STRATEGIES FOR CLEANING

Transcription

1 STRATEGIES FOR CLEANING AND CLEANING VALIDATION THAT MINIMIZE DOWNTIME FOR PRODUCT CHANGEOVERS JOHN HYDE HYDE ENGINEERING + CONSULTING

2 PRESENTATION OUTLINE Importance of Cleaning Process Development at Lab and Pilot Scale for Transfer to Commercial Scale Equipment to Support Effective and Efficient Cleaning Operations Commercial Scale Cleaning Cycle Development Strategies that Enable Expeditious Cleaning of Process Equipment for Product Changeover Cleaning Circuit Configurations that Minimized the Number of Cleaning Cycles per Lot of Product Manufactured FDA Process Validation Guidance Three Stages of Validation Importance of Cleaning Cycle Development Lab and Pilot Scale Methodologies Commercial Scale Testing Strategies Ongoing Monitoring Statistical Analytical Methodologies Application of PAT to CIP Operations

3 CLEANING AND QUALIFICATION OBJECTIVES Primary Operational Concerns Product and Patient Safety Cleaning Consistency Cleaning Quality Cost Effectiveness Bases of Assessment of Cleaning Validation Acceptance Criteria Based Upon Well Understood Design Space Scientifically Proven Operating Ranges Testing Scale Lab, Pilot Plant, Commercial Plant Risk Bases of Cycle Development, Full Scale Testing and Ongoing Monitoring

4 TRADITIONAL APPROACH TO VALIDATION Established, Highly Controlled Procedure Three Consecutive, Successful Commercial Runs Confidence Placed in the Consistent Performance of the Controlled Procedure Every Time Some Late Stage Cleaning Cycle Development Often Occurs During Validation At The Time Of Commercial Manufacture Excursions/Deviations Are Evaluated and Compared to Historical Norms

5 RISK BASED APPROACH TO VALIDATION Focused on Cleaning Cycle Development Validation Studies Design and Execution Based Upon Risk Analysis and Management Buffer Prep and Holding Versus Final Filling Established Process Design Space Provides Identification of Critical Control Parameters and Boundary Conditions for Effective and Tight Process Controls Ongoing Monitoring of Critical Cleaning Parameters Provides Bases of Risk Review and Management With Ongoing Real Time Confirmation of Process Operation Within Validated Design Space Monitoring Sampling Plan Based Upon Risk

6 NEW APPROACHES TO CLEANING QUALIFICATION AND MONITORING Utilization of FDA 2011 Process Validation Guidance Approaches for Bases of Cleaning Validation Program Extensive Utilization of Risk Analysis and Management to Establish Focus Areas for Cleaning Validation and Ongoing Monitoring Development of Existing and New In-Process Material Residue Matrix from Laboratory and Pilot Scale Cleaning Data Usage of Residue Matrix Data for Determination of Extent of Full Scale Cleaning Validation Testing (e.g., Utilization of Laboratory Derived Data and Residue Matrices Rather Than Three Full-Scale Runs for Validation of Cleaning for New Products)

7 NEW APPROACHES TO CLEANING QUALIFICATION AND MONITORING Generation of Product Inactivation Data to Justify Analytical Methodologies and Residue Limits for Multi-Product Facilities Residue Limits not Based Upon MAC Calculations Unless Residues Contain Significant Levels of Active Drug Product Usage of PAT Methodologies and Data for Basis of Initial Cleaning Validation Studies and On-Going Monitoring for Defining Re-Validation Requirements

8 NEW CLEANING PRACTICES FOR CLEANING OF MULTIPRODUCT PROCESS EQUIPMENT Re-Use of Elastomers Between Manufacturer of Different Products Utilization of Normal Cleaning Cycles Between Manufacturer of Different Products Limited Cleaning Verification Between Manufacturer of Different Products if Justified by Existing Lab and Pilot Scale Cleaning Data

9 CLEANING CIRCUIT DESIGN OPTIMIZATION CIP circuits are configured such that each vessel, its inlet piping and its outlet piping are cleaned as separate CIP circuits This results in 2 to 3 times as many cleaning cycles per lot than if the vessels and inlet and outlet piping are cleaned together in one circuit Cleaning circuit system flow path sequencing used to clean interconnecting piping attached to vessels and piping branches in piping circuits Cleaning flow paths grouped to optimize flow rates or downstream pressure drops Cleaning flow path groupings optimized based upon post production residue contact 9

10 2011 GUIDANCE-BASED PRACTICES New guidance describes process validation activities in three stages Stage 1: Process design Stage 2: Process qualification Stage 3: Continued process verification Stated another way, process validation may be defined as: Process Validation = Lab Studies + Development History + Commercial Scale Target Values + Ongoing Monitoring

11 STAGE 1 CLEANING DESIGN Test Plan Author an experimental test plan describing the approach used to conduct bench scale cleaning process developmental studies for post production residues. Cleaning Agent Selection Test each residue using a designed experiment to screen alkaline, neutral, and acidic post production residues over a range of typical cleaning process temperatures to determine an appropriate cleaning agent for a particular post production residue.

12 STAGE 1 - CLEANING DESIGN Cleaning Process Design Space Exploration Using the appropriate cleaning agent, explore combinations of temperature, turbulence, and concentration to assess the response of removal rate over typical ranges of these process variables via a DOE based study Worst Case Residue Evaluation Compare the removal rates of selected post production residues to empirically determine which are worst case with respect to the cleaning process

13 TESTING METHODOLOGY 5 cm ~1 in 2 5 cm Consistent soiling Amount of material Reproducible surface area Control Dirty Hold Time Cleaning Process Control PID Temperature Control Controlled Agitation Precisely Formulated cleaning solutions

14 DETERMINING REYNOLDS NUMBER - density - viscosity N Impeller speed in revolutions per second D Impeller Diameter N Re < 2100 N Re > 3000 Laminar Example: T=25ºC D = 2 ( m) = 997 (kg/m 3 ) µ = poise N = 64 rpm (1.07 rps) N Re = 3082 Turbulent Agitated Immersion: N Re 2 D N 2

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17 COUPON SOILING Representative Post- Production Residue Applied to Coupon Soiled Coupon Dried to Simulate Post- Production Conditions

18 COUPON TESTING

19 GRAVIMETRIC ASSESSMENT Laboratory Microbalance Accuracy ± grams Tare mass of coupons Amount of residue spiked on coupons Amount of residue remaining after cleaning assessment

20 Rate of Removal [mg/sec] RANGE FINDING RESULTS Range Finding Tests Water 25C Water 65C COSA-CIP-92 25C COSA-CIP-92 65C COSA-CIP-72 25C COSA-CIP-72 65C COSA-PUR-80 25C COSA-PUR-80 65C Duration [sec]

21 % Residue Remaining WORST CASE RESIDUE IDENTIFICATION 100% % Removal vs. Time A B 90% C D 80% 70% 60% 50% 40% E G I K F H J L 30% Q M 20% 10% 0% Cleaning duration (seconds) N P O

22 COSA-CIP-72 [ph2] COSA-CIP-72 [ph2] COSA-CIP-72 [ph2] Distilled Water [ph7] Distilled Water [ph7] Distilled Water [ph7] COSA-PUR-80 [ph7] COSA-PUR-80 [ph7] COSA-PUR-80 [ph7] COSA-CIP-92 [ph12] COSA-CIP-92 [ph12] COSA-CIP-92 [ph12] Average Removal Rate [mg/sec] EFFECTS OF PH AND TEMPERATURE 7 Average Removal Rate [mg/sec] % Detergent and Temperature [ C]

23 SURFACE RESPONSE PLOT Surface Plot of Rate vs Temp, ph 6 Rate ph Temp 60

24 TURBULENCE ASSESSMENT AND SCALE-UP CIP Supply Re 34,000 CIP Return Re 3,000 CIP System Variable Low Level (-) High Level (+) Concentration 1% 2% Temperature 25 C 65 C Energy N Re 3,000 34,000

25 TECH TRANSFER TO COMMERCIAL SCALE Protein Containing Residues Full CIP (Rinses, Alkaline Wash and Acid Wash) Buffer Containing Residues Typically Rinse Only Periodic Full CIP for Maintenance Purposes Cleaning Cycle Critical Parameters Grouped by Residues Media, Buffer, Cell Culture and Harvest, and Purification Residue-Based CCCPs Provide for More Effective and Economical Cleaning One Cycle Fits All Approach Very Ineffient and my also be Ineffective

26 TECH TRANSFER TO COMMERCIAL SCALE Input of Critical Cleaning Control Parameters (CCCPs) Analysis of CIP Cycle Operational Sequence Input of CIP Cycle into Control System Setpoint Format Hydraulic Balancing Equally Important to Implementation of CCCP Values Cleaning Efficacy Confirmed with Concurrent Process Validation and Cleaning Validation Runs

27 PRODUCT FRAGMENTATION/INACTIVATION Conduct Studies to Show Fragmentation / Inactivation of Active Molecule by Cleaning Process Expose Formulated Bulk Product to Cleaning Solutions at Use Strength and Temperature Analyze Residues with SDS-Page and Western Blot to Prove Fragmentation / Inactivation Favorable Results Justify Non-Product Specific Residue Testing Methods, Re-Use of Elastomers and Utilization of Normal CIP Cycles Between Manufacture of Different Products

28 STAGE 2 CLEANING QUALIFICATION During this stage, the cleaning cycle design is confirmed as being capable of effective and reproducible at commercial manufacturing scale Cleaning cycles challenged with typical post-production residues Dirty and clean hold times also assessed Qualification of the facility, utilities and equipment is required Cleaning systems, clean and plant utilities and process equipment systems are of primary interest

29 STAGE 2 CLEANING QUALIFICATION Usually run at operating parameter set points within proven acceptable range or design space Boundary condition testing is not typically performed at this stage as it has been assessed in Stage 1 May require additional testing to prove the process Qualification testing typically requires the analyses of more samples than for ongoing monitoring of cleaning Risk analysis used to determine extent of testing requirements Equipment and residue groupings used to determine testing requirements

30 CIP CYCLE, PHASE AND STEP HIERARCHY CIP Phases # Example Cycle Description Full CIP Drain Cycle Rinse Cycle Acid Wash Pre-Rinse Alk. Wash Post Rinse Air Blow & Drain Full CIP Cycle Wash Supply Air Blow RInse Final Rinse Supply Air Blow Final Drain # Example Phase Description 1 Rinse Phase 2 Post Rinse 3 Alkaline Wash 4 Final Rinse # Example Step Description 1 Check Interlocks 2 Fill Water Tank 3 Air Blow 4 Delay to Conductivity CIP Steps

31 STAGE 3 CONTINUED CLEANING VERIFICATION Ongoing assurance that cleaning is in control Monitor, collect information, assess, continuous verification, cleaning process improvements No longer revalidation, instead ongoing periodic evaluation 21 CFR (e) Annual review to determine whether changes in specifications or manufacturing or control procedures are needed Study trends, OOS/OOT to make improvements Feedback into design stage for significant process shifts or changes

32 CONFIRMATION OF CCCPS IN REAL TIME Essential for Control and Ongoing Monitoring of Cleaning Parameters Factors Affecting Cleaning Efficiency Measured via: Supply/Return Temperature Supply Flow Rate Supply Pressure Supply/Return Conductivity

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34 TRADITIONAL VS. QBD APPROACHES Aspects Traditional QbD Cleaning Development Empirical; typically single variable experiments Systematic; multi variable experiments Cleaning Process Fixed Adjustable within design space; opportunities for innovation (PAT) Cleaning Control Cleaning Specification Control Strategy Lifecycle Management Annual re-validation; very risky because of product quality implication of test failures Primary means of quality control; based on cycle completion w/o errors Black-box; Validated cycles are relied upon as basis of cleaning success Reactive to problems and OOS; improvements driven by CAPAs and remediations PAT utilized for feedback and feed forward at real time and ongoing monitoring Part of the overall quality control strategy; based on operation within design space Data-based; monitoring and analysis of critical parameters Continual improvement enabled within design space

35 SUMMARY Risk Based Approach to Validation Results in More Comprehensive and Effective Result FDA Process Validation Guidance Three Stages of Validation Provides Excellent Basis to Cleaning Validation Study Design Importance of Cleaning Cycle Development Studies Crucial to Commercial Scale Success Ongoing Monitoring Provides Real-Time Assurance of Cleaning Efficacy

36 CONTACT INFO John M. Hyde, B.Sc., M.Sc. Principal Consultant Chairman and Founder Hyde Engineering + Consulting, Inc. john.hyde@hyde-ec.com