Background on QRM. Pharma EXPO September 2015 Las Vegas, NV. Your QRM Program. Paul H. Ahlijanian

Transcription

1 Using Quality Risk Management to Evaluate Compliance for Multiproduct and Inventory Facilities in the Pharmaceutical Industry Paul H. Ahlijanian Senior Manager, Pharmaceutical Sciences Quality Assurance Pfizer, Inc. 1 Background on QRM The International Conference on Harmonisation (ICH) Q9 document states that QRM is a systematic process for the assessment, control, communication, and review of risks to the quality of the drug product across the product lifecycle In all likelihood you are already building QRM into your work processes when you make risk-based decisions. QRM formalizes these decisions and provides a way for different workstreams to collaborate and determine an outcome based on science, engineering, and quality. Your QRM Program Do you have a documented QRM Program? Do you have one or more SOPs describing your company s QRM Program? Does your QRM SOP allow for and delineate formal and informal QRM evaluations? Do you have a Consistent, Time-Based QRM Review Program or are Reviews conducted Ad Hoc? 1

2 Overview of the QRM process Identify all risks in a proposed change or continuous improvement initiative Risk to patient Risk to compliance Risk to business Define an acceptable level of risk Quantify the level of each risk Multidisciplinary team assessment Is risk at an acceptable level? Yes can it be further reduced to as low as is reasonably possible? No can measures be put in place to reduce this risk to an acceptable level? Yes risk is mitigated, change can take place No change or CI initiative not acceptable QRM Process Lifecycle & Communication (ICH Q9) Keep line management informed Risk assessments teams: Multi-disciplinary membership Knowledgeable QRM facilitators Results are formally reviewed and approved (including by the Quality Unit) Periodic review to assess any changes that could impact the risk assessment. Key Steps 2

3 Define the Risk Question The Risk Question needs to include: Risk Factors Results Scope (Define what is in and out) Example Risk Question: What is the risk to patient safety, product quality and compliance of manufacturing different higher risk classes of compounds in a multiproduct facility? Key Step - Choose Assessment Tool Suitable for facilities, equipment, and processes. Capable of assessing process systems and their physical and operational environments Capable of assessing operational and procedural controls Selection based on products/process/systems knowledge Consider product/process expertise of team and experience with QRM Risk severity do risks need to be quantified, or is L/M/H sufficient to determine a course of action Factors to Consider Key Step - Determine Risk Criteria & Scales Probability Severity Detection Risk to: Patient Compliance Business Examples only! The QRM Team will determine the scales Scales, Medium, 1, 3, 5, 7, 10 1, 2, 3 Etc., Discretion of QRM Team 3

4 QRM Practical Application Multi-Product or Inventory Management Facility Cross Contamination Control Background Why are we doing this? Industry Regulatory Observations Recent market regulations have mandated the segregation or separation of certain classes of compounds manufactured in a multiproduct facility 4

5 Why are we doing this? Facility Cross Contamination Statistics Review of 2013 and 2014 FDA 483 observations (noncompany specific) reveal approximately 10% attributed to cross contamination findings related to product handling and storage, equipment, and/or facilities.* Business Driver/Initiative Our company needs a comprehensive risk-based program to ensure that potential cross-contamination and mix-up risks within multi-product facilities are appropriately identified, systematically assessed and controlled. * - ( ( Begin the Process Global Alignment Identify global manufacturing/inventory management locations. Review product class storage and inventory. Establish Project Leads/Facilitators from each location and facility Initial facility assessments/walkthroughs Develop an assessment approach and template that is consistent throughout all sites and facilities Form facility and site QRM teams and initiate the process. Begin the Process Site & Facility Teams Select Team Members All participants should be trained in QRM SOPs prior to any QRM sessions, including kickoff meeting. Give them Lunch!! QA (Specific Facility Quality Experience) Shift Lead (Production Expertise) Facilities Expert (Quick access to plans, P&IDs, HVAC, etc.) Process Technician Experienced QRM Facilitator Mfg Area Manager Mfg Area Compliance Environmental Health & Safety (Industrial Hygiene Experience) Engineer or Coordinator (may not be staffed for IM Facility) 5

6 Begin the Education Process Cross Contamination Need a risk assessment to determine how to balance: Processes sharing of common facility areas or equipment (e.g., reactors, raw material storage, personnel, support areas, etc.) Prevention of potential crosscontamination through process containment and facility design and controls Begin the Process Documents Needed to Get Started Detailed information will need to be gathered to ensure the assessments are both effective and comprehensive Facility Design Documents Facility Diagrams (flows, HVAC plans, etc.) PFDs (Process Flow Diagrams) Key Facility Operating SOPs including: Procedures governing open operations Cleaning and inactivation SOPs (including spill response) Facility & surface sanitization SOPs Changeover SOPs Maintenance Maintenance/Calibration Vendor Practices Cross-contamination how it happens Cross contamination between processes is dependent upon three events occurring together: Release Transport Ingress Unintended hazard release from spills, open operations, material mix-ups, waste, etc. Unintended carriage of hazards between manufacturing areas via flow of materials, product, equipment, personnel, waste etc. across doorways, through piping, pass-throughs, etc. Unintended hazard ingress into a receiving process due to breach of system closure, material additions, open operations, etc. Approach: prevent or control each of these events so that the equation cannot be satisfied 6

7 Assessment of Facility Interfaces How does material escape? Determine facility boundary and scope of operations Components physical items or pathways that could intentionally or inadvertently carry product or materials throughout the facility, i.e., how material carried is out Air (HVAC) Sampling Cleaning Personnel Equipment Packaging Materials Utilities Warehouse Operations Waste Dispening/Weighing Hazard Operability Analysis (HAZOP) chosen as the primary risk assessment tool Hazop Tool HAZOP is based on a theory that assumes risk events are caused by deviations from design or operating intentions Break up processes into individual steps for analysis Risk Identification: Identify deviations from design or operating intentions in a systematic fashion Similar to a what if? analysis Risk Analysis: Risk Rating System LOW Likelihood of Deviation Occurrence MEDIUM HIGH : Hazard condition or contamination event not common or expected, but theoretically possible. Medium: Hazard condition or contamination event is not a routine occurrence, but has been observed. : Hazard condition or contamination event is likely, common, or observed routinely. Note: The rating scales may be customized for each manufacturing facility as applicable 7

8 Risk Analysis: Risk Rating System Severity of Deviation Consequences : No product impact anticipated. Medium: Direct impact on assessed component elevated, yet not anticipated to have product impact. : Direct impact on assessed component is high or product impact likely. Direct ingress of contamination directly into product or product components (includes non-product areas, solutions and equipment). LOW MEDIUM HIGH Note: The rating scales may be customized for each manufacturing facility as applicable Evaluate Mitigated Risk Likelihood Medium More Than One Control Required One or More Controls Required More Than One Control Required More Than One Control Required Engineering Or Design Control Required More Than One Control Required Controls may be procedural, training, or engineering / facility design controls and may consider the ability to detect deviations or hazard components as part of a mitigating control No Action Required One or More Controls Required More Than One Control Required Medium Severity Facility Assessments 8

9 Facility Assessments GMP Facilities API Area API Area 2 (Chromatography) Solid Dose Inventory Management Small Pack/Label Facility Liquid Dose Facility Assessments Hazard Classes Product Classifications in Scope of the QRM creating the business case for each facility Certain ly Active or Toxic Products Certain Steroids Cytotoxics Certain Hormones Immunosuppressors Biologicals Exclusive For Animal Use Non-Medicinal Products (pesticides, herbicides) Other Not Yet Classifiable Product Classifications out of Scope ly Sensitizing Products Certain Antibiotics Radiopharmaceuticals Segregation Categories Dedicated Building (For Product Class) Physically separate building which provides complete and total separation of all aspects of all operations. Dedicated Segregated Areas (For Product Class) Areas within a multiproduct facility dedicated to a product class. Campaign Segregation Segregated areas within a multiproduct facility that are used for more than one product class that require segregation. More than one product class cannot be processed at the same time. Campaign segregation is referred to as segregation by time. Validated cleaning and/or inactivation procedures should be established. 9

10 Facility Assessments Facility and Process Mapping Facility Interface Example Defines Boundary Facility Assessments Risk Table Two Facility Interfaces Areas Annex (Milling, Storage of raw materials) and intermediates Each evaluated based on the following pathways (components): Warehouse Ops Packaging Sampling In-Process Sampling Dispensing/Weighing HVAC Personnel For both facilities, 60 operations (elements) evaluated For both facilities, 90 deviations evaluated Example Risk Table API Annex Milling Operations 10

11 Facility Interface Severity of Comments/ Probability of Component Element Deviations Possible Causes Safeguards (controls) Risk Occurrence Consequences Evaluation Recommended Actions Airborne Transfer to outside areas Engineering controls, HVAC Milling Operation system design/preventive Med maintenance Open mill charge Engineering controls, PPE Unloading mill Engineering controls, PPE Reference API Consider Plant and alternative Milling milling area, Operations consider lock Industrial out facility Hygiene (IH) entrance Surrogate during milling Testing Annex (Labs, Milling, Raw Material Storage, Intermediate Storage, Dispensing) Use of Mill Room Engineering control Visual indication, gage failure (i.e., inadequate monitoring, batch record design) verification Med Procedure, engineering Spillage Open Mill Charge controls, PPE Procedure, engineering Open Mill Charge controls, PPE No anteroom, improper gowning, Mfg SOPs, technician Human Transfer improper personnel training, PPE flow, insufficient training Operations would stop Potential gap, Swab and air test results to Suggest two be reviewed to person confirm Prob of operation at all Occurance/ time to aide in Severity, IH PPE decon Surrogate Testing Reuse of PPE (i.e., hood) Procedures (disposal) Med Labeling Errors Human Error Second person verification Equipment Transfer Cleaning procedure, material Open mill charge handling procedure (SOI-GRcontaminating balance API-EQP-1044), engineering carts, scoop, containers control, PPE controls Engineering/ Facility Controls Failure Inadequate design (i.e., Procedures, cleaning, open tray charge) training, PPE Visual indication, gage Power Failure monitoring, Groton site control Med room notification Med Med Magnehelic gauge installation Facility Interface Component Element: Use of Mill Room Annex Deviation: Airborne Transfer to outside areas Possible Causes: Milling Operations Safeguards: Engineering controls, HVAC system design/preventive maintenance Probability of Occurrence: Severity of Consequences: Medium Comments/Risk Evaluations: Reference API Plant and Milling Operations Industrial Hygiene (IH) Surrogate Testing Recommended Action: Consider alternative milling area, consider lock out facility entrance during milling Facility Interface Component Element: Use of Mill Room Annex Deviation: Human Transfer Possible Causes: No anteroom, improper gowning, improper personnel flow, insufficient training Safeguards: MFG & Cleaning SOPs, Technician Training, PPE Probability of Occurrence: Severity of Consequences: Comments/Risk Evaluations: Potential gap, Swab and air test results to be reviewed to confirm Prob of Occurance/Severity, IH Surrogate Testing Recommended Action: Suggest 2 person operation at all time to aide in PPE decon 11

12 Example Risk Table API HVAC Facility Interface Component Element Deviations Possible Causes Safeguards (controls) Probability of of Severity Occurre Consequences nce Comments/ Risk Evaluation Recommended Actions Incorrect pressure differentials Makeup/ result in Supply air migration of and exhaust product air not from one balanced, Reactor system suite to malfunction hallway or to another suite Room balancing is checked and certified every 3 years. All charging is done in closed hood that has its own downflow and exhaust. Preventive maintenance Medium Improve/correct air balance. Increase frequency of balance testing and 3 years is certification. Provide a clear not status of air pressure at each sufficient room, i.e., individual frequency magnehelic gauges with to transmitters to allow display perform of pressure in hallways, balancing. alarms, etc. Allows for detectability. Recommend conducting smoke test. Area HVAC Air Current air Balancing Incorrect balancing has in Mfg Area pressure 134C positive, Room balancing is differentials 134D neutral, checked and result in and 134B certified every 3 migration of (common years. Current product general measurement from Dryer purpose area) show air flow out suites to neutral. All 3 of balance. Open another rooms solids handling Dryer suite negative to takes place (134C and airlock 134A. directly in front of 134D) or Supply air in HEPA exhaust 129B (and 134C higher (cross flow Processing flow than exhaust?) Suites) HEPA exhaust. Positive pressure from 134C could result in product migration into Recommend conducting general smoke test. purpose area (134B) and possibly 134D dryer suite. 12

13 Facility Interface Component Element: Air Balancing in Area Mfg Area HVAC Deviation: Incorrect pressure differentials result in migration of product from one Reactor suite to hallway or to another suite Possible Causes: Makeup/Supply air and exhaust air not balanced, system malfunction Safeguards: Room balancing is checked and certified every 3 years. All charging is done in closed hood that has its own downflow and exhaust. Preventive maintenance Probability of Occurrence: Severity of Consequences: Medium Comments/Risk Evaluations: 3 years is not sufficient frequency to perform balancing Recommended Action: Improve/correct air balance. Increase frequency of balance testing and certification. Provide a clear status of air pressure at each room, i.e., individual magnehelic gauges with transmitters to allow display of pressure in hallways, alarms, etc. Allows for detectability. Recommend conducting smoke test. Facility Interface Component Element Deviations Possible Causes Safeguards (controls) Comments/ Risk Evaluation Probability of Severity of Consequences Occurrence Recommended Actions Area HVAC Cross contamination between Walkin hood and fans shuts down failure One of the exhaust Power Lab hood and Hallway 129B Confirm the following: Mfg Rm 1: EF-1 shuts Hoods are far down and SF-3 shuts enough away to down. avoid migration Mfg Rm 2: EF-2 shuts from one to - down and SF-3 shuts another. This Could - down. was confirmed change Could Mfg Rm 3: EF-3 shuts by recent air based change down and SF-3 shuts Recommend measurements. on based on down. conducting According to Exhaust Exh. and Dry. Rms: EF-4 shuts down smoke test. HVAC SME, and Supply and SF-3 shuts down. makeup air Supply data handlers shut 132 (Subd. Rm.): EF-5 air data down when shuts down SF-5 shuts exhaust fans down. shut down. And vice versa for all above scenarios. Outside hallway None, other pressure is higher Air than open than airlock. Imbalance, reactors only in Outside hallway is pressure in hoods. Any exposed to oustide Air Balancing product in the outside conditions hallway too at outside outside via an overhead high. Both hallway and hallway is in door. Potential doors to entry "airlock" secondary for dirt, dust, etc. airlock open containment or to migrate at the same drummed or through airlock time (not a shrink and into all Mfg true airlock) wrapped, etc. Area rooms Medium Reestablish as a true Not a true cross airlock, i.e., contamination issue, but doors critical quality issue due interlocked to the high probability of to open one dust and debris impacting at a time. product. Recommend conducting smoke test. 13

14 Facility Interface Area Component HVAC Element: Air Balancing at outside hallway and entry airlock Deviation: Outside hallway pressure is higher than airlock. Outside hallway is exposed to outside conditions via an overhead door. Potential for dirt, dust, etc. to migrate through airlock and into all Mfg Area rooms. Possible Causes: Air Imbalance, pressure in oustide hallway too high. Both doors to airlock open at the same time (not a true airlock) Safeguards: None, other than open reactors only in hoods. Any product in the outside hallway is in secondary containment or drummed or shrink wrapped, etc. Probability of Occurrence: Severity of Consequences: Medium Comments/Risk Evaluations: Not a true cross contamination issue, but critical quality issue due to the high probability of dust and debris impacting product Recommended Action: Reestablish as a true airlock, i.e., doors interlocked to open one at a time. Recommend conducting smoke test. Facility Assessments Six Facility Interfaces Rooms (with and without Misting Showers) In Process Testing Room Hallway-type Rooms (No Open Product) Gown/Degown Rooms for GMP Area Wash Rooms Clean Equipment (No product) Each evaluated based on the following pathways (components): Warehouse Ops Packaging Sampling In-Process Sampling Dispensing/Weighing HVAC Personnel 35 operations (elements) evaluated 55 deviations evaluated for all facility interfaces Facility Assessments Four Facility Interfaces Warehouse Area Dispensing Booths Handoff Areas Sampling Areas (future) Each evaluated based on the following pathways (components): Warehouse Ops Packaging Sampling In-Process Sampling Dispensing/Weighing HVAC Personnel For both facilities,15 conditions (elements) evaluated For both facilities, 25 deviations evaluated 14

15 Write the Report What s Required References Team members Scope Working Group Table (Attachment) Scope QRM Methodology & Assumptions Periodic Review Interval Action Item Table in ES Executive Summary (ES) of Results Summary/Lessons Learned Obtain Management support up front. Consider resource utilization Be specific with scope and risk question. Use an agreed upon QRM tool. Facilitator must be energetic and continue to challenge the group and maintain energy level Make sure facility drawings are current for layout and HVAC. Line up HVAC expert early as this expertise is very important and can be overlooked when forming the team. Summary/Lessons Learned Choose report author up front. Lunch and Coffee!! Minimize sessions by employing full day meetings if possible. Actions item responsibilities well defined, with timetables. Management and approver signatures predetermined (should be in QRM SOP) 15

16 Any Questions Background Slides 16

17 Additional Facility Assessment Tables Facility Assessments Risk Table Example Drug Product Facility Interface Component Element Deviations Possible Causes Safeguards (controls) Probability of Occurrence Actions Comments/ Severity Recommended for of Consequences Contain- Risk Evalua-tion ment and Open Transfers Open product is Product leak transferred to bin (elephant trunk). API sieving. Improper transfer technique, product bag rips, bin valve left open. Experienced technicians, training, all sieves are one time use, then discarded. Only larger sieves that are dedicated to a product are cleaned and tracked as dedicated to that product. Any leaks are immediately cleaned up. Rooms (with and without Misting Showers) Cleaning Cleaning Validation Cleaning Validation Product Assesment (CVPA) checked everytime product is used. ADE values and swab sampling measures assessed as part of CVPA. CVPA Reversioned if toxicity information or Cleaning Validation Data classification changes. No not available notification if classification changes until next use, however QRM assessment is performed to determine risk of products previously manufactured. SOPs in place for individual pieces of equipment. Consider improved Marginal notification solubility from EHS or increases Master severity. Planner to facility solubility (internal and would have external rinsed off. coordina-tors solubility when a would have product been classifica-tion swabbed changes Facility Assessments Risk Table Example Drug Product Facility Interface Component Element Deviations Possible Causes Safeguards (controls) Probability of Occurrence Actions Comments/ Severity Recommended for of Consequences Contain- Risk Evalua-tion ment Rooms (with and without Misting Showers) Equipment visually inspected, equipment always under observation, equipment is stopped in case of leak, personnel in PPE within mfg Human error, equipment module, processing rooms malfunction, tear in negative to air locks and flexible transition piece corridor. Airflow designed to from one piece of Closed contained Leakage during keep product low and away equipment to another, mfg process, manufacturing, Transfer from clean corridor. Any spill mill screen plugs. Medium closed transfer to sleeve tears during bin would be cleaned following Overpressurization mill to mill transfer spill. Technician air shower /material weakness and PPE removal prior to clean during transfer to a mill. corridor entry. All equipment Sleeve not properly is cleaned within the module attached prior to exit. Cleaning is validated or swabbing is performed for compounds with solubility outside of validated range. 17

18 Facility Assessments Risk Table Example Inventory Management Facility Comments/ Actions Probability Severity Recommended for Facility Interface Component Element Deviations Possible Causes Safeguards (controls) of of Consequences Evalua- Risk Occurrence Containment tion Scoops, Minimal quantity of product is weigh boat, sampled/subdivided. Downflow disposed in booth minimizes dust that would Booth, be on PPE. SOPs and trained gloves technicians minimize product on removed PPE. Only one material allowed after Consider use of in Subdivision room at a time. sampling, Dispensing Booths Product carried over disposable Visual wipe down after each and new Sampling Dispensing Room after sampling and Product retained on PPE sleeves for subdivision of materials for the gloves before first wipedown. sampling/dispe same batch, full cleandown donned for nsing. between each batch. Sampled first product and sample containers wipedown, move from Dispensing Booth to containers Airlock. Is not staged post wiped 3X Sampling/Dispensing in before Dispensing Room. removed from booth. Other QRM Tools Considered Failure Modes and Effects (& Criticality) Analysis FMEA/FMECA Fault Tree Analysis FTA Hazard Analysis and Critical Control Points - HACCP Preliminary Hazard Analysis (PHA) Risk Ranking and Filtering 18