A Case Study for an Improved Approach to Cleanroom Disinfection, Minimizing the Impact and Reducing Downtime James Tucker Global Scientific Affairs Manager Ecolab Life Science
A Case Study for an Improved Approach to Cleanroom Disinfection, Minimizing the Impact and Reducing Downtime Agenda Introduction Trade Offs Impact Assessment Operating Time / Costs Conclusion
Why Do Residues Matter? Regulatory Visual impact Theoretical impact
Cleaning The process of removing residues and soiling from surfaces to the extent that they are visually clean Will slightly reduce the microbial population; will not achieve the same level as a disinfectant Surfaces to be disinfected must be clean Disinfectants can be chemically inactivated by the presence of soiling Soiling can present a physical barrier preventing the disinfectants reaching the microbial cells Regulation Annex 1-Section 5.31 They (clean areas) should be cleaned and disinfected thoroughly in accordance with a written programme (for disinfection to be effective, cleaning to remove surface contamination must be performed first) GMP Annex 1 draft Dec 2017 (3 month consultation period) released by PIC/S
Regulatory Impact Annex 1 - Section 5.31 Annex 1 - Section 5.33 Annex 1 - Section 6.5 They (clean areas) should be cleaned and disinfected thoroughly in accordance with a written program (for disinfection to be effective, cleaning to remove surface contamination must be performed first) Cleaning programs should be effective in the removal of disinfectant residues Disinfectants should be shown to be effective when used on the specific facilities, equipment and processes that they are used in. PIC/S PI 007-6 Recommendation on the Validation of Aseptic Processes The effectiveness of disinfectants and the minimum contact time on different surfaces should be validated FDA Guidance for Industry - Sterile Drug Products Produced by Aseptic Processing The suitability, efficacy, and limitations of disinfecting agents and procedures should be assessed. The effectiveness of these disinfectants and procedures should be measured by their ability to ensure that potential contaminants are adequately removed from surfaces. The cleaning process should be validated so that it can be demonstrated that it: Can remove any residues that would otherwise create a barrier between the sterilizing agent and the equipment surfaces Prevents chemical and particulate contamination of the product during the process and prior to disinfection
Regulatory Guidance USP <1072> The removal of residual disinfectants should be monitored for effectiveness as a precaution against the possibility of product contamination
Regulatory Requirements USP <1072> A sound cleaning and sanitization program is needed for controlled environments used in the manufacture of Pharmacopeia articles to prevent the microbial contamination of these articles.
Regulatory Impact February 2017
Regulatory Impact February 2017 November 2017
Visual Impact The appearance of residues is not the same White smeary residues An even sticky / oily layer A glossy, sticky uneven layer White, crystalline powder Low level streaking
Visual Testing All Surfaces Left side without product right side worst case Glass Stainless steel Wall Panel Scale for visual observation: 1 Without product 2 very low visible residues slight visible spots in good light 3 low visible residues slight visible spots 4 visible residues in bad light, in all conditions. Rinsing required PVC Terrazzo 5 strong visible residues at all times. Immediate Rinsing required
Residues: Visual Appearance Results 4.5 Purified Water 4 Visual rating score 3.5 3 2.5 2 1.5 1 0.5 PVC Stainless steel Terrazzo Even purified water leaves water spots! 0 0 2 4 6 8 10 12 Number of Applications of Product Wall panel Window Glass
Residues: Visual Appearance Results Reflective Surfaces increase the appearance of all residues T-Test groupings performed for differences between average ratings The mean ratings for steel and glass are in their own group, which indicates they are statistically significantly different from other surfaces (95% confidence level) Level Least Sq Mean Stainless steel A 3.6896345 Window Glass A 3.4277298 PVC B 2.6420155 Wall panel B 2.5705869 Levels not connected by same letter are significantly different. Terrazzo C 1.7977695
Residues: Visual Appearance Results Control Differences 5 4 3 2 UDL 1 Control LSMean = 1.34 0 LDL
Theoretical Impact Risk The undesirable by-products of a chemical reaction Interaction between different chemistries Ineffective in killing microorganisms EHS Build up of residues Compatibility issues with different disinfectant products Regulatory questions over the control of cleaning and disinfection Corrosion / damage to surfaces Media neutralization overcome
A Case Study for an Improved Approach to Cleanroom Disinfection, Minimizing the Impact and Reducing Downtime Agenda Introduction Trade Offs Impact Assessment Operating Time / Costs Conclusion
The Ideal Disinfectant Kills all micro-organisms Non-corrosive Safe to use Leaves no residues Sterile ISO Classes (for Grade A and B areas) Fast acting Material Compatibility Available in a variety of formats Cost effective
The Ideal Disinfectant No one disinfectant will tick every box! Compromise right disinfectant for a specific application
Surface Residues in a Cleanroom: The Hidden Impact Agenda Introduction Trade Offs Impact Assessment Operating Time / Costs Conclusion
How Do You Validate Clean? Visually clean? Residue measurement? Micro counts? SOPs? All these are good tools but how do you make the invisible visible?
Additional Considerations So what? Chemical analysis Full profile of product & impact?
Comparative Residues (@ use conc.) Rotational disinfectants 12000 RoE in ppm Product Name RoE in ppm X the Best A 400 10000 8000 6000 4000 B 2000 5 C 2600 7 D 3400 9 E 3900 10 F 6800 17 G 11000 28 2000 RoE in ppm Residue on evaporation does not correlate to visual 0
Backcalibration Dilution Curve Example: 10000 9000 8000 7000 6000 5000 y = 0.7473x + 168.45 R² = 0.9939 Backcalibration was done to calculate the ppm for the leftover residue on a surface Calculation: using the measured conductivity and the calibration curves Backcalibration curves were done in duplicate 4000 3000 2000 1000 0 0 2000 4000 6000 8000 10000 12000 14000 concentration ppm
Build Up Over Time on Stainless Steel Linear Relationship Start & remain high with fluctuations Start & Remain Low
Residues: Rate of Accumulation Line of slope comparison LIFE SCIENCES
Residues Removal Conductivity Analysis Data Conductivity model averages with 95% Confidence Intervals 30 25 20 Result: On average: Water removes significantly more residue than IPA or detergent. 15 IPA Neu Det Water Medium
Micro Impact Regulation TDA, SDA Media from 2 suppliers QAC, Phenol, H2O2/PAA and QAC Applied: 1, 7, 14 & 28 Test A not removed Test B removed (WFI wipe) Test C control
Preliminary Results Examples Low Residue Product Standard Product
A Case Study for an Improved Approach to Cleanroom Disinfection, Minimizing the Impact and Reducing Downtime Agenda Introduction Trade Offs Impact Assessment Operating Time / Costs Conclusion
Additional Considerations PRODUCTIVITY EMPLOYEE HEALTH & SAFETY COMPLIANCE PRODUCT QUALITY
Additional Considerations Cost of Additional Cleaning Continued Risk Indirect Costs Productivity Compliance / Quality Health & Safety Risks Cost of labour, chemicals, training, supplies Cost of SOPs and validation Extended SOPs = increase complexity Residues = audit severity Risk of non compliance Corrosion or degradation of surfaces CAPEX Particle count - EM investigation Remedial cleaning costly, time consuming and loss of production time Effort required for training / understanding Additional hours required for rinsing Lost hours for production Visual issues Environmental monitoring effect Disinfection variability Risk of cross contamination Audit observations Slips and falls sticky floors Volatilization and unfavourable interactions with chemistry
Process Flow: Preparation of disinfectant from concentrate Area consideration Transfer items in Cool WFI Filter integrity test Filter compatibility if with biocide use Volume and time dispense Cool WFI Sterilise filter Calibration/ cleanliness Volume measurement (measuring vessel or weight) Test / confirm blend Prepare for use (correct volume / area etc.)
Process Flow: Application & residue removal Clean room with detergent / vacuum Apply disinfectant in controlled manner Leave for contact time Finish? Every application? Dry Remove residue with WFI / IPA
Risk to in-house Preparation Risk Sub-optimal use of environment Inefficient use of personnel Support services use: micro, quality Documentation of process and product creation Warehousing and managing additional raw materials (validated storage etc.) Annex 1 requirement to test water system post use Cleaning and storage of additional equipment items for make up Time to cool WFI (if not done impact on disinfectant or filter) SOP for filter integrity testing, dilution process Filter sterilisation Additional autoclave load and equipment required Validation and SOP for scales / measuring vessel Validation of filter compatibility Biocide hold time / concentration WFI cost including flush to waste (increase in volume) Total process time affects responses to requirement (i.e. lead time for availability)
Standard High Residue Concentrated Product Assumptions & Costs Example 1 15m 2 Room Cleaned 350 time per annum Cleaned once a day Filter single use Quarterly Micro and Quality testing 1 hour per day on warehouse handling Cost based on Irish source and OH costs All time exc. Autoclave could be used on production $250K production per shift (8 hour shift) 10L disinfectant for room use (conc and RTU) Reduced disinfection Total Cost $14,500 $58,000 Increase production revenue due to less downtime $38,000 $500 $0 $0 $2,000 $112,500 $77,000 $77,500 Support Services Raw Materials Time (Labor costs) Chemistry Concentrate Ecolab RTU Total
Standard High Residue Concentrated Product Assumptions & Costs 50% reduction in actions required 300,000 more vials produced 0.6 FTE saving 50% reduction in lead batch time 2/3 hours less time spent on process Min $100K net saving/year
Surface Residues in a Cleanroom: The Hidden Impact Agenda Introduction Trade Offs Impact Assessment Operating Time / Costs Conclusion
We should care because Residues cause visual & physical impact Latent effects of residues can impact EM Residues have an effect on efficiency, HSE, compliance & overall operation of the cleanroom!
Thank You and Any Questions?