Airborne Assessment for Aerosols During Manufacturing of Large Molecule Biologics
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Transcript of Airborne Assessment for Aerosols During Manufacturing of Large Molecule Biologics
Airborne Assessment for Aerosols During Manufacturing
of Large Molecule Biologics
AIHCE – Portland, OR
Pharma Forum – Wednesday, May 18, 2011
Dave Pearson – Johnson & Johnson PRD
Discussion
Marc Abromovitz, J&J Global Pharma
Brett Chronister and Steve Nowakowski, J&J Malvern EHS
Dave Pearson, J&J Spring House EHS
Kevin Turner, J&J Radnor EHS
Mark Tartaglia, EHS Impact Solutions, LLC
Acknowledgements
Only Qualitative Risk Assessments had been used to evaluate manufacturing processes for large biomolecules
Most large molecule compounds characterized as being low hazard
• Not easily absorbed through the skin, digestive system or respiratory tract
Biologics manufacturing processes also characterized as low risk
• Primarily wet, closed processes
Consequently, never developed OELs or performed air sampling
More recent decision to apply hazard banding instead of developing OELs for large biomolecules
Interest within EHS to validate these positions
J&J Historical Background- IH and Large Molecule Compounds -
Not absorbed through the skin
Not likely absorbed through the upper respiratory tract
Due to their large molecular weight, those that reach the deep regions of the lungs have low absorption into the bloodstream:
Insulin (MW = 5,700) approximately 10% absorption
Human Growth Hormone (MW = 30,000) 5% absorption
Typical Biologic (MW > 100,000) 10% absorption conservatively assumed
How well do large biomolecules (proteins, monoclonal antibodies, etc.) get absorbed?
Inhalable Fraction – The fraction of suspended material in ambient air that actually enters the nose or mouth with the volume of air inhaled (typically up to 100 microns in size).
Respirable Fraction – The fraction of inhalable aerosols that can reach pulmonary region (up to 10 microns in size)
Aerosols greater than 10 microns will often deposit in the nasopharyngeal and tracheobronchial regions. These are trapped in the mucous blanket and removed from the body or swallowed.
Airborne Exposure to Large Molecule Aerosols vs. Actual Bloodstream Uptake
Readily break down due to exposure to light, low pH and high temperature
For those compounds that are swallowed, expect compound to be denatured when exposed to acidic environment of the stomach. Therefore, uptake into the bloodstream via the digestive tract is also not expected.
After settling on work surfaces, expect biological activity to be eliminated due to environmental exposure. Therefore, effects of re-suspension in air after drying should be negligible.
What are other influences on biological activity for large molecular weight compounds?
Identify all potential sources of aerosol generation during production of large molecule compounds.
Evaluate methods for potential measurement of employee exposure to large molecule respirable aerosols and compare with lower end of OEL-2 band (20 ug/m3).
Methods considered:
Gravimetric Respirable Aerosol Sampling
Total Protein
Compound-specific IH Method
Real-time Aerosol Monitoring
Purpose of Monitoring
Advantages
More specific than Total Dust
LLD (100 ng/m3 ) is below the lower end of OEL-2 band
Disadvantages
Does not differentiate between naturally occurring protein
Historically Total Protein IH sampling has not given an accurate picture of true exposure
Monitoring Methods Considered -Measuring Total Protein
Advantages
Most accurate way to determine airborne employee exposure levels
Compound-specific
Disadvantages
Compound-specific, therefore need new method for each molecule
Delayed time to receive results
Monitoring Methods Considered -Specific IH Method
Advantages Can provide accurate real time data on respirable aerosols
Can be used at multiple sites for multiple products
Can immediately identify activities and locations of leakage/release
Disadvantages Not validated for real-time measurement of inhalable aerosols
>10 microns
Does not differentiate aerosol that is not part of the process. Need to assume that the detected aerosol is 100% product.
Not a personal sample
Monitoring Methods Considered -Real-Time Aerosol Monitoring
Real-time monitoring conducted at two (2) of the J&J Biologics
production facilities.
Malvern – GMP, commercial product facility
Spring House – Pilot scale, clinical product facility
Area readings taken at workstation operator breathing zones and at
the point source for tasks that have the highest potential for generating
aerosols.
Work area background samples taken during non-processing periods
for comparison purposes.
Monitoring Strategy For Real-Time Aerosol Monitoring
DustTrak™ II Model 8530 Aerosol Monitor (TSI, Inc.)Desktop and Handheld modelsBattery operatedLight scattering LASER photometerSimultaneous measurement of mass and size fractionData logger
Real Time Aerosol Monitor
Desktop Handheld
Releases during equipment purging or in-process sampling
Leaks at connections, hoses, tri-clamps, etc.
Final Fill Process (product is dispensed into bulk containers)
Equipment Disassembly
Potential Aerosolization Points in Manufacturing
Typical Monoclonal Antibody Bulk Process
AffinityChromatography
2L - 20L
BioreactorPre-CultureCell BankClarificationHarvest
(ATF)
Recovery
VirusInactivation
VirusFiltration Step
Anion Exchange
Chromatography
Cation Exchange
Chromatography
BulkProduct
FinalFiltration
Media Prep
Buffer Prep
s s
ss
s
s = Sampling Location
Examples of processes with potential for aerosolization
Air Sampling Results – GMP Operations
GMP Total GMP Respirable GMP Background
ORDER STATISTICS ORDER STATISTICS ORDER STATISTICS
n = 17 n = 17 n = 10
min = 1.0ug/m3 min = 1.0ug/m3 min = 1.0ug/m3
max = 10ug/m3 max = 10ug/m3 max = 5.0ug/m3
median = 1.0ug/m3 median = 1.0ug/m3 median = 1.0ug/m3
DESCRIPTIVE STATISTICS DESCRIPTIVE STATISTICS DESCRIPTIVE STATISTICS
mean = 2.3ug/m3 mean = 1.8ug/m3 mean = 1.4ug/m3
sd = 2.4 sd = 2.3 sd = 1.3
gm = 1.6 gm = 1.3 gm = 1.2
gsd = 2.14 gsd = 1.95 gsd = 1.66
COMPLIANCE STATISTICS COMPLIANCE STATISTICS COMPLIANCE STATISTICS
X0.95 = 5.795%LCL =
3.995%UCL =
11 X0.95 = 4.095%LCL =
2.895%UCL
=6.9 X0.95 = 2.795%LCL =
2.095%UCL =
5.2
Data analysis performed using IHDataAnalyst, V1.05, Exposure Assessment Solutions, Inc.
Air Sampling Results – nonGMP Operations
Non-GMP Total Non-GMP Respirable Non-GMP Background
ORDER STATISTICS ORDER STATISTICS ORDER STATISTICS
n = 7 n = 7 n = 2
min = 5.0ug/m3 min = 4.0ug/m3 min = 3.0ug/m3
max = 6.0ug/m3 max = 5.0ug/m3 max = 9.0ug/m3
median = 5.0ug/m3 median = 4.0ug/m3 median = 6.0ug/m3
DESCRIPTIVE STATISTICS DESCRIPTIVE STATISTICS DESCRIPTIVE STATISTICS
mean = 5.4ug/m3 mean = 4.3ug/m3 mean = 6.0ug/m3
sd = 5.0 sd = 5.0 sd = 4.2
gm = 5.4 gm = 4.3 gm = 5.2
gsd = 1.1 gsd = 1.12 gsd = 2.17
COMPLIANCE STATISTICS COMPLIANCE STATISTICS COMPLIANCE STATISTICS
X0.95 = 6.395%LCL =
5.995%UCL =
7.5 X0.95 = 5.195%LCL =
4.795%UCL =
6.2 X0.95 = 1995%LCL =
7595%UCL = 3.76E0006
Data analysis performed using IHDataAnalyst, V1.05, Exposure Assessment Solutions, Inc.
Discussion
95% UCL for both Respirable and Total aerosol fraction sampling results were one-half or less lower end of OEL-2 band [20 ug/m3] without adjusting for % Active Ingredient content.
No operations were identified that require additional engineering controls or use of respirators per J&J criteria.
Respirable aerosol sampling results were similar to Background results (substantial overlap in 95% CL band).
Respirable aerosol sampling results for GMP operations were similar to non-GMP operations (non-GMP 95% CL band contained within GMP 95% CL band).
Conclusions
Discussion
DustTrak useful as survey instrument to provide real-time concentrations for Respirable fraction during large biomolecule processing.
Handheld unit may provide more flexibility for field work.
Clean room environment aided in ability to use non-selective instrument to measure target aerosols.
Conclusions (cont.)
Discussion
Complete additional comparative statistical analysis of data
Respirable data sets vs. Background sets
GMP data set vs. non-GMP set
Collect additional data at PA facilities
Collect data at other J&J Biologics facilities
St. Louis
Leiden (The Netherlands)
Cork (Ireland)
Next Steps
? QUESTIONS ?
07.14.2010 22
Sample # Conc LOD
16 0.001
19 0.004
21 0.001
25 0.003
26 0.001
27 0.001
28 0.001
29 0.001
30 0.001
35 0.001
37 0.001
39 0.001
41 0.001
42 0.01
43 0.001
45 0.001
47 0.001
DATA
Respirator Decision Analysis (Respirable GMP - No LOD)
07.14.2010 23
Sample # Conc LOD
16 0.001
19 0.004
21 0.001 Y
25 0.003
26 0.001 Y
27 0.001 Y
28 0.001 Y
29 0.001 Y
30 0.001 Y
35 0.001 Y
37 0.001
39 0.001 Y
41 0.001 Y
42 0.01
43 0.001 Y
45 0.001 Y
47 0.001 Y
DATA
Respirator Decision Analysis (Respirable GMP - LOD)
Discussion
References:
Model 8530/8531/8532, DUSTTRAK™ II Aerosol Monitor Operation and Service Manual; TSI Incorporated, Revision E, March 2010
“Counting and particle transmission efficiency of the aerodynamic particle sizer”; J. Volckens, T.M. Peters / Aerosol Science 36 (2005) 1400–1408
References
Discussion
DustTrak II Instrument Calibration
• Factory calibration maintained
• Factory calibration factor used– Specific aerosol calibration factor not determinable due to aqueous nature
– Instrument design not include accelerating nozzle that has been reported to underestimate liquid aerosols in other instruments [J. Volckens, T.M. Peters / Aerosol Science 36 (2005) 1400–1408]
Maintenance performed per Operation Manual. Desktop model difficult to handle for field work due to size/weight.
Product Formulations Range of typical Active Ingredient % concentration is up to 5% Results were not adjusted to account for AI concentration.
Discussion
Data collected early 2010
Limited number of pharmaceutical organizations surveyed
Two (2) companies have developed compound-specific IH methods with contract IH lab (compounds were Carcinogenic or Cytotoxic). Both companies sampled stages in the process that they believed presented the greatest risk of employee exposure. Both companies reported results in low ng/m3 or ND.
Three (3) companies currently relying on qualitative risk assessments. They believe qualitative risk assessments are adequate due to the nature of the compounds and the processes.
Summary of Benchmarking
Discussion
95% UCL for both Respirable and Total aerosol fraction sampling results were one-half or less lower end of OEL-2 band [20 ug/m3] without adjusting for % Active Ingredient content.
No operations were identified that require engineering controls or use of respirators per J&J criteria <INSERT CRITERIA> .
Comparative aerosol sampling results between Respirable fraction and Background results were <INSERT CONCLUSION> .
Comparative aerosol sampling results between GMP and non-GMP operations were <INSERT CONCLUSION> .
Conclusions (Alternate)