Air quality: is it that important? And if so, how to measure and control it?
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Quality and Risk Management in the IVF Laboratory; Redlara Brasil, Belo Horizonte, 14-15 September 2016 Content: 1.Air quality: is it that important? 2. How to control? 3. How to measure?
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Air quality: is it that important? And if so, how to measure and control it?
- 1. Air quality: is it that important? And if so, how to measure and control it? Sandro ESTEVES, MD., MSc., PhD.! Medical & Scientific Director ! ANDROFERT! Campinas, BRAZIL! Quality and Risk Management in the IVF Laboratory; Redlara Brasil Belo Horizonte, 14-15 September 2016
- 2. AGENDA Esteves, 2 ! 1. Air quality: is it that important? 2. How to control? 3. How to measure? Quality and Risk Management in the IVF Laboratory; Redlara Brasil Belo Horizonte, 14-15 September 2016
- 3. Esteves, 3 ! WHO Limits PM10 50 μg/m3 24-hour mean; 20 μg/m3 annual mean PM2.5 25 μg/m3 24-hour mean 10 μg/m3 annual mean O3 100 μg/m3 8-hour mean NO2 200 μg/m3 1-hour mean SO2 20 μg/m3 24-hour mean TVOC <100 ppb (formaldehyde) • Carcinogenic (lung, urinary tract) • Childhood leukemia • Obstructive pulmonary disease • Ischemic heart disease & stroke • Respiratory infection • Aggravation of asthma & bronchitis Source: Air quality & Health, WHO; Available from: http://www.who.int/topics/air_pollution/en/; Accessed July 19, 2016 Air pollution 'is single biggest environmental health risk’ Indoor and outdoor air pollution linked to around 7 million deaths a year – more than double previous estimates
- 4. Particulate Matter (particle pollution) Esteves, 4 ! A mixture of microscopic solids and liquid droplets found in the air: PM10 : inhalable particles, with diameters of 10 micrometers and smaller PM2.5 : fine inhalable particles, with diameters of 2.5 micrometers and smaller (penetrate deep in the lungs)
- 5. Gases (CO, O3, NOx, SO2) Esteves, 5 ! Primary sources are motor vehicles, electric utilities, and other industrial, commercial and residential sources that burn fuels (eg. coal, wood, charcoal, oil, kerosene, propane, and natural gas) Ozone (O3) formed by photochemical reactions in the presence of precursor pollutants (Gases, VOC)
- 6. Volatile Organic Compounds (VOC) Esteves, 6 ! Any organic (carbon-containing) solid or liquid compound that evaporates at room temperature Paints, solvents, lubricants, aerosol sprays, cleansers and disinfectants, building material, furnishings, glue, adhesives, permanent markers, plastics, pesticides, resins, cigarette smoke, synthetic fibers, nylon, particle-board, plywood React with indoor ozone and form submicronic particles and harmful by-products; some genotoxic/mutagenic
- 7. Air quality: is it that important for fertility? Esteves, 7 !
- 8. Esteves, 8 ! Among women exposed to air pollution, LBR is reduced and miscarriage is increased both in general and IVF populations, even with short-term preconceptional exposure. • 10 studies (animal and human) • Pollutants: PM, Toxic Gases, VOC
- 9. Air quality in the IVF lab: is it that important? Esteves, 9 ! 3 facts: Preimplantation in vitro embryogenesis complex phenomenon critically dependent on the culture environment. Many incubators consist of 90-95% ambient air. ! Benchtop incubators and TL systems not air tight, and IVF processes expose gametes and embryos to air Human embryos are largely unprotected and sensitive to environment influences (lack epithelial surfaces, immunological defenses, detoxifying mechanisms)
- 10. Air quality in the IVF lab: is it important? Esteves, 10 ! 3 problems related to source of air: Outside air serving IVF labs influenced by activities both common to and outside control of the IVF program Road resurfacing, construction, vehicle traffic and exhaust, industrial emissions, waste management, restaurant exhaust, accidents, generator exhaust, seasonal pollutants Sources of VOCs, viable and non-viable particles (PM) common within IVF lab Plasticware, compressed (CO2, LN2, etc.) and refrigerant (HVAC) gases, cleaning agents, personnel, new equipment and construction materials HVAC Systems heavily contaminated Pathogens (viruses, bacteria, fungi); allergens (mold); toxins (endotoxins, mycotoxins) PM! O3! NOx! VOC!SO2!
- 11. 1. Outside air serving IVF labs Esteves, 11 ! 20! 0! 10! 20! 30! 40! 50! PM10 Annual mean, ug/m3! PM2.5 Annual mean, ug/m3! PM10 PM2.5 Source: Global urban air pollution, PAHO; Available from: http://www.paho.org/ Accessed July 19, 2016 2008-2015
- 12. Not surprinsing… Esteves, 12 ! Campinas! Porto Alegre!Belo Horizonte! Salvador! Rio! São Paulo!
- 13. 2. VOCs major indoor pollutant Esteves, 13 ! Vapor pressure and coefficient partition associated with VOC molecular structure dictate entry into culture media! • Water soluble (ethanol, acetone, formaldehyde)! • Oil soluble (benzene, isobutylene, styrene)! Attach directly to DNA, causing DNA fragmentation and altering cell replication! Miller & Pursel 1987; Little & Mirkes1990; ! Cohen et al. 1997; Hall et al. 1998; Rubes et al. 2005! Hall et al. HR 1998 Main VOCs found in IVF labs! Styrene! Octane! Acetone! Nonane! Benzene! c-Decane! Toluene! C11 Alkane! C8 Alkane! n-Undecane! n-Dodecane! m&p Xylenes! Methylcyclohexane! Schimmel et al. FS 1997
- 14. 2. VOCs major pollutant in IVF labs Esteves, 14 ! Hall et al. Hum Reprod. 1998! 533! 1152! 2862! 2769! Mean VOC levels ! (μg/m3)! Hall et al. HR 1998 ppm! % Blastocyst! Control! 87.9! 0.58! 80.1*! 1.4! 41.3*! 2.8! 3.0*! 5.6! 0.0*! Effect of acrolein (aldehyde) on mouse embryo development P<0.01!
- 15. Bioaerosol Health-Risk Exposure Analysis of Indoor Air in Different Areas of a Hospital in the United States Larrañaga et al. 2011! Esteves, 15 ! 3. HVAC heavily contaminated
- 16. Esteves, 16 !
- 17. Esteves, 17 !
- 18. Esteves, 18 ! 1990! 2015!2006! 2007! 2013! 2014! Embryotoxicity of acrolein (Little et al)! 1997! High levels VOC incubators and CO2 tanks; efficiency of carbon- activated filters to remove VOC (Schimmel et al) ! High levels VOC laboratory air despite HEPA (Cohen et al)! 1999! Better embryo development in incubators with VOC filtration (Mayer et al.)! 2002! Reduction PM associated with better embryos (Boone et al)! Decreased miscarriage in IVF cycles performed in labs with VOC filtration (Racowsky et al.)! 1998! Embryotoxicity of acrolein; Reduction aldehyde by carbon- activated and permanganate ! (Hall et al.)! 2004! Better embryo development, CPR and lower miscarriage in IVF performed in cleanroom lab with VOC filtration (Esteves et al.)!Seasonal variation in IR due to VOC fluctuations caused by humidity and T (Worrilow et al)! Better embryo development, CPR and lower miscarriage in ICSI for severe male factor performed in cleanroom lab with VOC filtration (Esteves et al.)! Better IR and PR after move to cleanroom lab as per EU directive (Knaggs et al.)! Better IVF outcomes cleanroom lab with VOC filtration (Khoudja et al.)! Better embryo quality and LBR with centralized particulate and VOC filtration as per Brazilian directive (Esteves & Bento)! Pre- and post-IVF outcomes markedly affected by VOC filtration (Munch et al.)! Better IR and LBR centralized particulate and VOC filtration (Heitmann et al.)! Improvement in IVF outcome with molecular media and UV light for control of ambient air (Forman et al.)! Esteves & Bento. Asian J Androl 2016!
- 19. OBSERVATIONAL CLINICAL STUDIES 25.0%! 32.7%! 14.1%! 43.1%! Miscarriage rate CPR General IVF Population (N=468)! Cleanroon IVF lab Standard IVF lab 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 Esteves, 19 !
- 20. N=820 fresh cycles! 819! 14!32! 5.2! TVOC (μg/m3)! Aldehyde (μg/m3)! Old facility! New facility!
- 21. Esteves, 21 !
- 22. Esteves, 22 ! Impact of indoor (IVF lab) air pollution CONCLUSIONS (1) A critical association exists between levels of chemical and biological pathogens and laboratory ambient air. Air filtration systems, integrating particulate matter and VOC filtration, reduce levels of pollutants in the IVF environment. New and significant data indicate that air quality in the IVF lab play a critical role for successful embryogenesis, implantation and conception.
- 23. Esteves, 23 !
- 24. AGENDA Esteves, 24 ! 1. Air quality: is it that important? 2. How to control? 3. How to measure? Quality and Risk Management in the IVF Laboratory; Redlara Brasil & SBRA Belo Horizonte, 14-15 September 2016
- 25. Principles of Air Quality Control IVF lab and associated areas should be constructed and used in such way to minimize the introduction, generation and retention of particles and volatile organic compounds! Esteves, 25 !
- 26. Esteves, 26 ! 1. Physical characteristics! 2. Air filtration! 3. Good Lab Practices! How to control?
- 27. 1. Physical Characteristics Low off-gassing materials Surfaces and coatings Lighting fixtures Flush-mounted and sealed Coved junctures Stainless steel & aluminum Furniture, doors, windows, air vents, workstations Workflow Dressing area, airlocks (anterooms) ! Legends: Return vent HEPA diffuser HEPA filter Biological safety cabinet Mini- hood Anteroom Embryo transfer suite Operating theater Embryology suite Heat, ventilation, and air conditioning (HVAC) room Cryo-storage suite Staff changing room Emergency exit Storage room Cleaning and sterilization Andrology lab Anteroom Anteroom Esteves, 27 ! Minimize generation
- 28. 2. Air Filtration Any particles/VOC generated are carried away, and any particles/VOC remaining are diluted with new clean air Design, qualification and operation part of QMS, and should involve a risk management analysis and compliance with regulatory requirements (if any)! • New or existing facility • Age and size of laboratory • Equipment/furniture (low off gassing?) • Constructing materials (low off gassing?) • Atmospheric (outside) air pollution • Disposable materials (storage location) • Human activity Esteves, 28 ! Minimize retention
- 29. Regulatory Directives Region (directive)! European Union (EU directive 2004/23/EC; 2006/86/EC)! Brazil (Anvisa RDC33/2006; RDC23/2011)! Particle filtration! ! 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! ! Microbial colony counts equivalent to those of Grade A as defined in the current GMP guide with a background environment at least equivalent to Grade D! Microbiological monitoring required; specifications not defined! ! Volatile organic compounds filtration! Not required! ! Ventilation systems should be equipped with filters imbedded with activated carbon! Esteves, 29 !
- 30. Esteves, 30 ! 1. CENTRALIZED AIR HANDLING UNIT • Dedicated room • Costly • Highly efficient Pressurized air! Recirculation of filtered air (~80%)! High VOC/particulate removal capacity! Air renovation (~20%)! ! Courtesy of VECO! Air filtration systems
- 31. Esteves, 31 ! Air filtration systems Courtesy of VECO! 2. PORTABLE/COMPACT • Easy to install • Less costly • Less efficient Positive pressure low/absent! Air renovation low/absent ! Variable residence time & VOC removal capacity ! !
- 32. Esteves, 32 ! Air Quality Control Principles Turbulent air Air pressure differential HEPA terminal filter of ventilation system Tim Sandle. Clean room design principles. ! In: Esteves, Varghese, Worrilow. Cleanroom technology in ART Clinics, CRC Press! • ≥20 air exchanges/hour (flow rate & area)! • Minimizes ‘dead’ air spots! ~5-20 Pascals! (0.5-2.1 mmWC)!
- 33. Esteves, 33 ! Removal of air particles by forced air movement using positive air pressurization through a series of filters with increased efficiency
- 34. Esteves, 34 ! Airborne particles Residues of cleaning agents and clothing, skin shedding; temporary suspension; 1< μm <100 Microorganisms Viruses, spores, bacteria; constant suspension in air; size <1 up to 8μm ! ! Particle Filtration - Rationale Humans shed roughly a billion skin cells daily, with each square centimeter of skin per human hand having a concentration between 102 to 107 bacteria. Each person disperses up to 107 particles per minute. Bacteria and other contaminants can attach themselves to particles, therefore a decrease in particles equates to a decrease in contamination risk
- 35. Design Principles (2): VOC filtration VOCs are 100–1000x smaller than the effective pore size of HEPA filters Esteves, 35 ! ! • Sorption filtration (mass transfer from air to adsorbent) Activated carbon (traps high molecular weight VOCs; eg. Benzene, toluene)! Potassium permanganate (oxidizes low molecular weight VOCs; ! eg. Alcohols & aldehydes)! Activated Alumina (acidic gases, polar organic compounds)! Zeolites; silica gels • Photocatalytic oxidation (VOC degradation) • Engineered molecular media (Life-aire®) Fox, JT. Volatile organic compounds: mechanisms of filtration. ! In: Esteves, Varghese, Worrilow. Cleanroom technology in ART Clinics, CRC Press!
- 36. Esteves, 36 ! What influence VOC adsorption! Type of sorbent Residence time (contact time) • filter bed (mass of sorbent material) ! • flow rate! Humidity (ideally 40-60%) Time between filter change • Periodic replacement (eg., every 6 months or as per manufacturer instructions)! • Activated-carbon saturation estimates using the using carbon tetrachloride activity method Ncube & Su. Int J Sustain Built Environment 2012
- 37. 0! 50! 100! Benzene! Freon! Isopropanol! n-Pentane! Acetaldehyde! n-Butane! VOC (μg/m3) in compressed CO2 ! 0! 5! 10! 15! 20! 25! Aromatic VOCs (μg/m3)! Benzene! Toluene! Xylene! Styrene! Design Principles (2): VOC filtration Esteves, 37 !
- 38. Esteves, 38 ! Our system at ANDROFERT Cleanroom facility 4 stage filtration: • Primary: G8 • Secondary: F8 • 16 VOC filter beds: KMnO4 impregnated zeolyte + activated carbon (coconut shell) • Terminal HEPA Turbulent air (80% recirculation) Residence time: 0.082s IVF lab: 103 air exchanges/h OR: 12 air exchanges/h (Esteves & Bento. Reprod Biomed Online 2013;26:9-21) !
- 39. Esteves, 39 ! ISO 7 Total VOC levels <2 µg/m3 (~0.5 ppb) of air. Aldehyde levels below detectable limit of 1 µg/m3. ISO 5
- 40. 0! 20! 40! 60! 80! before! after! % TQE! 0! 10! 20! 30! before! after! % miscarriage! 0! 20! 40! 60! before! after! % LBR! P=0.01! N=2,315 IVF/ICSI cycles! P=0.01!P<0.001! Esteves, 40 !
- 41. 3. Good Laboratory Practices The most sophisticated cleanroom IVF lab will not overcome improper practices of staff not committed to preserve a clean environment ! • Use of correct garment • Minimize human traffic • Proper personal behavior • Use of sterile techniques • Proper use of cleaning/disinfectants Esteves, 41 ! Minimize introduction and generation
- 42. Esteves, 42 ! DO’s DON’T’s Keep the work site clean and use sterile techniques Smoke Cover hair, nose and arms, and use gloves Hair sprays, nail varnish, cosmetics, jewelry Cleanroom garments (100% polyester) and dress in pre- changing zone Use natural fabrics Clean from the cleanest (ceiling, walls) towards less clean (doors, floors), using parallel streaks Use circular movements for cleaning Move slow; talk less; avoid creating air turbulence Talk too much; move fast Limit access to lab (visitors and other staff always properly dressed and accompanied) Touch work surfaces, masks & garments Place sticky mats outside lab Lean over the walls/workstations Unpack supplies outside; Off-gas materials before bringing into lab Store unnecessary material/equipment in the lab Wash hands each time entering the lab Enter lab unless air filtration system operational Create an atmosphere of discipline Work if sick Clean surfaces with distilled water and decontaminate with peroxide (daily activities) Use hand sanitizer in the lab (alcohol)
- 43. How to control air quality in the IVF lab? CONCLUSIONS (2) Esteves, 43 ! Minimize introduction, generation and retention of particles and volatile organic compounds: 1. Design and construction 2. Air pressure cascade and filtration system 3. Personnel and operational procedures
- 44. AGENDA Esteves, 44 ! 1. Air quality: is it important? 2. How to control? 3. How to measure? Quality and Risk Management in the IVF Laboratory; Redlara Brasil & SBRA Belo Horizonte, 14-15 September 2016
- 45. Critical Air Cleanliness Elements to Control Esteves, 45 ! 1. Particles • No. particles in air suspension • Air pressure differential • Air exchanges/h 2. VOC • TVOC & Aldehydes! 3. Microorganisms 4. Temperature & Humidity 5. Personnel compliance with GLP & SOPs !
- 46. How to Measure (1) Esteves, 46 ! TEST EQUIPMENT Air volume flow rate Termoanemometer Air exchange rate 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 Third-part certification company (CCL, Brazil); semi-annually ! IEST 006.2 standards! Semi-annual
- 47. VOC Monitoring 1. Active air sampling on Tenax TA sorbent and 2,4 dinitrophenyl hydrazine Summa canisters; Thermal desorption! Gas chromatography analysis (Limits <2 μg/m3 TVOC)! 2. Direct reading (daily; weekly) Snapshot reading using VOC probes (ppb; μg/m3) ! Photo ionization detector! 3. Badge sensors (quarterly) Analyze absorbed levels on ! chromatography paper (low accuracy) ! Esteves, 47 ! Brauer & Griesinger. Testing and monitoring VOCs and microbials. ! In: Esteves, Varghese, Worrilow. Cleanroom technology in ART Clinics, CRC Press!
- 48. Detection limits of VOC analytical instrumentation critical, because negative impact seen even at low levels Worrilow 2016. The role of ambient air in preimplantation toxicology and clinical outcomes. ! In: Esteves, Varghese, Worrilow. Cleanroom technology in ART Clinics, CRC Press! Esteves, 48 !
- 49. In addition to periodic measurements, spatial distribution must be considered to confirm compliance with user/ regulatory specifications Multiple sampling should be obtained both at rest and in operation, and results should be analyzed Esteves, 49 !
- 50. Quarterly or if contamination is suspected! Limits Colony Forming Units (CFU)! Settle plates (90mm diameter) CFU/4 hours! Contact plates (55mm diameter) CFU/plate! Glove print CFU/glove! <3! <3! <3! Microbiological Monitoring Settle plates! Mold and blood-agar Petri dishes! Surface sampling! Swabs and contact plates! Five-finger glove printing ! Incubators, workstations, air, floor, wall! Esteves, 50 !
- 51. Esteves, 51 ! Quality Manager & Lab Supervisor play critical role Bento, FC: The role of quality manager in clean room ART Units. ! In: Esteves, Varghese, Worrilow. Cleanroom technology in ART Clinics, CRC Press 2016! Be the quality expert Understand how the clean room works, what is needed to work inside such a facility. Implement quality policies • Establish policies with details about how to work in the clean room laboratory, to guarantee the desired cleanliness level. • Train the team who will be working inside the cleanroom unit. Manage the QMS efficiently Guarantee the filter replacement and clean room certification expenses are included in the annual budget. Promote communication Encourage the clean room team to report any deviation and any problem that may compromise the laboratory air quality. Audit Make sure the team understands, respects, and works adequately inside the clean room laboratory, following the established policies Focus on prevention • Check the air quality system periodically, to ensure efficiency. • Replace filters with initial signs of saturation.
- 52. Air Quality Integral Part of QMS Esteves, 52 ! 1. Specific SOPs 2. Training 3. Auditing 4. Benchmarks In essence, it’s everyone’s responsibility.! Bento, FC: The role of quality manager in clean room ART Units. ! In: Esteves, Varghese, Worrilow. Cleanroom technology in ART Clinics, ! CRC Press 2016!
- 53. How to measure air quality in the IVF lab? CONCLUSIONS Esteves, 53 ! 1. Critical elements to measure include: No. particles in air suspension, Air pressure differential, Air exchanges/h, VOC and microbials, and adherence of personnel to good laboratory practices concerning air quality control 2. Air quality control integral part of QMS ! Specific SOP, training & auditing program, benchmarks ! 3. Successful AQC everyone’s responsibility!
- 54. Precautionary Principle: *Convention on Biological Diversity, UN 1992; Ratified by 192 countries and the EU, except USA, Andorra and South Sudan Esteves, 54 !
- 56. Esteves, 56 ! Obrigado Thank you!