness of risk controls Estimate and evaluate associated risks Slide 276 PharmOut 2013

277 (ISO) Risk management overview Slide 277 PharmOut 2013

278 Intended use The intended use/intended purpose and any reasonably foreseeable misuse of the medical device must be considered Slide 278 PharmOut 2013

279 Risk Management Process The risk management process must be documented. One challenge for manufacturers is how to establish the risk reports and risk management files: what rationale will be used to set up the system? Where a documented design and development process exists, appropriate parts of the risk management processes must be included Slide 279 PharmOut 2013

280 Compliance Compliance is verified by inspection of the risk management file. The risk management file is a set of records and other documents, that are produced by a risk management process Slide 280 PharmOut 2013

281 Management Responsibilities Define a risk management policy Ensure the provision of adequate resources and the assignment of trained personnel Review risk management activities regularly to ensure continuing suitability and the effectiveness of the process Document the process Maintain the risk management file Slide 281 PharmOut 2013

282 Qualification of Personnel The manufacturer s risk management personnel must have the knowledge and experience appropriate to the tasks assigned to them This shall include, where appropriate: knowledge and experience of the medical device knowledge and experience with risk management techniques Slide 282 PharmOut 2013

283 Risk Management Plan The risk management plan shall be part of the risk management file and needs to include: The plan scope, identifying and describing the medical device and the life cycle phases for which the plan applies A verification plan Assignment of responsibilities Requirements for review of risk management activities Criteria for risk acceptability (guidelines in Annex E) Change management Slide 283 PharmOut 2013

284 Justification Quality risk management is not exclusively a quantitative process. Risk justifications are critical and must be adequately structured and supported by evidence Slide 284 PharmOut 2013

285 Intended use of the medical device For the particular medical device being considered, the manufacturer shall describe the intended use/intended purpose and any reasonably foreseeable misuse Slide 285 PharmOut 2013

286 Intended use of the medical device The manufacturer shall list all those qualitative and quantitative characteristics that could affect the safety of the medical device and, where appropriate, their defined limits Slide 286 PharmOut 2013

287 Post production Risk management is an ongoing process and requires the ongoing capture and analysis of knowledge Slide 287 PharmOut 2013

288 Competition and regulation Need to focus skilled resources where risks to patient safety are highest Do more with less Maximise resource effectiveness Slide 288 PharmOut 2013

289 Competition and regulation A thorough understanding of business processes and Critical Quality Attributes (CQAs) is essential Risk management methodologies Different methodologies may be more applicable throughout the product lifecycle The result should be the ability to better prioritise your work Slide 289 PharmOut 2013

290 How do we practically use this risk based approach? Dr. H. Gregg Claycamp Director, Division of Compliance Risk Management and Surveillance, FDA, CDER Office of Compliance. There is no magic bullet! It is a multi disciplinary team applying an agreed methodology, making an educated and experienced judgement and then seeking ways to mitigate the risk. Slide 290 PharmOut 2013

291 Risk management process Management establish and maintain risk management policies Ongoing part of the Quality Management System Hazard identification Monitor the effectiveness of risk controls Estimate and evaluate associated risks Slide 291 PharmOut 2013

292 Risk management process Analyse Ongoing part of the Quality Management System Evaluate Production and Post Production information Control Slide 292 PharmOut 2013

293 Activity 6 ICH Q9 Quality risk management Read and review ICH Q9 Quality risk management Sections 3-6 Summarise the main points in your workbook Work in pairs or individually Contribute to group discussion WB 6/ 60 mins Slide 293 PharmOut 2013

294 Regulators and Quality Risk Management Presented by John Montalto 13 May, 2013

295 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 295 PharmOut 2013

296 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 296 PharmOut 2013

297 Australian TGA -Risk management approach for GMP ratings of manufacturers Consider the type of products manufactured High Medium Low Manufacturer of sterile medicines Manufacturer of OTCs Manufacturer of vitamins Slide 297 PharmOut 2013

298 Risk management approach for GMP ratings of manufacturers Quantify the categories of compliance A1 Good compliance <10 other deficiencies A2 Satisfactory compliance 1-5 majors. <11 others A3 Basic >5 majors Unacceptable 1 or more critical Slide 298 PharmOut 2013

299 Australian TGA -Risk management approach for GMP ratings of manufacturers Consider the (more recent) compliance history to determine the frequency of reaudit Risk Category A1 A2 A3 Unacceptable Frequency of Reaudit (months) High Internal review Medium panel to decide Low Slide 299 PharmOut 2013

300 US FDA s risk based model for prioritising inspections The US FDA could not meet its self imposed target of biannual inspections for US manufacturers 1st goal efficient risk management Recognition of previously informal risk management approaches Slide 300 PharmOut 2013

301 US FDA s risk based model for prioritising inspections Risk management goals Product Ie. Dosage form Facility Ie. Poor compliance history Process Ie. Complexity; mixing compared to filling Slide 301 PharmOut 2013

302 US FDA s risk based model for prioritising inspections Product Intrinsic factors; sterility, OTC, Rx Recalls and history Process Complexity and novelty of process Maintaining process controls Process vulnerabilities Facility History of violation and inspections Estimated volume of production output Type of establishment (3 rd party or other) Slide 302 PharmOut 2013

303 QRM and regulators 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. (GMP Frequently Asked Questions, MHRA, UK, June 2010) It is critical that a robust quality system incorporate a scientific and risk based approach. (Pre-approval Inspections Guidance Manual, US FDA, Dec 2010) Slide 303 PharmOut 2013

304 QRM and regulators The concept of QA, GMP, QC & QRM are interrelated aspects of quality management & should be the responsibility of all personnel. (WHO GMP for pharmaceutical products, main principles, 2011) Slide 304 PharmOut 2013

305 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 approaches, relevant scientific knowledge and expertise in risk assessment, evaluation and mitigation. Documented QRM processes. QRM must be reviewed on a periodic basis. Slide 305 PharmOut 2013

306 QRM and regulators That the approach and documentation should be commensurate with the complexity and criticality of the system. The evaluation of risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient. Slide 306 PharmOut 2013

307 Audit observations relevant to QRM 1. There were no formal SOPs for QRM and impact assessment. 2. The SOP relating to QRM did not provide specific information about how QRM was to be performed and implemented. 3. The SOP for QRM did not include coverage of supplier qualification, deviation management, complaints and defects. 4. There was no risk register to facilitate the management, monitoring and review of formal risk assessments. Slide 307 PharmOut 2013

308 Historic use of risk based approaches Quasi-risk based approach: Lack of formalisation Process lacks acceptance criteria, therefore companies err on the side of caution QA is the most basic form of risk management Slide 308 PharmOut 2013

309 Historic use of risk based approaches Previously a quasi-risk based approach was relied on where Quality Control was seen as the last line of defence (or a catch all) for quality issues Previous systems would not be formalised and would lack acceptance criteria. This forces organisations to err on the side of caution Slide 309 PharmOut 2013

310 Tried and true methods We are using risk management to an extent: Implementation is too often informal Stand alone system not integrated into the QMS Slide 310 PharmOut 2013

311 Quality Risk Management Multidisciplinary teams Presented by John Montalto 13 May, 2013

312 What makes the ideal team? Slide 312 PharmOut 2013

313 Multi disciplinary teams Ensure you consider different people with different skill sets and different personalities to your own QRM is a mechanism to allow different people to contribute to a process The QRM policy and process must be structured Establishing criteria allows for clear decision making and transparency Slide 313 PharmOut 2013

314 Multi disciplinary teams Uncertainty The QRM process should identify areas of uncertainty and the response should be to further investigate uncertainty Subject Matter Experts (SMEs) Use your SMEs wisely Be sure to detail what qualifies someone as an SME Slide 314 PharmOut 2013

315 Multi disciplinary teams Use your SMEs wisely Approach 1 Use your SMEs to develop a process flow for the process under review Use your SMEs to identify and detail risk scenarios Use a team to quantify risk scenarios Utilise a team to establish control strategies Slide 315 PharmOut 2013

316 Multi disciplinary teams Approach 2 Use a team to develop a process flow for the process under review Use a team to identify and detail risk scenarios Use your SME to quantify risk scenarios Slide 316 PharmOut 2013

317 Multi disciplinary teams Approach 3 Use an expert facilitator Use your team and SME to review the process, detail risk scenarios and quantify risks Slide 317 PharmOut 2013

318 Multi disciplinary teams Be sure to detail what qualifies someone as an SME Slide 318 PharmOut 2013

319 Multi disciplinary teams Experience with the process refers to: Experience with the process under review Experience with the risk management process Slide 319 PharmOut 2013

320 Multi disciplinary teams Document the people involved in any risk effort This provides greater transparency in decision making Qualify your SMEs Will you require a certain number of years experience? Will you require a technical competence? Justify the selection of SMEs Slide 320 PharmOut 2013

321 Multi disciplinary teams When establishing your team be sure that the experts from relevant areas are included. Build risk management as a formal competence within your organisation. This will allow a group of QRM experts to coordinate the activities and call upon SMEs as needed Slide 321 PharmOut 2013

322 Multi disciplinary teams Ensure responsibility for coordinating quality risk management across various functions and departments of the organisation is detailed and performed As your QRM database grows you will need systems capable of supporting your business needs and making the risk knowledge easily accessible to all users Slide 322 PharmOut 2013

323 Activity 7 Integration of QRM into QMS Establish a risk based strategy for the following QMS components: Product quality review Premises and equipment Documentation Training Contract manufacture and analysis Deviation management Change management Corrective Action and Preventive Action Complaints handling Auditing (internal/external) WB 7/ 180 mins Slide 323 PharmOut 2013

324 Risk Justifications Presented by John Montalto 13 May, 2013

325 Risk justifications and reports ICH Q9, 2005 Slide 325 PharmOut 2013

326 Risk justifications and reports Quality risk management is not about justifying non-compliance, it is about effective communication of hazards and the associated control strategies Slide 326 PharmOut 2013

327 Risk justifications and reports Every risk effort demands a written report and justification of findings and outcomes. Empirical models are always recommended. Not all risk efforts will be formal in their structure and approach. Slide 327 PharmOut 2013

328 Risk justifications and reports The requirements of chapter 4 of the code of GMP apply: Quality risk management demands that risk policies and procedures are in place Establish a framework for risk efforts so people focus on the process under review Slide 328 PharmOut 2013

329 Risk justifications and reports The high level policies and procedures need to: Demonstrate management commitment and an overall approach to risk management Detail risk acceptance criteria Detail responsibilities for the process and the selection of people involved Slide 329 PharmOut 2013

330 Risk justifications and reports continued The high level policies and procedures need to: Detail the process for responding to the outcomes of risk management Establish communication strategies for risk outcomes Ensure that quality risk management is integrated into the quality management systems Slide 330 PharmOut 2013

331 Risk justifications and reports What will be the focus of discussions in your risk reports? Sometimes high risk items are exclusively discussed, this approach may come under regulatory scrutiny The discussion of all risk findings is an emerging trend The risk criteria utilised may be different for different processes under review Slide 331 PharmOut 2013

332 Risk justifications and reports continued What will be the focus of discussions in your risk reports? For example a preliminary hazard analysis will focus on GxPcriteria where other efforts may detail more specific criteria Ensure that the risk report adequately cross references the quantitative risk findings and any supporting evidence Slide 332 PharmOut 2013

333 Project specific approach Your risk management process needs to allow for a project specific approach and the ongoing implementation of a risk based methodology into the quality management systems Slide 333 PharmOut 2013

334 Project approach Project approach Slide 334 PharmOut 2013

335 Ongoing routine approach All quality management systems must integrate a risk based approach The supporting documentation should allow for this inclusion and ensure risk outcomes are effectively documented Slide 335 PharmOut 2013

336 What to watch out for A lack of evidence to support risk based decisions and outcomes Unjustified assumptions Incomplete identification and relevant resources Sometimes risk efforts will highlight a lack of knowledge and you will need to respond to this lack of knowledge Clearly denote your assumptions and justify the assumptions This demonstrates a lack of management commitment and an inability to effectively identify risk will result in an incomplete risk effort Slide 336 PharmOut 2013

337 Risk registers Presented by John Montalto 13 May, 2013

338 Risk registers The risk management process is dynamic and as knowledge is acquired, this must be fed back into the risk management system. Some systems that may trigger a risk review Complaints Deviations and non-conformances Change management Product quality reviews Essentially, any new information may trigger a risk review Slide 338 PharmOut 2013

339 Risk registers The risk register may be treated as a catalogue of risk documentation. A catalogue should be searchable and kept up to date With so many potential inputs your risk registers need to be readily accessed and reviewed Slide 339 PharmOut 2013

340 Risk registers The risk register you establish must support your approach. Some questions you will need to answer Will the risk register be product based, process based or department specific? How will you collate the information and ensure the registers continually cross reference? How will you streamline your quality risk management efforts Slide 340 PharmOut 2013

341 Streamlining your efforts Understand the products and processes within your organisation and establish a suitable mechanism for grouping. For example, where you are manufacturing a product with different API strength, which product can be chosen as representative and provide a justification for this Slide 341 PharmOut 2013

342 Streamlining your efforts Instead of performing multiple product quality reviews, you may be able to focus on certain products within the range Consider the manufacture process and formulation Consider the equipment train Consider the route and mechanisms of transport Slide 342 PharmOut 2013

343 Risk management models Presented by John Montalto 13 May, 2013

344 The two stages of risk management Impact assessment/preliminary hazard analysis High level determination of GxP impact This is arguably the most critical part of risk management Targeted risk management effort Focus effort on process or component using a recognised risk model Slide 344 PharmOut 2013

345 Impact Assessment Components Critical Non-Critical Direct Impact Systems Indirect / No Impact Not Possible Design for Impact GEP only GEP + Qualification Slide 345 PharmOut 2013

346 Preliminary hazard analysis This analysis should take an overall approach to a process and identify areas and components that require a more detailed review. The justifications of preliminary hazard outcomes must be afforded attention Use a more general criteria, for example, patient safety, product quality to determine what to review in more detail Slide 346 PharmOut 2013

347 Severity Opportunity Detection Severity The impact of the hazard Opportunity The likelihood that the hazard occurs Detection The ability to detect the hazard before it occurs Slide 347 PharmOut 2013

348 3x3 model (traffic light model) Slide 348 PharmOut 2013

349 The traffic light model This model gives an immediate sense of risk and can be readily understood. This model is recommended for organisations that are inexperienced with risk management As experience with risk management increases then this model may be superseded There is a greater likelihood to categorise hazards as high The model does not consider root causes of hazards Slide 349 PharmOut 2013

350 A 5x5 model Consequence Likelihood Negligible (4) Inconvenience Temporary issue Minor (3) Minor injury - may or may not require medical attention Critical/Major (2) Serious injury requiring medical attention. Possible permanent impairment or life threatening injury Catastrophic (1) Loss of Life or limb severe permanent damage Improbable (A) not expected to occur Unlikely (B) not expected to happen, but is possible Occasional (C) could occur in some circumstances Probable (D) is expected to occur in most circumstances Frequent (E) will occur on every occasion LOW LOW MEDIUM MEDIUM LOW LOW MEDIUM HIGH LOW MEDIUM HIGH HIGH LOW MEDIUM HIGH HIGH MEDIUM MEDIUM HIGH HIGH Slide 350 PharmOut 2013

351 A 5x5 model The model presentedgives an immediate sense of risk and can be readily understood The disadvantage of this model is that no consideration of detection is factored in Slide 351 PharmOut 2013

352 10x10 model severity likelihood Detection (considering current control s only) 10 Death,serious permanent injury 9 Serious permanent injury Very high, almost certain (1 in 2) Very high, almost certain (1 in 3) Almost impossible Very remote 8 Verysevere High (1 in 10) Remote 7 Severe High (1 in 20) Very low 6 Moderate Moderate (1 in 80) Low 5 Low Moderate (1 in 500) Moderate 4 Very low Moderate (1 in 2500) High 3 Minor Low (1 in 20000) High 2 Insignificant Very low (1 in ) Very high 1 None Unlikely(1 in ) Almost certain Slide 352 PharmOut 2013

353 10x10 model This model is suited for organisations with significant risk management experience. This model almost demands an independent facilitator Too much time can be devoted to disputes that will have very little effect on the overall hazard score Your discussions should not be about extremes in risk scores Slide 353 PharmOut 2013

354 Risk management techniques Preliminary Hazard Analysis (PHA) Impact assessment Is there an impact on patient safety, product quality or a business process? GxP impact Slide 354 PharmOut 2013

355 Risk management techniques Preliminary Hazard Analysis (PHA) Focuses on finding weaknesses early in the life of a system Another risk management tool may be used after this process This model considers pervious experience with a process This analysis usually leads to more detailed risk efforts Slide 355 PharmOut 2013

356 Risk management techniques Preliminary Hazard Analysis (PHA) Likelihood and possibilities Qualitative evaluation Ranking based on severity and likelihood Identify controls and strategies Slide 356 PharmOut 2013

357 Risk management techniques Fault Tree Analysis (FTA) Top down approach where the top is an undesirable event Step by step analysis of the next lower functional system level When at the root cause level, implement remediation Slide 357 PharmOut 2013

358 Risk management techniques Fault Tree Analysis (FTA) This analysis provides opportunities to identify causal flows Without previous knowledge of a process, or a subject matter expert this process will not work effectively Because this model is useful in identifying multiple causal factors it is very effective for investigating deviations and complaints Slide 358 PharmOut 2013

359 Risk management techniques Hazard analysis critical control points (HACCP) This model works well where there is significant product and process knowledge The ongoing focus of this model is on the effectiveness of monitoring and the control strategies Slide 359 PharmOut 2013

360 Risk management techniques Hazard analysis critical control points (HACCP) Step Process 1 Conduct hazard analysis and identify existing controls 2 Determine critical control points 3 Establish critical limits 4 Monitor the critical control points 5 Establish correctiveactions based on monitoring and feedback 6 Establish a verification and feedback system 7 Document and formalise the process Slide 360 PharmOut 2013

361 Risk management techniques Hazard and Operability (HAZOP) study This model is useful to review a process as opposed to a machine The main assumption is that risk events are caused by variations from the design/operating intentions This model is not appropriate for novel systems Slide 361 PharmOut 2013

362 Risk management techniques Failure Mode Effects Analysis (FMEA) This model is one of the more commonly used models Within an FMEA framework there is some consideration given to root cause analysis of hazards To identify potential process failure modes and their likely effect on product performance Used to prioritise risks and monitor the effectiveness of risk controls Applied to equipment, facilities and processes Slide 362 PharmOut 2013

363 Risk management techniques Failure Mode Effects Analysis (FMEA) The consequences of a fault mode are identified and evaluated what happens if...? A single fault condition is reviewed at a time Bottom up approach Slide 363 PharmOut 2013

364 Fish bone root cause analysis Slide 364 PharmOut 2013

365 Fish bone root cause analysis Slide 365 PharmOut 2013

366 Risk management advice Establish a multi disciplinary team Define the scope Define the criteria Map the process Perform preliminary hazard analysis (GxP impact) Slide 366 PharmOut 2013

367 Risk management advice Identify processes that require more detailed analysis Use the appropriate model and consider existing controls Reduce or accept the hazard Determine review strategy Formalise, document and maintain risk register and documentation Slide 367 PharmOut 2013

368 Quality Risk Management (QRM) Bungee Jumping Video 1 Slide 368 PharmOut 2013

369 Activity 8 QRM- Bungee jumping Perform a risk assessment on bungee jumping Complete the FMEA table in your workbook Work in groups Contribute to group discussion WB 8/ 60 mins Slide 369 PharmOut 2013

370 Quality Risk Management (QRM) Bungee Jumping Video 2? 2mins Slide 370 PharmOut 2013

371 Activity 9 and 10 Slide 371 PharmOut 2013

372 Quality Risk Management Summary Presented by John Montalto 13 May, 2013

373 Quality Risk Management Process The manufacturer shall establish, document and maintain throughout the life-cycle an ongoing process for identifying hazards ISO 14971:2009 Medical devices Application of risk management to medical devices. Slide 373 PharmOut 2013

374 Quality Risk Management The quality risk management system should ensure that: -The evaluation of the risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient; Scientific knowledge refers to 1. Assumptions 2. Incomplete identification of risk 3. Not using Quality Risk Management to justify non compliance Slide 374 PharmOut 2013

375 Quality Risk Management The quality risk management system should ensure that: -The evaluation of the risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient; Experience with the process refers to 1. Experience with the process under review 2. Experience with a quality risk management process Slide 375 PharmOut 2013

376 Quality Risk Management - Integration All quality management systems should include quality risk management considerations Slide 376 PharmOut 2013

377 Quality Risk Management Consider the approach for handling a project specific risk effort Management commitment is critical to the success of any quality system Slide 377 PharmOut 2013

378 Quality Risk Management - Formalisation Collective or disparate Quality Risk Management registers: Quality Management Systems based Department based Process based Equipment based Slide 378 PharmOut 2013

379 Quality Risk Management - Review What will initiate a review of your completed quality risk management efforts? Slide 379 PharmOut 2013

380 Quality Risk Management - Lifecycle The context of Quality Risk Management efforts must be carefully considered Slide 380 PharmOut 2013

381 Risk management Slide 381 PharmOut 2013

382 Thank you for your time. Questions? John Montalto Training Manager / Lead Consultant John.montalto@pharmout.net Slide 382 PharmOut 2013