Process Risk through Application of FMEA. A Case Study. INTERPHEX March 17, 2009

Transcription

1 Managing Process Risk through Application of FMEA to Batch Records A Case Study INTERPHEX March 17, 2009 Jon Hardy Lonza Head of Operations Hopkinton, MA Fred Greulich Maxiom Consulting Group, Inc. Director of Operational Excellence Maxiom Consulting Group, Inc. 230 Third Avenue 3 rd Floor Waltham, MA (781)

2 Case Study Topics Case Background and Situation Risk Discussion Introduction to Failure Mode & Effects Analysis (FMEA) and Root Cause Analysis (RCA) FMEA and RCA Project Approach Current Status and Results 2

3 Case Background and Situation Lonza is a worldwide leader in providing development and manufacturing services for the pharmaceutical and biotechnology industries Portsmouth, NH is a large scale mammalian cell culture site Strategically important to Lonza Operational Excellence, including risk management, are ongoing business imperatives Project objective was to reduce manufacturing process risk Lonza had previous experience utilizing Failure Mode and Effects Analysis and Root Cause Analysis Lonza partnered with Maxiom Group to utilize FMEA and RCA applied to batch record steps to reduce risk in the purification process for one key customer s s product 3

4 Risk in Biologics Manufacturing Risk and uncertainty exist across the entire value chain as a result of many factors Product & process technology Commercial process improvements Changing product specifications Human/operator variability Supplier vulnerabilities Scale-up and launch uncertainty Demand fluctuations Raw material & component pricing Supply base market dynamics It is essential to identify and understand risks in order to effectively manage the many sources of uncertainty t 4

5 Categories of Value Chain Risks Value chain risks can be grouped into four categories Diversion Authentication Product Security Risks Brand security Physical facility Information security Supply Risks Production Risks Demand Risks Supply disruption Facility & equipment Demand upside/ Continuity planning Pricing fluctuations Material variability Process variability Process failures Production scale-up downside Capacity constraints Product expiry Non-Compliance FMEA applied to batch records is the key tool for helping Lonza - Portsmouth manage process failures 5

6 Introduction to FMEA FMEA is a rigorous method of identifying and preventing process problems before they occur An established tool for identifying, prioritizing and managing process and business risk Focused on preventing defects, enhancing safety, and increasing customer satisfaction Minimizes Cost Of Quality Focuses on Prevention vs. Detection Applied to manufacturing batch records, FMEA results in more robust processes and reduction/elimination of the need for corrective action 6

7 Introduction to FMEA There are a few terms that are important to understand Failure Mode Failure Effects Risk Priority Number (RPN) The manner in which a process fails to meet its intended purpose The consequences if the failure occurs RPN = (Potential Severity) x (Likelihood of Occurrence) x (Ability to Detect) t) Used for each process step/failure mode combination. The RPN is used to prioritize failure modes. High priority failure modes are analyzed to identify their root causes and solutions are then developed which lead to reduced risk 7

8 FMEA and RCA Approach FMEA and RCA work is completed in three phases, starting with education and ending with implementation PHASE I. FMEA Assessment & RPN Scoring Conduct team education on FMEA Identify RPN s for each failure mode Determine top priority failure modes PHASE II RCA & Solution Identification Conduct RCA for top priority failure modes Develop solutions for selected root causes PHASE III Detailed Design & Implementation Develop detailed implementation designs and action plans for solutions identified in Phase II Implement action plans All Phases were completed with the active involvement of cross-functional teams of Lonza employees to ensure quality and ownership of results 8

9 Phase I - FMEA Assessment & RPN Scoring Results from Phase I, FMEA Assessment and Risk Priority Scoring, were captured in a spreadsheet format Process Step Potential Failure Mode Potential Failure Effects S E V Potential Causes O C C Current Controls D E T R P N What is the process step? In what way could the process step go wrong? What is the impact if the failure mode occurs? What causes the failure mode? What is the likelihood of this occurring? What are the existing controls/ that prevent the failure mode? How difficult is it to detect if the failure mode occurs? 9

10 Phase I - FMEA Assessment & RPN Scoring Templates were customized by the Lonza team to ensure standards were applied to the assessment and scoring process Effect Categories & Severity Rating Scale Severity = The seriousness of the effect of a failure mode on a downstream operation, equipment, safety, product, customer, or regulation. Rating Description Definition Product Impact Operator Safety Impact Compliance Impact Schedule Impact 5 4 Dangerously High High Lose batch Potentially salvageable Could result in death Would require calling 911 Occurrence Rating Scale Notify FDA Months Occurrence = How likely a failure mode is to occur for a given cause. Major deviation Weeks Rating Description Definition Detection Rating Scale Moderate Low Minor Salvageable with substantial rework Salvageable with minimal rework No impact Proprietary & Confidential 19 Would require first aid First aid not required No impact NOTE: Take the highest effect rating for the severity score 5 Very High Minor deviation Days 4 High Comment Hours 3 Moderate No impact No impact 2 Low 1 Remote Failure is almost inevitable; 5 or more occurrences Detectability likely in = 10Difficulty events of detecting the defect or failure with current process controls. Failure is likely; repeated failures have been observed in similar processes; 3 or more occurrences likely in 10 Rating events (approximately Description 1 Definition Sigma) Occasional failures have been experienced in similar processes; 3 or more occurrences likely in 100 events Very difficult to No known controls available to detect failure mode, or defect is not 5 (approximately 2 Sigma) detect detectable. Relatively few or isolated failures experienced in similar processes; 3 or more occurrences likely in 1000 events (approximately 3 Somewhat Sigma) difficult to 4 Remote likelihood current controls will detect failure. Failure is unlikely; Never been experienced; No failures detect ever associated with similar processes 3 Moderate Moderate likelihood current controls will detect failure. Proprietary & Confidential 20 2 Somewhat easy to detect High likelihood current controls will detect failure. 1 Easy to detect Current controls almost certain to detect the failure mode. Proprietary & Confidential 21 This customization was done in a project kickoff session at the beginning of Phase I of the project 10

11 Phase I - FMEA Assessment & RPN Scoring Here is a example of the completed FMEA Assessment and Priority Scoring Template PROCESS STEP POTENTIAL FAILURE MODE (HOW) EFFECT (WHAT) SEV CAUSE (WHY) OCC CURRENT CONTROLS DET RPN 7.2 Starting Material preparation Record harvest batch Do not record Lost traceability 1 Oe 2 batch record 3 6 number ; room temperature Record harvest batch number ; room temperature Temperature out of specificxation noncompliance with quality systems (deviation) 2 Probe oot 2 PM Program Harvest confirmation Temperature out of specification lost process time (bad temp probe, out of spec temperature) Harvest confirmation Print,record weight not done noncompliance with quality systems (deviation) Mix permeate Not able to mix Lost process time (mixer problem) Mix permeate Mix time out of specification noncompliance with quality systems (deviation) 2 probe oot 2 Metrology program Oe 2 batch record equipment failure 2 PM Program Oe 2 batch record Setup and obtain a bulk Sampler expired lost administration time 2 Oe 3 batch record 3 18 sample of the harvest (comments) Setup and obtain a bulk Sampler not connected negligible XXXX XXXXX sample of the harvest 11

12 Severity = The seriousness of the effect of a failure mode on a downstream operation, equipment, safety, product, customer, or regulation. Rating Description Definition Product Impact Operator Safety Impact Compliance Impact Schedule Impact 5 Dangerously High Lose batch Could result in death Notify FDA Months Potentially Would require calling 4 High Major deviation Weeks salvageable 911 Rating Description Definition Salvageable with 3 Moderate substantial Would require first 5 aid Minor Very High deviation Days Failure is almost inevitable; 5 or more occurrences likely in 10 events rework Failure is likely; repeated failures have been observed in similar Salvageable with 2 Low First aid not required 4 Comment High Hours processes; 3 or more occurrences likely in 10 events (approximately 1 minimal rework Sigma) Occasional failures have Rating been experienced Description in similar processes; 3 or Definition 1 Minor No impact No impact 3 No Moderate impact No more impact occurrences likely in 100 events (approximately 2 Sigma) NOTE: Take the highest effect rating for the severity score Very difficult to No known controls available to detect failure mode, or defect is not Relatively few or isolated failures 5 experienced in similar processes; 3 or 2 Low detect detectable. more occurrences likely in 1000 events (approximately 3 Sigma) Failure is unlikely; Never been experienced; No failures ever associated Proprietary & Confidential 19 1 Remote Somewhat difficult to with similar processes 4 Remote likelihood current controls will detect failure. detect Proprietary & Confidential Moderate Somewhat easy to detect Easy to detect Proprietary & Confidential 21 Moderate likelihood current controls will detect failure. High likelihood current controls will detect failure. Current controls almost certain to detect the failure mode. Phase I - FMEA Assessment & RPN Scoring The Lonza team began with 8 batch records which eventually mapped to 25 critical failure modes... 8 Purification Batch Records Analyzed >2600 Batch Record line items 266 High Risk RPN Steps 25 Critical Failure Modes Chrom BRs: - Chrom A - Chrom B - Chrom C - Chrom D UF BRs: - UF A -UF B -UF C Fill Finish: - Bulk Fill A Customized Rating Scales Effect Categories & Severity Rating Scale Occurrence Rating Scale Occurrence = How likely a failure mode is to occur for a given cause. Detection Rating Scale Detectability = Difficulty of detecting the defect or failure with current process controls. FMEA Table to Calc RPN S O D R Process Potential Failure Potential Failure E Potential Causes C Current Controls E P Step/Input Mode Ef fects V C T N What is the In what ways What is the impact What causes the Key What are the process step does the Key on the Key Output Input to go wrong? existing controls and Input Input go wrong? Variables (Customer and procedures under Requirements)? (inspection and test) investigation that prevent eith the? cause or the Failure Mode? Introduced 2-Slope Plots y-axis x-axis 50 Determined High Risk RPN steps for each batch record Grouped High Risk RPN Steps by Failure Mode Q FF Chrom Phenyl Chrom

13 Phase I - FMEA Assessment & RPN Scoring Of the 25 critical failure modes, 6 were selected to move into Phase II based on alignment with existing initiatives at Lonza and anticipated magnitude of impact The selected failure modes fell into categories such as - Skid or equipment preparation Process limitations Filter set-up/testing 13

14 Phase II RCA & Solution Identification Root causes were identified and solutions were created and prioritized Six Failure Modes (from FMEA Assessment Phase) Perform Root Cause Analysis for Each Failure Mode Group Root Causes Develop Solutions for Each Root Cause(s) Prep for Implementation Root Cause Analysis Workshops Training Root Cause Analysis Develop Fishbone Diagrams/ 5 Why s Converge on root causes Root cause grouping Identify teams for Solutions Solution Sessions Develop solution(s) for each root cause Rate solutions against batch record steps Develop Implementation Approach Management Team Review 14

15 Phase II RCA & Solution Identification RCA was performed for each of the six failure modes Cause & Effect Analysis Structured brainstorming of potential root causes Utilized fishbone diagrams 5Why s Asks why does that happen? Supports fishbone diagram by helping to drill deeper Large set Potential Root Causes Narrowing Narrows potential root causes down to the likely ones Based on judgment of the people who are familiar with the process Smaller set Likely Root Causes Selection Selects the root cause(s) for solution identification Based on qualitative/ ti quantitative basic data Actual Root Causes As a result, 23 actual root causes were identified 15

16 Phase II RCA & Solution Identification The 23 actual root causes were then grouped by affinity to help in the identification of teams and the approach for solution development... UF Operations Chromatography Operations Root Cause 1 Root Cause 2 Root Cause 3 Root Cause 4 Root Cause 5 Root Cause 6 Root Cause 7 Root Cause 11 Root Cause 12 Root Cause 13 Root Cause 14 Root Cause 15 Root Cause 16 Root Cause 17 Root Cause 18 Root Cause 19 Documentation Root Cause 8 Root Cause 9 Root Cause 10 Root Cause 20 Root Cause 21 Root Cause 22 Root Cause Filter Integrity Testing

17 Phase II RCA & Solution Identification Solutions for the 23 root causes were then developed and captured in a standard format... Solution Name: Root Cause: Install Vent to Improve Draining of Caustic Header in UF Developed By: Andy, Derek, Stuart, Dan Date: 01Apr2008 XXXXXX Failure Mode: Solution Description: XXXXXX Install block and bleed/vent after liquid filter housings of caustic tanks (T-35013/T-35014) to improve header draining. Solution Sketch/Notes: New vent & valve block Key Install block and bleed/vent after liquid id filter housings of Characteristics caustic tanks (T-35013/T-35014) of Solution: Engineering and Technical Requirements SOP updates Validation (I, Q, CSV) Controls work, EM s Equipment downtime to install Will likely require a vent filter Could be done with ambient or pressurized air Key Assumptions: Additional Benefits: Solution can be applied to chromatography skids as well Opening bleed/vent valve will provide a high point vent of drain line quickly and effectively Impact Rating: 750 No issues with pipe slope, introducing air to filter housing Don t change drain header from T Feasibility Rating: 3 Wet test required to better determine feasibility & impact Prioritization Index:

18 Phase II RCA & Solution Identification Solutions were then prioritized based on estimated impact and implementation feasibility Potential Impact to RPNs For each impacted batch record line item, we will calculate a potential RPN if the solution were to be implemented Example: Incorrect Probe Standardization 36 batch record line items are impacted 1. If solution were implemented, here is (Chrom & UF) what RPN we would For each impacted line item, we will assess expect solution impact 2. Potential impact of the solution Solution X for Incorrect Probe Standardization BR Line Item Baseline RPN RPN To Be RPN 1 USPO Ensure conductivity probes have been cleaned USPO Post standardization conductivity standard check result Feasibility of Implementation The team used this table to evaluate solution feasibility Feasibility Rating Extent of Control Within Team Within Group Within Plant Mgr. Impact on Customer Internal Change Control only (e.g. SOP Changes) Customer notified, no approval needed Customer signoff required as CC Capital Cost to Implement Time to Implement Resource Commitment $0 - $8K Days 0-20 hrs $8K - $25K Weeks hrs $25K - $50K Months hrs MORE FEASIBLE 36 USPO Standardize UF Sum of all conductivity probe RPN values Total Potential Impact of this Solution: Within NH Site Beyond NH Site FDA Notified; CMC filing changes necessary New Clinical trials / approval necessary $50K - $150K Quarters hrs >$150K > 1 year > 1600 hrs 8 Low feasibility number is better Proprietary & Confidential 17 RPN (beginning) RPN (estimated after action) Feasibility Rating = Solution Priority Index 18

19 Phase III Detailed Design & Implementation Detailed Design & Implementation typically includes the following Deployment Planning Detailed Design Implementationn Sustain Improvements Charter teams Develop detailed d Conduct testing/ ti Develop metrics and Develop design design for each validation tracking methods and implementation solution Complete SOP/ Develop processes to plan for each Conduct vendor Batch Record sustain improvements solution selection(s) as rollout and training Conduct regular required status/update reviews Ensure integration across the plans Establish timelines and milestones Complete SOP / Batch Record updates and obtain approvals Obtain management & customer approvals Implement solution elements Obtain management & customer sign-off Identify and implement continuous improvement ideas that occur in day Sprints to ensure focus and momentum. 19

20 Phase III Detailed Design & Implementation The schedule for these implementation Sprints typically looks as follows Month 1 Month 2 Month 3 Month 4 Month 5 Deployment Planning Detailed Design Implementation LEGEND: Wave 1 Sprint Sustain Improvements Deployment Planning Wave 2 Sprint Detailed Design Implementation This aligns with Lonza s overall Operational Excellence approach of Plan, Do, Check, Act Sustain Improve- ments 20

21 Current Status and Results Cross functional teams have begun, and in some cases completed, implementation of the 23 solutions as targeted projects utilizing the current systems within Lonza Implementation progress varies due to the nature and scope of the solution. Since most solutions were identified at a high level, Lonza was able to then take them through detailed design and into the implementation phase through its change control and document change systems. The solutions were mainly championed through Manufacturing with significant support from Engineering, Controls, Validation, and Quality Assurance. Benefits in terms of reduced failures are already being realized 21

22 Maxiom Group Overview Maxiom Group is a business and information technology consulting firm exclusively serving the life sciences industry Our clients include emerging, established, and mature Biotechnology, Pharmaceutical, Diagnostic and Medical Device companies Maxiom Group helps life science companies transform their strategies, business processes, and business systems to achieve excellence at each stage of their life cycle From drug discovery to clinical development From clinical development to commercial launch From commercial launch to market leadership Clients rely on our Focus, Insight and Approach to guide them in transforming their business and in addressing their ongoing business challenges 22