XQ Lin, Yayi Nestiti April Downflow booths are used in the pharmaceutical, fine chemical and food industries, for operations such as sampling,

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1 Performance Verification of Esco Pharmacon Downflow Booth via Surrogate Air Monitoring Exposure to Lactose During Material Transfers Involving 25 kg Of Active Pharmaceutical Ingredient By XQ Lin, Yayi Nestiti April 2009 Introduction Downflow booths are used in the pharmaceutical, fine chemical and food industries, for operations such as sampling, grinding, dispensing and filling, which generate airborne particles; when processes involve hazardous, toxic or sensitizing materials and when operators, adjoining areas require protection from exposure to aerosols of the process materials. Surrogate Powder Containment testing on an Esco Pharmacon Downflow Booth (model DFB-1.5S1-10-C, serial number ) was conducted to assess the performance characteristics of these booths in containing and controlling airborne concentrations of particulate powders generated during typical powder handling and transfer operations. Three test iterations were conducted, each involving the transfer of 25 kg of lactose from a bulk product drum into a receiving drum. The tests results prove that the booth delivers excellent containment significantly below industry-accepted criteria. Performance Testing The downflow booth was first tested to ensure it meets filter integrity, airflow and operator comfort performance criteria. HEPA Filter Test This test ensures that the HEPA filters meet filter integrity requirements for allowable penetration of PAO (Poly Alpha Olefin) test aerosol. The upstream face of each filter was challenged with an aerosol generated from Shell Ondina EL oil, producing particles with a mass diameter of less than 0.8 µm. The volume of aerosol produced was sufficient to provide a challenge of between 20 µg/l and 50 µg/l. A forward light scattering photometer with a sampling probe was then used to scan each filter downstream for leaks. Aerosol penetration was % for the all downflow HEPA filters (rear left, rear right, front left, front right) and bleed HEPA filter 1. These measurements were within industry accepted acceptance criteria, that no reading of the photometer shall exceed % of the challenge value.

2 Downflow Test This test ensures that the downflow velocity across the filter faces is of a sufficient velocity and is uniform. Downflow velocity was measured at a distance of 100mm (4 ) below the filter face, with a total of 20 points measured across 4 filters, using the manufacturer s grid. The average velocity for all 20 points was 0.5m/s (98fpm), with a maximum deviation of 16%. This met industry accepted criteria, which specifies the downflow booth s average downflow velocity should be 0.5m/s (98fpm) ± 10%, and that individual readings for each filter should have a maximum deviation of 20% from the filter s average downflow velocity. Bleed Airflow Test This test ensures the bleed airflow volume is within the manufacturer s specifications. Bleed airflow velocity was measured at a distance of 100mm (4 ) from the filter face, using a calibrated anemometer positioned according to the manufacturer s grid. The measured bleed airflow volume was 436 m 3 /h (257 cfm). The bleed airflow volume as a percentage of booth total airflow (4676 m 3 /h, or 2752 cfm) was 9.32%. This met the manufacturer s acceptance criteria, which specified that bleed airflow volume should be 10% ± 2% of the total airflow volume. Light Intensity Test This test ensures that light intensity, at a working height of 1200mm (4 ) from the floor, is sufficient for operator comfort. The average measured light intensity, according to the manufacturer s grid, was 891 lux (83 ft. candles). This met the manufacturer s acceptance criteria, which specified that the average light intensity should be more than 500 lux (46 ft. candles), and that no light level should be less than 40% of the average. Noise Level Test This test ensures that the noise level, measured at 1200mm (4 ) above the floor, and 1000mm (3 3 ) from the front centre, using a calibrated sound meter, is not excessive for operator comfort. The measured noise level was 65.3dBA. This met the manufacturer s acceptance criteria that the noise level should not exceed 68dBA.

3 Surrogate Testing The surrogate testing method is in accordance with the ISPE Good Practice Guideline Assessing the Particulate Containment Performance of Pharmaceutical Equipment. Surrogate Material According to the ISPE Good Practice Guideline Assessing the Particulate Containment Performance of Pharmaceutical Equipment, lactose monohydrate (lactose) is preferred as a surrogate test agent to identify the "range" of potential exposures and containment during a powder handling operation. Although not a crystalline material, lactose is recommended because its particle size and bulk density are comparable to many Active Pharmaceutical Ingredients (APIs). Lactose is also non-toxic, safe to handle and is readily detectable at very low concentrations, thus enabling the assessment of very short duration tasks. The surrogate material used met the requirements specified in the ISPE Good Practice Guide (Lactose-313, NF Monohydrate; Foremost USA cat # W406313). The lactose used had a particle size distribution of 75% (by weight) less than 37 micrometers; 24% between 75 and 37 micrometers; and one percent larger than 75 micrometers. Air Sampling Air sampling locations were set up as illustrated in Figure 1, and consisted of: 1. Operating Breathing Zone (OBZ): the sampler was attached to the operator s shirt s collar and was placed less than 300mm (12 ) from the mouth. 2. Inside booth 200mm (8 ) off left side wall & 200mm (8 ) outside safe work zone. 3. Inside booth, center, 200mm (8 ) outside safe work zone. 4. Inside booth 200mm (8 ) off right side wall & 200mm (8 ) outside safe work zone. 5. Outside booth 200mm (8 ) outside booth in front of left side wall. 6. Outside booth 1500mm (5 ) outside and in the center of the booth. 7. Outside booth 200mm (8 ) in front of right side wall. 8. Background samples inside and outside the booth, midway between the booth side walls, 200mm (8 ) from floor and 2000mm (6 7 ) from open face of booth.

4 Figure 1. Plan View of Sampling Locations

5 Air sampler cassettes to capture lactose (25 mm, 1.0 µm PTFE filter) were connected to the pumps. The pumps were operated at a flow rate of approximately 2.0 liters per minute (0.07cfm). Powder Handling Operation Fiber drums were used in this test and were fitted with two liners. The inner liner holds the lactose and the outer liner provides redundant protection. Two drums (bulk product drum and receiving drum) were moved into the downflow booth. The receiving drum was positioned as close as possible to the exhaust located at the back of the booth. The bulk drum was positioned beside the receiving drum, to minimize the distance required for lactose transfer. The operator de-lidded the drums and staged the liners. Lactose was scooped by hand using a 1000 cc scoop until most of the material was transferred. The liner containing the remaining material was then lifted out of the bulk drum, and the remaining material was directly discharged to the receiving drum. The liner was then placed back into the empty bulk drum. Finally, the receiving drum was tied off and the drums were re-lidded. The powder handling operation was repeated three times to yield a greater number of test samples. At the end of each iteration, the operator remained in the booth for 15 minutes to ensure all dust emitted from the task was collected. The operator wore several layers of impermeable gloves. To prevent cross contamination, a layer of gloves was removed after each iteration and/or after performing a task that results in a high level of dust on the gloves. Used gloves were disposed into a lined waste collection bin, sited at the corner of the booth. In total, 25 air samples were collected for analysis 9 outside booth samples, 9 inside booth samples, 3 operator breathing zone samples, 2 background samples and 2 field blanks (as controls). Samples were analyzed for lactose at an independent laboratory, ESA Laboratories, Inc, USA, using High Performance Liquid Chromatography (HPLC). Analytical data from the laboratory is appended to this report.

6 Summary of Results Date Air Sample # Type of Sample Description Time (min) Iteration 1 (Average Environmental Conditions: Temperature: 29 0 C, Humidity: 73%) Concentration of Lactose (µg/m3) 3/20/ Background Background air sample (inside) /20/ Background Background air sample (outside) 114 < /20/ OBZ Drum to drum transfer of 25 Kg lactose by hand scooping 3/20/ Inside Static sample inside booth: left 40 < /20/ Inside Static sample inside booth: center 40 < /20/ Inside Static sample inside booth: right 40 < /20/ Outside Static sample outside booth: left 40 < /20/ Outside Static sample outside booth: center 40 < /20/ Outside Static sample outside booth: right 40 <0.024 Iteration 2 (Average Environmental Conditions: Temperature: 30 0 C, Humidity: 72%) 3/20/ OBZ Drum to drum transfer of 25 kg lactose by hand scooping 3/20/ Inside Static sample inside booth: left 36 < /20/ Inside Static sample inside booth: center 36 < /20/ Inside Static sample inside booth: right 36 < /20/ Outside Static sample outside booth: left 36 < /20/ Outside Static sample outside booth: center 36 < /20/ Outside Static sample outside booth: right 36 <0.027 Iteration 3 (Average Environmental Conditions: Temperature: 31 0 C, Humidity: 70%) 3/20/ OBZ Drum to drum transfer of 25 kg lactose by hand scooping 3/20/ Inside Static sample inside booth: left 38 < /20/ Inside Static sample inside booth: center 38 < /20/ Inside Static sample inside booth: right 38 < /20/ Outside Static sample outside booth: left 38 < /20/ Outside Static sample outside booth: center 38 < /20/ Outside Static sample outside booth: right 38 < /20/2009 Field blank #1 Control sample NA < /20/2009 Field blank #2 Control sample NA <0.002 This test assesses the performance characteristics of the Esco Pharmacon Downflow Booth in containing and controlling airborne concentrations of particulate powder generated during a typical powder handling and transfer operation. The powder handling operation was transferring 25kg of lactose from a bulk product drum to a receiving drum in three iterations. Drum to drum transfers by hand scooping or direct discharge from a drum liner are common tasks performed at

7 a majority of pharmaceutical facilities. Being an open and manual process, reliant on operator technique (instead of manufacturer-specific equipment), it challenges the downflow booth to a reasonable level and provides a suitable parallel for real world tasks. Summary of Exposure Outcomes Iteration Background Duration 40 minutes 36 minutes 38 minutes 114 minutes Operator Breathing Zone 6.35 µg/m 3 36 µg/m µg/m 3 NA Inside Range µg/m µg/m µg/m µg/m 3 Inside Mean µg/m µg/m µg/m 3 Outside Range µg/m µg/m µg/m µg/m 3 Outside Mean µg/m µg/m µg/m 3 Exposure values inside the booth and in the operator breathing zone were within industry accepted criteria (<100 µg/m 3 ). These values prove that the booth provides good containment. In particular, the operator breathing zone values were significantly below industry accepted criteria. Exposure values outside the booth were relatively low indicating the booth provided good containment, and that samples inside the booth did not falsely register external contamination.

8 Conclusion A comprehensive battery of tests including filter integrity, downflow, bleed airflow, light intensity and noise level was carried out to verify the performance of the Esco Pharmacon Downflow booth. Booth performance was established to be within industry accepted and manufacturer s criteria. A surrogate powder test involving the hand transfer of 25kg of lactose, in accordance with the ISPE Good Practice Guidelines, was then carried out. Multiple air sampling positions were strategically located at the operator breathing zone, inside, and outside the booth. Laboratory analysis of the sampling discs recovered indicated that booth performance was excellent, with all sampling locations, including the critical operator breathing zone, reading less than 100 µg/m 3. The result is specified for lactose. The downflow booth s containment with other compounds can only be known by testing with those compounds. Real world results may differ depending on the material handled and process. References Floura, Hari & Kremer, John. Performance Verification of a Downflow Booth via Surrogate Testing. The Official Magazine of ISPE, November/December Vol 28 No. 6 Floura, Hari Performance Verification of a Downflow Booth via Surrogate Air Monitoring Guideline Document. Floura LLC Containment Consultants. ISPE Good Practice Guide: Assessing the Particulate Containment Performance of Pharmaceutical Equipment, International Society for Pharmaceutical Engineering (ISPE), First Edition, January 2005,

9 Date Results of lactose surrogate air sampling downflow booth Type of Sample Activity Time Pre- Post- Sample Air flow Flow Flow # (min) rate rate Rate Sample amount of lactose airbone concentration volume (L) (ng/cassette) of lactose (µg/m3) Iteration #1 3/20/ Background background area air sample (inside) /20/ Background background area air sample (outside) < /20/ OBZ drum to drum transfer of 25 Kg lactose by hand scooping (iteration #1) 3/20/ Area (in) Static area air sample inside booth: LEFT side (iteration #1) < /20/ Area (in) Static area air sample inside booth: CENTER (iteration #1) < /20/ Area (in) Static area air sample inside booth: RIGHT side (iteration #1) < /20/ Area (out) Static area air sample outside booth: LEFT side (iteration #1) < /20/ Area (out) Static area air sample outside booth: CENTER (iteration #1) < /20/ Area (out) Static area air sample outside booth: RIGHT side (iteration #1) < /20/2009 Field Blank #1 N/A N/A < Iteration #2 3/20/ OBZ Drum to drum transfer of 25 kg lactose by hand scooping (iteration #2) 3/20/ Area (in) Static area air sample inside booth: LEFT side (iteration #2) < /20/ Area (in) Static area air sample inside booth: CENTER (iteration #2) < /20/ Area (in) Static area air sample inside booth: RIGHT side (iteration #2) < /20/ Area (out) Static area air sample outside booth: LEFT side (iteration #2) < /20/ Area (out) Static area air sample outside booth: CENTER (iteration #2) < /20/ Area (out) Static area air sample outside booth: RIGHT side (iteration #2) < /20/2009 Field Blank #1 N/A N/A < Iteration #3 3/20/ OBZ Drum to drum transfer of 25 kg lactose by hand scooping (iteration #3) 3/20/ Area (in) Static area air sample inside booth: LEFT side (iteration #3) < /20/ Area (in) Static area air sample inside booth: CENTER (iteration #3) < /20/ Area (in) Static area air sample inside booth: RIGHT side (iteration #3) < /20/ Area (out) Static area air sample outside booth: LEFT side (iteration #3) < /20/ Area (out) Static area air sample outside booth: CENTER (iteration #3) < /20/ Area (out) Static area air sample outside booth: RIGHT side (iteration #3) < /20/2009 Field Blank #1 N/A N/A <

10 Representative Photos Transferring of Lactose ESCO Pharmacon Downflow Booth Setup Operator de-lidded the drum and staged the liners of both drums Operator was scooping the lactose from bulk product drum (left picture) to receiving drum (right picture)

11 The inner liner was taken out from the bulk product drum (left picture) to be discharged directly to receiving drum The liners was tied off for the receiving drum (left picture) and both of drums were re-lidded

12 The sampler cassette on operator breathing zone (left picture) and position of overall samplers (right picture)

13 ESA LABORATORIES, INC. Page 1 22 ALPHA ROAD CHELMSFORD, MA (978) FAX: (978) PO#/RELEASE: YAYI NESTITI/NA ESAL BATCH#: CLIENT JOB#: NA DATE RECEIVED : DATE ANALYZED : YAYI NESTITI DATE REPORTED : ESCO MICRO PTE LTD 21 CHANGI SOUTH STREET 1 SINGAPORE, SINGAPORE Revised Test Report Paul A. Ullucci Laboratory Director TEST CODE TEST DESCRIPTION REFERENCE ANALYTICAL METHOD REPORTING LIMIT LACTOSE LACTOSE ESA L40102REVC 2.0NG LACTOSE-M LACTOSE IN MASS ESA SOP L40102REVC 2.0NG SAMP DATE LACTOSE LACTOSE-M NO. CLLCT SAMPLE ID/OTHER UG/M3 NG MESSAGES < < <0.024 < <0.025 < <0.022 < <0.026 < <0.024 < <0.024 < <0.027 <2.0

14 ESA LABORATORIES, INC. Page 2 22 ALPHA ROAD CHELMSFORD, MA (978) FAX: (978) PO#/RELEASE: YAYI NESTITI/NA ESAL BATCH#: CLIENT JOB#: NA DATE RECEIVED : DATE ANALYZED : YAYI NESTITI DATE REPORTED : ESCO MICRO PTE LTD 21 CHANGI SOUTH STREET 1 SINGAPORE, SINGAPORE Revised Test Report TEST CODE TEST DESCRIPTION REFERENCE ANALYTICAL METHOD REPORTING LIMIT LACTOSE LACTOSE ESA L40102REVC 2.0NG LACTOSE-M LACTOSE IN MASS ESA SOP L40102REVC 2.0NG SAMP DATE LACTOSE LACTOSE-M NO. CLLCT SAMPLE ID/OTHER UG/M3 NG MESSAGES <0.028 < <0.025 < <0.029 TR< <0.027 < <0.027 < <0.025 < <0.026 < <0.024 < <0.027 <2.0

15 ESA LABORATORIES, INC. Page 3 22 ALPHA ROAD CHELMSFORD, MA (978) FAX: (978) PO#/RELEASE: YAYI NESTITI/NA ESAL BATCH#: CLIENT JOB#: NA DATE RECEIVED : DATE ANALYZED : YAYI NESTITI DATE REPORTED : ESCO MICRO PTE LTD 21 CHANGI SOUTH STREET 1 SINGAPORE, SINGAPORE Revised Test Report TEST CODE TEST DESCRIPTION REFERENCE ANALYTICAL METHOD REPORTING LIMIT LACTOSE LACTOSE ESA L40102REVC 2.0NG LACTOSE-M LACTOSE IN MASS ESA SOP L40102REVC 2.0NG SAMP DATE LACTOSE LACTOSE-M NO. CLLCT SAMPLE ID/OTHER UG/M3 NG MESSAGES <0.026 < <0.025 < BLANK <2.0NG < BLANK <2.0NG <2.0 RESULTS ARE BLANK CORRECTED ON ESAL'S MATRIX BLANK END OF REPORT