CLEANING OPTIMISATION STUDY - THE CLEANING OF AN OEB5 COMPOUND VESSEL IN THE HIGH CONTAINMENT SUITE AT MSD SWORDS

Transcription

1 CLEANING OPTIMISATION STUDY - THE CLEANING OF AN OEB5 COMPOUND VESSEL IN THE HIGH CONTAINMENT SUITE AT MSD SWORDS Fearghal Downey Technical Director Hyde Engineering and Consulting 31 st August 2017

2 1.Acknowledgements Content 2.Introduction 3.Project Definition phase 4.Project Measurement phase 5.Project Analysis phase 6.Project Improvement phase 7.Project Control phase 8.Questions

3 Content originally presented by Emmet Manning, Global Technical Operations, MSD Swords at ISPE Conference in Cork on 13 th November Published in Pharmaceutical Engineering November/December 2014 Volume 34 No. 6 under Application of Lean Six Sigma to Optimise a Legacy Cleaning Process by E. Manning, B. Earls, K. Bader, F. Downey and K. Scalva.

4 Introduction 1. Hormonal tablets containing APIs with an Occupational Exposure Band (OEB) rating of 5 are processed in a high containment suite at MSD Swords 2. Micronized hormones with an OEL of <50ng/m 3 pose a considerable IH challenge 3. Containment techniques employed Enclosed processes using High Containment Isolators with RTPs High air change rates HEPA filtration 4. High containment achieved in dispensary using HC isolator

5 Introduction contd 5. The Bolz-Summix mixer is used to process active blends & granulate with APIs classified at OEB level 4 & 5 for 2 separate products respectively 6. The Bolz mixer CIP project was initiated in Jan 2012 as a result of a cleaning event 7. The Project was governed by LSS principles via DMAIC approach 8. The Project investigation, design, implementation and close out was completed in May The Control phase is continuous utilizing a PPA/CPV approach

6 Problem Statement: DEFINE Cleaning process post Bolz granulate & blend operation takes up to 5 days thus affecting OA due to a non robust & unreliable cleaning process. 1. Detergent dosing susceptible to intermittent failure and under dosing 2. Bolz ports soiled post CIP tank Jet spray balls and recipe incapable of robust/reproducible cleaning

7 DEFINE 3. Tank jet spray balls soiled with talc deposits post CIP 4. Bolz vessel ports & pipework retaining moisture post DIP leading to agglomerates in active blends

8 DEFINE 5. Confined space entry required to replace spray balls following CIP 6. Bolz ports require removal & manual cleaning prior to subsequent batch manufacture

9 DEFINE

10 DEFINE Goal statement: Provide a robust CIP/DIP process for the Bolz mixer thus reducing CIP times by ~80% to support market supply. Voice of Customer established with Production Director Dedicated Cross functional team assigned Clear link to the Sites Priorities Ensure Process Robustness look at the process from first principles Project Planning with key milestones and timelines It needs to be robust ok is not good enough

11 MEASURE Detailed Review of Current State: Process Mapping Equipment Process Steps Review of Historical Data and Issues Process/Mechanical Past failures/deviations Work Orders/known issues Established data based understanding of process Defined Future State based on known issues

12 ANALYZE FMEA of Process Major Issues identified: Spray Ball Design and CIP Flow path Cleaning chemistry not understood Drying System not robust Sequence of Process Steps were not efficient Recipe not optimal Benefit-Effort Matrix to define appropriate options Involve stakeholders in decisions via decision analysis approach Update Future State Status based on FMEA and Options Schedule re-evaluated based on need moved from 2 phase to single shutdown in April incorporating annual shutdown. Plan critically challenged/critiqued to minimise impact on production

13 IMPROVE Small Scale Trials (contracting Hyde Engineering) Small scale cleaning trials performed using SS coupons Scientific Thinking : CPPs evaluated offline at Hyde labs (Colorado) using DoE Parameters of Contact Time, Detergent Conc, Detergent type, ph, Temperature evaluated Re number mimicking turbulent flow was maintained for the coupon studies Temperature parameter identified as most significant Parameter for cleaning difficult soils Parameter selection identified for introduction to pilot scale Surface Plot of Rate vs Conc, Temp 6 Rate Conc Temp 60

14 Pilot Scale Trials (contracting Hyde Engineering) Recipe robustness determined off site at Hyde in parallel to CIP mods on site at MSD Parameters of Contact Time & Temperature evaluated (All other parameters fixed) Detergent selection fixed with CIP92 Re number mimicking turbulent flow was maintained during pilot studies Effectiveness of straight through rinsing Vs. recirculation evaluated Rinse/Wash volumes scaled down from max CIP make up volume to pilot scale (1200L v 40L). Process optimization on pilot scale allowed for more rapid implementation at MSD with greater sense of confidence for RFT. Recipe successfully tested including edge of failure The pilot study was performed on a worst case basis (single sprayball at lower pressure Vs. multiple sprayball at higher pressures), thus increasing confidence. IMPROVE

15 IMPROVE Mechanical Changes New Toftjorg Spray Ball design (Greater cleaning efficiency) New pipework & spray ball locations in Bolz vessel based on computer imaging New 6kW Air Heater (Increased thermal mass) New Air supply to heaters (Continuity of air supply) New Conductivity probe (Guarantee homogeneity of CIP solution) New detergent pumps & set-up (Obviates air locks & priming issues) Automation New recipe designed from 1 st principles to clean and dry New intelligent detergent dosing program incorporated Scale up of Development & Pilot CIP process New designed recipe, developed at Hyde labs introduced to production scale Successful Riboflavin & Edge of Failure performed IQ/OQ/PQ/CV successfully completed on schedule/budget

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17 Ports & Bolz interior post implementation of mechanical mods & new recipe IMPROVE

18 CONTROL Bolz mods & CIP Cycle recipe achievements: 100% CIP cycle success rate (n = >24) Eradication of confined space entry requirement Eradication of manual cleaning for Bolz ports 25% reduction in CIP cycle time 35% reduction in Detergent usage Eradication of pump air locking & leaking 33% reduction in Purified Water usage Equipment and CIP routes 100% dry Common CIP cycle for 2 separate products Reduction in CIP cycle turn around time from 5 days to 23 hours

19 CONTROL Detergent dose failures eradicated Process capability of low doses increased from Cpk 0.28 to 4.98 Process Capability of Before Dose 1 Process Capability of After Dose 1 Process Data LSL 2.75 Target * USL 8.25 Sample Mean Sample N 15 StDev (Within) StDev (O v erall) LSL USL Within Overall Potential (Within) C apability C p 0.38 C PL 0.28 C PU 0.48 C pk 0.28 O v erall C apability Process Data LSL Target * USL Sample Mean Sample N 24 StDev (Within) StDev (O v erall) LSL USL Within Overall Potential (Within) C apability C p 5.53 C PL 6.12 C PU 4.93 C pk 4.93 O v erall C apability Pp 0.46 Pp 3.99 PPL 0.35 PPL 4.42 PPU 0.58 Ppk 0.35 PPU 3.56 Ppk 3.56 C pm * C pm * O bserved Performance Exp. Within Performance Exp. O v erall Performance O bserv ed Performance Exp. Within Performance Exp. O v erall Performance PPM < LSL PPM < LSL PPM < LSL PPM < LSL 0.00 PPM < LSL 0.00 PPM < LSL 0.00 PPM Total PPM > USL PPM Total PPM > USL PPM Total PPM Total 0.00 PPM Total 0.00 PPM Total I Chart of Combined Dose 1 by Combined Dose Individual Value _ X=2.37 UCL=2.57 LCL= Observation

20 CONTROL Detergent dose failures eradicated Process capability of low doses increased from Cpk 0.28 to 4.98 Process Capability of Before Dose 1 Process Capability of After Dose 1 Process Data LSL 2.75 Target * USL 8.25 Sample Mean Sample N 15 StDev (Within) StDev (O v erall) LSL USL Within Overall Potential (Within) C apability C p 0.38 C PL 0.28 C PU 0.48 C pk 0.28 O v erall C apability Pp 0.46 PPL 0.35 PPU 0.58 Ppk 0.35 C pm * Process Data LSL Target * USL Sample Mean Sample N 24 StDev (Within) StDev (O v erall) LSL USL Within Overall Potential (Within) C apability C p 5.53 C PL 6.12 C PU 4.93 C pk 4.93 O v erall C apability Pp 3.99 PPL 4.42 PPU 3.56 Ppk 3.56 C pm * O bserved Performance PPM < LSL PPM Total Exp. Within Performance PPM < LSL PPM > USL PPM Total Exp. O v erall Performance PPM < LSL PPM > USL PPM Total O bserv ed Performance PPM < LSL 0.00 PPM Total Exp. Within Performance PPM < LSL 0.00 PPM Total Exp. O v erall Performance PPM < LSL 0.00 PPM Total I Chart of Combined Dose 1 by Combined Dose Individual Value _ X=2.37 UCL=2.57 LCL= Observation

21 CONTROL Detergent dose failures eradicated Process capability of higher doses increased from Cpk 0.59 to 8.67 Process Capability of Before Dose 2 Process Capability of After Dose 2 LSL USL LSL USL Process Data LSL 3 Target * USL 9 Sample Mean Sample N 15 StDev (Within) StDev (O v erall) Within Overall Potential (Within) C apability C p 0.41 C PL 0.24 C PU 0.59 C pk 0.24 O v erall C apability Process Data LSL 2.5 Target * USL 7.5 Sample Mean Sample N 24 StDev (Within) StDev (O v erall) Within Overall Potential (Within) C apability C p 9.20 C PL 9.73 C PU 8.67 C pk 8.67 O v erall C apability Pp 0.54 Pp 9.17 PPL 0.32 PPL 9.70 PPU 0.77 Ppk 0.32 PPU 8.64 Ppk 8.64 C pm * C pm * O bserved Performance Exp. Within Performance Exp. O v erall Performance O bserv ed Performance Exp. Within Performance Exp. O v erall Performance PPM < LSL PPM < LSL PPM < LSL PPM < LSL 0.00 PPM < LSL 0.00 PPM < LSL 0.00 PPM Total PPM > USL PPM Total PPM > USL PPM Total PPM Total 0.00 PPM Total 0.00 PPM Total I Chart of Combined Dose 2 by Combined Dose Individual Value _ X=5.14 UCL=5.42 LCL= Observation

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