21st Century Regulatory Compliance
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This document provides an overview of ICH Q8, Q9, and Q10 guidelines and how they work together over the lifecycle of a pharmaceutical product. It discusses key aspects of each guideline including: - ICH Q8 focuses on quality by design and developing a control strategy. - ICH Q9 covers quality risk management processes. - ICH Q10 relates to pharmaceutical quality systems. The document then walks through various stages of product development and manufacturing providing examples of how the three guidelines can be applied together at each stage from formulation to commercial production. Tools for risk identification and analysis like flowcharts, cause and effect diagrams, and failure mode and effects analysis are also summarized.
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21st Century Regulatory Compliance
- 1. 21st Century Regulatory Step by Step Compliance Part-1 Presented By: Md. Saddam Nawaz ICH Q8 Q9 &Q10
- 2. LIFECYCLE OF A PRODUCT
- 3. ICH Q8, Q9 and Q10 Nov 2005 & Nov 2008 • High level guidances (not prescriptive) • Science and risk-based • Encourages systematic approaches • Applicable over entire product lifecycle • Intended to work together to enhance pharmaceutical product quality
- 4. Q8(R2) - Example QbD Approach • Quality Target Product Profile (QTPP) • Determine “potential” critical quality attributes (CQAs) • Link raw material attributes and process parameters to CQAs and perform risk assessment • Develop a design space (optional and not required) • Design and implement a control strategy • Manage product lifecycle, including continual improvement
- 5. Quality Risk Management Process - Q9 Process Development Control Strategy Development Continual Improvement of the product Team approach
- 6. Pharmaceutical Quality System - Q10
- 7. ICH Q8, Q9 and Q10 Working Together Formulation Activities: • QTPP Definition • Pre-Formulation Studies • Formulation Screening • Optimization & Selection Process Development Activities: • Process Screening • Lab Scale Development • Scale-Up Studies Manufacturing Activities: • Commercial Scale Manufacturing • Batch Release • Continual Verification & Improvement Q8 PharmaceuticalDevelopment Q9 QualityRiskManagement Q10 PharmaceuticalQualitySystems
- 8. Formulation Development Activities ICH Q8(R2) – Pharmaceutical Development Related Activities ICH Q9 – QRM Related Activities ICH Q10 – PQS Related Integrated Activities Quality Target Product Profile (QTPP) • Clinical and non-clinical studies on drug substance: bioavailability, PK/PD, and safety • Informal and/or formal risk assessment to evaluate patient needs and potential medication risks • Knowledge Management / Prior Knowledge (relevant information to support the understanding, risk assessment and scope of DOE) - Laboratory note book documentation - Development report - Etc… Pre-Formulation Studies • Characterization of drug substance (physical properties) • Chemical stability of drug substance, degradation and potential formulation interactions • Development of analytical tests • Determine failure modes and risk factors for drug substance physical and chemical stability Formulation Screening • Excipient compatibility • Dissolution method development • Screening DOEs • Determine failure modes and risk factors for excipient interactions Formulation Optimization and Selection • Excipient and drug substance material property & characterization • DOEs for excipient amounts • Stability of drug product and storage conditions • Develop IVIVC relationships • Opportunities for formal risk assessment
- 9. Process Development Activities ICH Q8(R2) – Pharmaceutical Development Related Activities ICH Q9 – QRM Related Activities ICH Q10 – PQS Related Integrated Activities Process Screening • Exploration of unit operations • Characterization of process intermediates • Determine failure modes, risk factors for unit operations and rank risk • Batch records and operational guidelines for manufacturing • Tech Transfer report • Identification and selection of suppliers that meet raw material needs Process Development and Optimization (Lab Scale) • DOEs for process parameters and interactions with material attributes • Development of Design Space • Operational ranges for scale- independent parameters • understanding of critical process operations • Screening risk assessment to determine potential parameters impacting product quality (e.g., Ishikawa) • Determine critical process steps, process parameters and material attributes (e.g., FMEA) • Potential issues of scale Process Development and Optimization (Pilot Scale) • Pilot to verify lab scale knowledge • DOE and modeling effects of scale • Development of design space • Development of on-line measurement technologies • Development of control strategy to control risks incl. for scale up
- 10. Technology Transfer ICH Q8(R2) – Pharmaceutical Development Related Activities ICH Q9 – QRM Related Activities ICH Q10 – PQS Related Integrated Activities • Gain product and process knowledge • Knowledge supports transfer between development and manufacturing to achieve product realization • Forms the basis for the manufacturing process • Improves effectiveness of control strategy • Contributes to processes validation and ongoing continual improvement •Advance understanding through scale- up activities • Provide preliminary indication of process performance and successful integration into manufacturing • Gain knowledge from transfer and scale up activities to enhance the basis for the control strategy
- 11. Commercial Manufacturing Activities ICH Q8(R2) – Pharmaceutical Development Related Activities ICH Q9 – QRM Related Activities ICH Q10 – PQS Related Integrated Activities Commercial Scale Manufacturing for Drug Product • Definition of commercial process design • Commercial scale runs to verify process design, with additional sampling to verify understanding • Implementation of on-line measurement technologies • Development of a control strategy for commercial manufacturing, including in- process controls, end-product testing, raw material controls and change control • Check procedures in the PQS regarding risk from Process specific procedure (e.g., sampling plans, design space and model verification, change control for movement within design space) • Process-specific operating procedures (e.g. sampling plans, design space etc.) • Documentation to support on-line testing methods • Validation to demonstrate process and analytical method reproducibility • Storage of development reports, risk assessments Continual Process Verification and Continual Improvement • On-going analysis and trending of process data, (multivariate SPC, etc.) • Evaluation of process changes and associated effect on intermediates and products • Manage risks of process or material attribute change (including changes within or outside of design space) • Review risks in audits/inspections and implement risk-based CAPAs • Procedures on process monitoring and action limits • Change control procedures including how and when to do risk assessment for process changes and evaluation of the change • Maintenance and update of knowledge management
- 12. QRM in the Product Life Cycle Opportunities to apply Quality Risk Managements Patient needs Business needs Quality Target Product Profile (QTPP) Critical Quality Attribute (CQA) Critical Process Parameters (CPP) Product design Manu- facturing Process design Control Strategy Technical regulatory Filing & Review Performance Review & Change Control Commercial Manufacturing Researchand clinicalstudies Process understanding PAT Inspections GMP Inspections Knowledge management Technical Transfer approx. life cycle time 1/4 3/4
- 13. Basic risk management facilitation methods • Flowchart • Check Sheets • Process mapping • Cause and Effect Diagrams (Ishikawa / fish bone) They might be helpful to support risk identification
- 14. Flow Charts • Pictorial representations of a process • Breaking the process down into its constituent steps Flowcharts Activity Start Decision Result Action Activity No Yes
- 15. Process Mapping • Process mapping Dispensing Blending Fluidized Bed Dryer Coating Tabletting Packaging Magnesium Stearate Granulation Sieving Sieving Air Air Scale
- 16. Cause and Effect Diagrams (Ishikawa / fish bone) Water Content Drying Granulation Raw Materials Compressing Plant Factors Temp/RH Precompressing Main Compressing Feeder Speed Press Speed Punch Penetration Depth Temp RH Air Flow Shock Cycle Drug Substance P.S. Process Conditions LOD Diluents P.S. LOD Other Lubricant Disintegrant Binder Water Binder Temp Spray Rate Spray Pattern P.S. Scrape Down Chopper Speed Mixer Speed Endpoint Power Time Age Tooling Operator Training Analytical Method Sampling Feed Frame Tablet Drying Granulation Raw Materials Compressing Plant Factors Temp/RH Precompressing Main Compressing Feeder Speed Press Speed Punch Penetration Depth Temp RH Air Flow Shock Cycle Drug Substance P.S. Process Conditions LOD Diluents P.S. LOD Other Lubricant Disintegrant Binder Water Binder Temp Spray Rate Spray Pattern P.S. Scrape Down Chopper Speed Mixer Speed Endpoint Power Time Age Tooling Operator Training Analytical Method Sampling Feed Frame Cause and Effect Diagrams
- 18. Failure Mode Effects Analysis (FMEA) • Evaluation of potential failure modes for processes • The likely effect on outcomes and/or product performance • Once failure modes are established, risk reduction can be used to eliminate, reduce or control the potential failures • FMEA relies on process understanding • Summarize the important modes of failure, factors causing these failures and the likely effects of these failures How to perform? Break down large complex processes into manageable steps
- 19. FMEA How to perform? 1. Establish a team 2. Identify the known and potential failure modes: Develop lists of known problems and brainstorm other potentials… e.g. – Product not meeting specification – Process not meeting yield requirements – Malfunctioning equipment – Software problems Newly identified failure modes should be added at any time
- 20. FMEA How to perform? 3. Characterise the severity, probability and detectability • Use different scales – Linear: 1, 2, 3, 4 – Exponential: 1, 2, 4, 8 – Logarithmic: 1, 10, 100, 1000 – Self made: 1, 3, 7, 10 Multiplying different scales will differentiate the outcome The aim is to come up with a method of prioritising
- 21. FMEA How to perform? 4. Define actions 5. Revisit the ranking 6. Define residual risk 7. Perform a short summary – Scope – Data from the assessment & control (e.g. No. of identified failure modes) – Level of accepted risk without actions i.e. residual risk (e.g. Risk priority Number < 50) – Recommended actions, responsibilities and due dates (including approval, if appropriate) – Person in charge for follow-up of FMEA
- 22. FMEA Severity (Consequences of failure) • 10 Extreme • Predicted to cause severe impact to quality (Product out of specifications, no Expert Statement possible) • 7 High • Predicted to cause significant impact on quality (Failure to meet specifications, no Stability data, Expert Statement possible) • 3 Moderate • Predicted to cause minor impact on quality (Failure to meet specifications, Stability data available) • 1 Low • Predicted to have no/minor impact on quality of the product (Quality within specifications)
- 23. FMEA Probability (Likelihood failure will happen) • 8 Regular failures • Expected to happen regularly • 4 Repeated failures • Expected to happen in a low frequency • 2 Occasional failures • Expected to happen infrequently • 1 Unlikely failures • Unlikely to happen
- 24. FMEA Detectability (Ability to find the failure) • 4 Normally not detected • Failure very likely to be overlooked, hence not detected (no technical solution, no manual control) • 3 Likely not detected • Failure may be overseen (manual control, spot checks) • 2 Regularly detected • Failure will normally be detected (manual control, routine work with statistical control) • 1 Always detected • Failure can and will be detected in all cases (monitoring, technical solution available)
- 25. FMEA: Quantitation of Risk : Severity 10 Dangerously High Failure could lead to death or permanent injury to the customer. Financial: >$1,000,000 9 Extremely high Failure could lead to injury to the customer. Failure would create non-compliance with registered specifications. Failure likely to lead to recall. Financial: $1,000,000 8 Very High Failure could lead to adverse reaction for customer. Failure would create noncompliance with GMP regulations or product registrations. Failure possible to lead to recall. Financial: $500,000 7 High Failure leads to customer percept ion of safety issue. Failure renders individual unit(s) unusable. Failure causes a high degree of customer dissatisfaction. Recall for business reasons possible but Authority required recall unlikely. Financial: $100,000 6 Moderate Failure causes a high degree of customer dissatisfaction and numerous complaints. Failure unlikely to lead to recall. Financial: $50,000 5 Low Failure likely to cause isolated customer complaints. Financial: $10,000 4 Very Low Failure relates to non-dosage form issues (like minor packaging problems) and can be easily overcome by the customer. Financial: $5,000 3 Minor Failure could be noticed by the customer but is unlikely to be perceived as significant enough to warrant a complaint. 2 Very Minor Failure not readily apparent to the customer. Financial: <$1,000 1 None Failure would not be noticeable to the customer. Financial: none
- 26. FMEA: Quantitation of Risk : Probability 10 Very High: Failure is almost inevitable More than one occurrence per day or a probability of more than three occurrences in 10 units (Cpk < 0.33 or <1σ). 9 One occurrence every three to four days or a probability of three occurrences in 10 units (Cpk ~ 0.33 or ~1 σ). 8 High: Repeated failures One occurrence per week or a probability of 5 occurrences in 100 units (Cpk ~ 0.67 or ~2 σ). 7 One occurrence every month or one occurrence in 100 units (Cpk ~ 0.83 ~2.5 σ). 6 Moderate: Occasional Failures One occurrence every three months or three occurrences in 1,000 units (Cpk ~ 1.00 or ~ 3 σ). 5 One occurrence every six months to one year or one occurrence in 10,000 units (Cpk ~ 1.17 or ~ 3.5 σ). 4 One occurrence per year or six occurrences in 100,000 units (Cpk ~ 1.33 or ~ 4 σ). 3 Low: Relatively few Failures One occurrence every one to three years or six occurrences in 10,000,000 units (Cpk ~ 1.67 or ~5 σ). 2 One occurrence every three to five years or 2 occurrences in 1,000,000,000 units (Cpk ~ 2.00 OR ~6 σ). 1 Remote: Failure is unlikely One occurrence in greater than five years or less than two occurrences in 1,000,000,000 units (Cpk > 2.00 OR >6 σ).
- 27. FMEA: Quantitation of Risk: Detection 10 Absolute Uncertainty The product is not inspected or the defect caused by the failure is not detectable. 9 Very Remote Product is sampled, inspected, and released based on Acceptable Quality Level (AQL) sampling plans. 8 Remote Product is accepted based on no defects in a sample. 7 Very Low Product is 100% manually inspected in the process. 6 Low Product is 100% manually inspected using go/no-go or other mistake-proofing gauges. 5 Moderate Some Statistical Process Control (SPC) is used in the process and product is final inspected off-line. 4 Moderately High SPC is used and there is immediate reaction to out-of-control conditions. 3 High An effective SPC program is in place with process capabilities (Cpk) greater than 1.33. 2 Very High All product is 100% automatically inspected. 1 Almost Certain The defect is obvious and there is 100% automatic inspection with regular calibration and preventive maintenance of the inspection equipment.
- 28. Severity / Probability / Detection (SPD)
- 29. FMEA Application • Severity (S) – Link to end product functional failure – Medical Department involvement • Probability (P) – Use historical data – Similar processes products • Detection – Method validation studies – Historical data Drying Process
- 30. Process Potential Failure Mode Potential Cause S P D RP N 1. Set up contamination disheveled gown of operator insufficient cleaning of equipment 2. Start drying contamination damage of inlet-air filter degradation of product damage of thermometer 3. Maintain temperatu re long drying time unstable supply-air volume high Loss On Drying (LOD) damage of timer low LOD high dew-point non-uniformity of LOD uneven temperature distribution Drying Process FMEA Application
- 31. FMEA Existing controls: IPC of LOD and degradation product after drying process Drying Process Process Potential Failure Mode Potential Cause S P D RP N 1. Set up contamination disheveled gown of operator 3 5 8 120 insufficient cleaning of equipment 7 2 8 112 2. Start drying contamination damage of inlet-air filter 7 3 6 126 degradation of product damage of thermometer 7 3 3 63 3. Maintain temperatur e long drying time unstable supply-air volume 2 4 5 40 high LOD malfunction of timer 2 2 2 8 low LOD high due-point 3 3 3 27 non-uniformity of LOD uneven temperature distribution 3 5 3 45 RPN: Risk Priority Number = S*P*D
- 32. FMEA Take action when RPN is over 100 Take action when severity is over 5 Remaining critical parameters after taking action; further controls required Drying Process Process Potential Cause RP N Recommended Action S P D RP N 1. Set up disheveled gown of operator 120 use long gloves and goggles 3 2 8 48 insufficient cleaning of equipment 112 change cleaning procedure 7 2 4 56 2. Start drying damage of inlet-air filter 126 change maintenance period 7 2 6 84 damage of thermometer 63 change calibration period 7 2 3 42 3. Maintain temperatur e unstable supply-air volume 40 ― 2 4 5 40 malfunction of timer 8 ― 2 2 2 8 high dew-point 27 ― 3 3 3 27 uneven temperature distribution 45 ― 3 5 3 45 RPN: Risk Priority Number = S*P*D
- 33. FMEA • Prepare a risk profile Severity / Consequences i negligible ii marginal iii critical iv catastrophic Probability A frequent B moderate C occasional D rare E unlikely F very unlikely Consequences Risk protection level
- 34. FMEA • Prepare a risk profile: Probability
- 35. FMEA • Risk Evaluation: Risk Profile – For high risks, which are not acceptable, risk reduction measures have to be taken as a high priority
- 36. FMEA Potential Areas of Use(s) • Prioritize risks • Monitor the effectiveness of risk control activities • Equipment and facilities • Analyze a manufacturing process to identify high-risk steps or critical parameters
- 37. Fault Tree Analysis (FTA) • Basic symbols: Basic Flow Fault in a box indicates that it is a result of previous faultsFAULT OR AND Connects two or more faults that must occur simultaneously to cause the preceding fault Connects preceding fault with a subsequent fault that could cause a failure
- 38. Fault Tree Analysis (FTA) • Basic symbols: End Points & Connector Root cause (= basic fault) (e.g. part failure, software error, human error)Root cause Fault to be further analyzed with more time or information if needed Transfer-in and transfer-out events
- 39. Fault Tree Analysis (FTA) • Additional Symbols Exclusive OR Gate: Fault occurs if only one of the input faults occurs m Priority AND Gate: Fault occurs if all inputs occur in a certain order Voting OR Gate: Fault occurs if “m” or more out of “n” input faults occurs
- 40. Fault Tree Analysis (FTA) • Investigation of laboratory failures Out of specification result Production Lab error others or outlier systematic random or or Calibration Interfaces other
- 41. Fault Tree Analysis (FTA) Hard to open Production Formulation Processing Cap Bottle Packaging Stability Too tightly Closed Supply Defect Solidify Ageing or andor or Bad fit Change closing torque and calibrate periodically
- 42. Risk ranking and filtering Evaluation of products and processes with recurring quality relevant problems Risk assessment: Risk evaluation Three columns based on a classical approach by multiplying factors 5 50 500 1 2 4 500 20105 20010050 20001000 Probability Resources
- 43. Risk ranking and filtering Evaluation of products and processes with recurring quality relevant problems Risk assessment: Risk Control Risk control actions added to process problems Process Products concerned Corrective actions instituted to date Proba- bility Resources Risk (Probability multiplied with Resources) ABC 4 500 2000 ACB 4 50 200 BAC 4 50 200 CAB 4 5 20 Missing prints of Variable Data CBA Project started, corrective measures under discussion 4 500 2000 ABC 2 500 2000 ACB 2 50 100 BAC 2 50 100 Blister: blister foil peels off CAB Task force established 2 50 100
- 44. Risk ranking and filtering Low Medium High Severity Probability High Low Medium Risk Class ONE Risk Class TWO Risk Class THREE Risk Matrix (1)
- 45. THREE TWO ONE Detection RiskClassification High Low Medium HIGH priority MEDIUM priority LOW priority Risk Filtering Risk Matrix (2) Risk ranking and filtering
- 46. Quality risk management as part of… Development Competent Authorities Industry See also next chapters using the intention to be applicable for development II.4: Facilities, Equipment and Utilities II.5: Materials Management II.6: Production II.7: Laboratory Control and Stability Studies II.8: Packaging and Labelling Note: Process understanding and criticality may be applied only to new products
- 47. About development All parameters and dimensions that define a product Parameters that impact customer requirements Critical Parameters that contribute to variation in customer requirements
- 48. QRM as part of development • To design a quality product and its manufacturing process – to consistently deliver the intended performance of the product (see ICH Q8) • To enhance knowledge of product performance over a wide range of – material attributes (e.g. particle size distribution, moisture content, flow properties) – processing options – process parameters
- 49. Quality by design: “Special Cause” or “Common Cause” • Consequence: Frequent, major OOS • Corrective actions eliminate Validation Production Based on A. Hussain, FDA, September 2004 Note: Non detected OoS could result in a patient risk
- 50. Quality by design : “Special Cause” or “Common Cause” • Reduce “Common Cause” Variability • Consequence: On the continuous Validation Production A. Hussain, FDA, September 2004
- 51. Quality by design : “Special Cause” or “Common Cause” • Consequence: Minor, occasional OoS • Reduce “Common Cause” Variability Result: Stable- Yes; Capable? Validation Production A. Hussain, FDA, September 2004
- 52. QRM as part of development • To assess the critical attributes of – Raw materials – Solvents – Active Pharmaceutical Ingredient (API) – Starting materials – Excipients – Packaging materials • To establish appropriate specifications, identify critical process parameters and establish manufacturing controls
- 53. QRM as part of development • To decrease variability of quality attributes: – reduce product and material defects – reduce manufacturing defects • To assess the need for additional studies (e.g., bioequivalence, stability) relating to scale up and technology transfer • To make use of the “design space” concept (see ICH Q8)
- 54. P2 of CTD as part of a regulatory submission In line with Quality Risk Management ?
- 55. Risk Review RiskCommunication Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality Risk Management Process RiskManagementtools P2 of CTD as Quality Risk Management process ? Process understanding Formulation & Process design Process control Concept Product release Concept Review the submission Regulatory strategy Manufacturing Concept
- 56. Target Product Profile Drug substance properties; prior knowledge Proposed formulation and manufacturing process Determination of Cause – Effect relationships (Risk Identification with subsequent Risk Analysis) Risk-based classification (Risk Evaluation) Parameters to investigate (e.g. by DOE) (Risk Reduction 1. proposal; 2. verified) FORMULATION DESIGN SPACE PROCESS DESIGN SPACE BY UNIT OPERATION CONTROL STRATEGY Formulationunderstanding Processunderstanding Re-evaluationandconfirmation Re-evaluationandconfirmation Product and process characteristics on the final drug product Review events Development Developm.Operation Research Phase 1 Phase 2 Phase 3 Launch QRM as part of development
- 57. Risk Management approach to focus on critical attributes QualityAttributes Unit operation Granulation Drying Blending TabletingDispensing Dissolution Disintegration Hardness Assay Content Uniformity Degradation Stability Appearance Identification Water Microbiology Control Strategy Formulation and Process understanding Prior knowledge Significant influence Initial assessment First & Second review cycle Third review cycle QRM as part of development
- 58. Risk to patient Unit operations / Quality attributes Dispensing (Raw Material Properties) Granulation Drying Blending (Magnesium Stearate) Tableting Packaging Dissolution Particle size API Power consumption Prior knowledge Not critical to quality Not critical to quality Prior knowledge Disintegration Particle size API water amount and feed rate Prior knowledge Not critical to quality Not critical to quality Prior knowledge Hardness Prior knowledge Prior knowledge Prior knowledge Not critical to quality Not critical to quality Prior knowledge Assay Prior knowledge Prior knowledge Prior knowledge Prior knowledge NIR measurement Prior knowledge Content uniformity Prior knowledge Power consumption Not critical to quality Not critical to quality NIR measurement Prior knowledge Degradation Prior knowledge Water amount and feed rate Not critical to quality Prior knowledge Prior knowledge Prior knowledge Stability Prior knowledge Prior knowledge Control water content Prior knowledge Prior knowledge Prior knowledge Appearance Prior knowledge Prior knowledge Not critical to quality Prior knowledge Not critical to quality Prior knowledge Identification NIR of raw material Prior knowledge Prior knowledge Prior knowledge Prior knowledge Prior knowledge Water Prior knowledge Prior knowledge Control water content Prior knowledge Prior knowledge Prior knowledge Microbiology Specification of starting material Purified water used Prior knowledge Prior knowledge Prior knowledge Prior knowledge 1 low Process understanding Control Strategy 1 Unit operation QualityAttributes
- 59. Risk Review Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Quality Risk Management Process RiskManagementtools RiskCommunication TeamfocusedInternalconsultationStakeholderinvolvement Responsibilities in regulatory operations Industry A) Reviewers B) Inspectorates
- 60. QRM as part of development provide risk-based knowledge to manufacturer Past Future Parameters and range We have additional dimensions • Open question: How to challenge information for submission? Answer the questions in ICH Q9 Chapter 4: – What might go wrong? – What is the likelihood (probability) it will go wrong? – What are the consequences (severity)?
- 61. Raw Materials Blending Tabletting Packaging Conventional approach: Testing after each step to minimize the risk prior to the next step Raw Materials Blending Tabletting Packaging PAT: Continuous or more frequent testing and control during each step to minimize/control the risk prior to the next step PAT: Process Analytical Technology Validation Development and Manufacturing
- 62. Q & A