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Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
Implementation of air quality control in the IVF laboratory and other critical areas
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Implementation of air quality control in the IVF laboratory and other critical areas

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  • 1. Sandro C. Esteves, MD, PhD Director, ANDROFERT Andrology & Human Reproduction Clinic Campinas, BRAZIL Implementation of air quality control in the IVF lab and other critical areas TQM Summit, CHINA 2014
  • 2. Contents ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 2 2014 March ANDROFERT Importance of air quality in IVF Regulatory bodies: what they say How we implemented AQC What we achieved
  • 3. ANDROFERT IMPORTANCE OF AIR QUALITY IN IVF Evidence from Animal/Experimental Studies Study Population Method Outcome Little and Mirkes, 1990 In vitro cultured rat embryos Protein and DNA analysis High levels of acrolein associated with embryotoxicity Cohen et al, 1997 Analytical measurement procedure Air sampling and VOC determination in human IVF labs Higher levels of VOC in HEPA-filtered lab ambient air and incubators compared with outside ambient air Hall et al, 1998 Analytical measurement procedure and bioassay Air sampling and VOC determination in human IVF laboratories; acrolein bioassay using 2-cell mouse embryos Increased levels of VOC in ambient air. Reduction in aldehyde levels by air filtration using carbon-activated and permanganate. In vitro mouse embryo development, implantation and post- implantation outcome inversely correlated with acrolein levels Worrillow et al, 2002 Analytical measurement procedure Design of a high velocity air control system and laboratory with VOC air filtration IVF laboratory and procedure rooms qualified as class 100 areas. No VOCs found above >0.1 parts per billion ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 3 2014 March ANDROFERT
  • 4. ANDROFERT IMPORTANCE OF AIR QUALITY IN IVF Evidence from Human Studies Study Population Method Outcome Mayer et al, 1999 RCT of infertile IVF couples Embryo culture in incubators with and without VOC filtration Higher PRs when embryos were cultured in incubators with VOC filters Racowsky et al, 1999 Infertile IVF couples, observational IVF and embryo culture in labs and incubators with and without VOC filtration Reduction in miscarriage in cycles performed in labs and incubators with carbon-activated filters Boone et al, 1999 Infertile IVF couples, observational Construction of cleanrooms for IVF activities Reduction in air particles associated with an increase in the number of high- quality embryos Worrillow et al, 2002 Infertile IVF couples, observational IVF in clean rooms with VOC filtration. Outside and inside ambient air monitored for 2 years Seasonal correlation between temperature/humidity of outside ambient air serving the IVF air system and VOC levels with impact on IR Knaggs et al, 2007 Infertile IVF couples, observational IVF lab redesigned to meet the EU directive Implantation and pregnancy rates increased after the move into the cleanroom ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 4 2014 March ANDROFERT
  • 5. IMPORTANCE OF AIR QUALITY IN IVF Evidence from Observational Human Studies 25.0% 32.7% 14.1% 43.1% Miscarriage rate CPR General IVF Population (N=468) Cleanroon IVF lab Standard IVF lab CPR Miscarriage rate 36.9% 23.0% 47.1% 15.0% Severe Male Factor Infertility (N=399) Standard IVF lab Cleanroom IVF lab P=0.01 P=0.03 Esteves et al. Fertil Steril 2004 Esteves et al. Fertil Steril 2006 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 5 2014 March ANDROFERT
  • 6. Importance of Air quality in IVF ANDROFERT ü High levels of VOC in unfiltered IVF lab air ü Efficient particle and VOC removal by air filtration ü Mouse embryo development inversely correlated with VOC ü Better outcome (PR, IR, miscarriage) in IVF cycles performed laboratories with air particle and VOC filtration ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 6 2014 March ANDROFERT
  • 7. What regulatory agencies ask for ANDROFERT ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 7 2014 March ANDROFERT
  • 8. Region (directive) United States (FDA 21 CFR 1271.195) European Union (EU directive 2004/23/EC; 2006/86/EC) Brazil (Anvisa RDC33/2006; RDC23/2011) Particle filtration Process-based; specifications not defined Equivalent to GMP Grade A air quality in the critical areas with a background environment at least equivalent to Grade D (exceptions apply) At least equivalent to ISO class 5 (NBR/ISO 14644–1) in the critical areas Microbial contamination Process-based; specifications not defined Microbial colony counts equivalent to those of Grade A as defined in the current GMC guide with a background environment at least equivalent to Grade D Microbiological monitoring required; specifications not defined Volatile organic compounds filtration Not required Not required Ventilation systems should be equipped with filters imbedded with activated charcoal ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 8 2014 March ANDROFERT
  • 9. Social responsibility to protect public health from exposure to harm, when scientific investigation has found a plausible risk even though a scientific consensus had not been reached PRECAUTIONARY PRINCIPLE *Convention on Biological Diversity, UN 1992; Ratified by 192 countries and the EU, except USA, Andorra and South Sudan ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 9 2014 March ANDROFERT
  • 10. CONTAMINATION Any undesirable material or substance that may affect the final product quality 1. Airborne particles Residues of cleaning agents and clothing, skin shedding; temporary suspension; 1< µm <100 2. Microorganisms Viruses, spores, bacteria; constant suspension in air; size <1 up to 8µm Contaminants are generated by laboratory personnel, processes, furniture and equipment ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 10 2014 March ANDROFERT
  • 11. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 11 2014 March ANDROFERT
  • 12. CONTAMINATION 3. Indoor Volatile Organic Compounds Chemical compounds that evaporate and react with indoor ozone; Result in submicronic particles and harmful by- products (toluene, benzene, alcohols, acetone, refrigerating gases, aldehydes) Cigarette smoke, automobile exhaust, detergents, lubricants, dyes, furniture, rubber, plastics, resins, synthetic fibers, nylon, particle-board, plywood ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 12 2014 March ANDROFERT
  • 13. REPRODUCTIVE LABORATORIES Indoor air Personnel Material and Equipment Cell, tissue and fluids 0 1000 2000 3000 Outside Air Indoor IVF Lab Air 533 2769 5-fold increase in VOC Anderson et al. 1997 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 14 2014 March ANDROFERT
  • 14. HOW TO PROTECT GAMETES AND EMBRYOS FROM CONTAMINATION Bacteria and other contaminants can attach themselves to particles, a decrease in particles equates to an increase in air quality Pre-Filters: >10µ Fine dust filters: 1<10µ HEPA filters: 0,3µ = 99,97% Removal of air particulates by forced air movement using positive air pressurization through a series of filters with increased efficiency ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 15 2014 March ANDROFERT
  • 15. VOCs are 100–1000x smaller than the effective pore size of HEPA filters Spaces between the carbon particles contain a cloud of delocalized electrons that act as electronic glue to chemical contaminants Alcohols and ketones are oxidized and thereby detoxified by potassium permanganate HOW TO PROTECT GAMETES AND EMBRYOS FROM CONTAMINATION Removal of VOCs by forced air movement using positive air pressurization through a series of filters containing activated carbon and potassium permanganate ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 16 2014 March ANDROFERT
  • 16. WHAT PATIENTS USUALLY SEE IS…
  • 17. …AND NOT WHAT IS BEHIND THE DOORS!
  • 18. HOW WE IMPLEMENTED AQC ANDROFERT ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 19 2014 March ANDROFERT
  • 19. LAYOUT AND CONSTRUCTION In situ wet construction Low off-gassing materials Surfaces and Coatings Lighting fixtures Flush-mounted and sealed Coved junctures Stainless steel and aluminium Furniture, doors, windows, air vents, workstations ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 20 2014 March ANDROFERT
  • 20. AIR-HANDLING VENTILATION SYSTEM ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 21 2014 March ANDROFERT
  • 21. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 22 2014 March ANDROFERT Particle size/m3 of air: ISO 14.644-1   0.3 µM   0.5 µM   1 µM   5 µM   ISO 1   ISO 2   10   4   ISO 3   102   35   8   ISO 4   1,020   352   83   IVF  lab   ISO 5   10,200   3,520   832   29   ISO 6   102,000   35,200   8,320   293   OR   ISO 7   352,000   83,200   2,930   Transfer   ISO 8   3,520,000   832,000   29,300   ISO 9   35,200,000   8,320,000   293,000   CLEAN ROOM CLASSIFICATION
  • 22. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 23 2014 March ANDROFERT
  • 23. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 24 2013 DECEMBER ANDROFERT
  • 24. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 25 2014 March ANDROFERT
  • 25. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 26 2014 March ANDROFERT
  • 26. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 27 2014 March ANDROFERT
  • 27. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 28 2014 March ANDROFERT
  • 28. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 29 2014 March ANDROFERT
  • 29. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 30 2014 March ANDROFERT
  • 30. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 31 2014 March ANDROFERT
  • 31. HOW WE MONITOR ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 32 2014 March ANDROFERT
  • 32. TEST EQUIPMENT Air volume flow rate Termoanemometer Air exchange rate Termoanemometer Air and room pressure differential Microanemometer and balometer HEPA-filter integrity leak Aerosol generator Airborne particle counts Electronic particle counter Recovery performance Smoke generator Lighting level Luxmeter Noise level Decibelmeter Temperature and humidity Thermometer and hygrometer Third-part certification company (CCL, Brazil); semi-annually IEST 006.2 standards ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 33 2014 March ANDROFERT
  • 33. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 34 2014 March ANDROFERT
  • 34. Esteves & Bento. RBM Online 2013 ü APPROVED ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 35 2014 March ANDROFERT
  • 35. Settle plates Mold and blood-agar Petri dishes Surface sampling Swabs and contact plates Five-finger glove printing Incubators, workstations, air, floor, wall Limits Colony Forming Unites (CFU) Settle plates (90mm diameter) CFU/4 hours Contact plates (55mm diameter) CFU/plate Glove print CFU/ glove <3 <3 <3 Microbiological Monitoring ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 36 2014 March ANDROFERT
  • 36. Volatile Organic Compounds Monitoring Activated-carbon life-time estimates Carbon tetrachloride activity method Active air sampling on Tenax TA sorbent and 2,4 dinitrophenyl hydrazine Summa canisters Thermal desorption Gas chromatography (Limits < 2 mcg/m3) ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 37 2014 March ANDROFERT
  • 37. WHAT WE ACHIEVED ANDROFERT ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 38 2014 March ANDROFERT
  • 38. Air Quality Control & IVF Results 2,315 patients; 14,660 embryos 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% Before After 2002-2004 After 2005-2007 After 2008-2010 TQE D3 (%) Miscarriage (%) LBR fresh (%) ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 39 2014 March ANDROFERT
  • 39. On average, an extra embryo for transfer or cryopreservation Air Quality Control & IVF Results 2,315 patients; 14,660 embryos ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 40 2014 March ANDROFERT
  • 40. Cumulative live birth rates in IVF 40.4% 48.0% Esteves, 41 ANDROFERT, Referral Center for Male Reproduction ET #3 (FET) 49 ET #2 (FET) 239 ET #1 (fresh) 822 50.5% +18.8% +25.0%Female  Age  ≤38   ANDROFERT 332/822 63/239 17/49
  • 41. Conclusions (1) Air quality (particulate matter and VOC) is associated with in vitro embryo development in animal and human studies Regulatory agencies have issued Directives with specific requirements for air quality in IVF labs We set up an IVF facility (embryology and andrology lab, operating room, embryo transfer room) with clean room technology, and demonstrated how feasible it is to work in such environments ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 42 2014 March ANDROFERT
  • 42. Conclusions (2) Our ART program have performed better in Clean Room environments for over a 7-year period Costs of Clean Room Technology: Implementation: USD 150,000.00 Operation: USD 15,000.00/year filters, clean room utensils/material, maintenance, certification Additional cost per cycle: ~USD 130 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 43 2014 March ANDROFERT
  • 43. ThankYou obrigado

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