This document summarizes the results of a study comparing airborne exposure monitoring for surrogates and actual APIs during pharmaceutical manufacturing processes. Personal and static air samples were taken for both a surrogate (mannitol) and an API during various unit operations. Exposures for the API were generally higher than the surrogate, likely due to differences in work practices. The study concluded that while surrogate monitoring can indicate particulate containment effectiveness, it may not accurately represent actual employee API exposures due to variability in properties and work practices. API exposure monitoring is needed to confirm particulate containment and exposure levels. Work practices were found to significantly impact personal exposures and differences between surrogate and API results.

1. Comparison of Surrogate and API Exposure
Monitoring Results at a
Pharmaceutical Industry in China
Shaobo Chen, Senior Industrial Hygienist
International Safety Systems, Inc. (ISS) China
www.issehs.com

2. Agenda
• Background
• Objectives of Study
• Methods and Evaluation Criteria
• Monitored Unit Operations
• Results
• Recommendations
• Lesson Learnt
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3. Background
Surrogate monitoring has been widely used as a substitute for
air sampling of Active Pharmaceutical Ingredients (APIs) to
determine particulate containment efficiency and employee
exposures. Common Surrogate used are:
• Lactose
• Naproxen sodium
• Mannitol
• Acetaminophen
• Sucrose
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4. Background
Advantages:
• Relatively low toxicity of the surrogate compounds
• Sensitive limit of detection
• Considered effective when validated API sampling and analytical method
are not available
• Considered effective to determine particulate containment efficiencies
before API manufacturing begins
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Disadvantages:
• Surrogate monitoring results may not be representative of API
particulate containment and exposures due to variabilities in surrogate –
API properties and work practices
• API exposure monitoring may not be done based on acceptable
surrogate monitoring results

5. Objectives of Study
• To identify personal breathing zone exposure to surrogate
and APIs for the same unit operations.
• To assess the particulate containment performance of
equipment.
• To assess the risk of contaminant spreading.
• To verify how best the surrogate monitoring result
represents API particulate containment and exposures.
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6. Methods
• Mannitol was chosen as surrogate – Limit of Quantitation
(LOQ) of 1 nanogram, which was more sensitive than that of
API.
• The actual API (Occupational Exposure Band (OEB) 4) – LOQ
of 0.6 micrograms.
• Active air sampling pumps were used as monitoring device.
• 25mm 1 micron Teflon® filters loaded into cassettes and IOM
samplers were used for the Mannitol and API sampling,
respectively. Sampling flow rates were approximately 2
L/min.
• AIHA accredited laboratory analyzed the samples.
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7. Evaluation Criteria
• The company recommended eight-hour OEL-TWA of 5 µg/m3
and Surface Guidance Value (SGV) of 5 μg/100 cm2 for API.
• The task based exposures for the sampling duration were
compared against the eight-hour OEL-TWA. The surface
concentrations of contaminant were compared against the
recommended SGV.
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8. Monitored Unit Operations
Monitored Unit Operations:
• QC Sampling
• Dispensing and Pre-blending
• Excipient charging and blending
• Tablet Compression
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Personal Exposure Monitoring and Static Air Sampling:
• Task based samples collected for the operator(s) involved in the unit
operations
• Static samples located according to International Society for
Pharmaceutical Engineering (ISPE) Good Practice Guide: Assessing the
Particulate Containment Performance of Pharmaceutical Equipment
• Air samples in corridor and wipe samples

9. Changes Between Surrogate and API
Monitoring
• QC Sampling
Work Practices - The operator performed cleaning after API
sampling.
Weight of materials handled - 20 g, 40 g and 60 g for
surrogate and 5 g*2 for API
Sampling duration - 18 min for surrogate and 64 min for API
• Dispensing and Pre-blending
Work practices - One small bag of API was sampled and
transferred through the pass box of isolator
Weight of materials handled - 55.5 kg for surrogate, 28.9 kg
(1st iteration) and 55.7 kg (2nd and 3rd iteration) for API
Sampling duration - 59 min and 123 min for surrogate and 79
to 348 min for API)
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10. Changes Between Surrogate and API
Monitoring
• Excipient charging and blending
Work practices
Sampling duration – 7 min and 8 min for surrogate, 61 min to 78 min for
API
• Tablet Compression
Work practices - The operator opened the tablet IBC after compression
during API monitoring.
Equipment - Loose connection between collecting chute and polybag
during API monitoring.
Weight of materials – Consistent with Dispensing and Pre-blending
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Surrogate API-1st and 2nd iteration API-3rd iteration

11. Results
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• QC Sampling with Glove Box
Surrogate (µg/m3) API (µg/m3)
Personal < 0.0279 10.8
Between the glove ports < 0.0274 < 4.35
Potential contributory factors for variability in Surrogate and
API results:
• The operator opened and covered the API drum outside the glove box.
• The operator opened the glove box and performed cleaning after QC
sampling of API.

12. Results
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• Dispensing and Pre-blending
Surrogate (µg/m3) API (µg/m3)
Primary Operator 0.0686 < 0.0171 < 3.75 < 1.25 < 1.42
Assistant Operator 5.86* 1.99 < 3.78 < 0.863 1.31**
SBV 5.13 2.99 < 3.1 < 0.871 < 1.24
Bag-out port 0.0182 0.0429 < 3.18 NA < 1.31
Pass box 0.0499 < 0.00714 < 3.15 < 0.838 4.07**
Outlet of filtered air 0.0248 0.0245 < 3.14 < 0.851 < 1.32
Drum loading port 0.036 0.0682 < 3.14 < 0.857 < 1.33
Control board 0.223 0.268 < 3.12 < 0.841 < 1.28
Potential contributory factors for variability in Surrogate and API results:
* The package of the surrogate might be contaminated which potentially contributed to the high
surrogate level for assistant operator.
** One small bag of API was sampled inside the isolator and transferred out of the isolator from
the pass box. The assistant operator opened the pass box for 6 to 7 times to transfer materials.

13. Results
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• Charging Excipient into IBC Which Contained Surrogate or API
Surrogate (µg/m3) API (µg/m3)
Primary Operator 3.83 0.199 6.25 6.3 < 4.68
Near the SBV < 0.0717 0.208 21.6 10.4 < 4.63
Potential contributory factors for variability in Surrogate and
API results:
• Change of work practices.

14. Results
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• Compression
Surrogate (µg/m3) API (µg/m3)
Operator 1 0.57 0.173 2.91 0.922 3.54
Operator 2 0.121 0.0632 < 0.731 < 0.743 1.77
Collecting chute 0.0698 0.00286 < 0.747 3.75 1.24
Control board 0.00637 < 0.00171 < 0.724 < 0.754 < 0.76
SBV of tablets IBC 0.0175 0.022 < 0.762 < 0.747 < 0.739
SBV of material IBC 0.0102 < 0.00176 < 0.739 < 0.753 < 0.744
SBV of material IBC 0.00925 < 0.00171 0.83 < 0.77 < 0.751
Potential contributory factors for variability in Surrogate and API results:
• Loose connection between collecting chute and polybag.
• Work practices: the operator opened tablet IBC to check the status of the tablets.

15. Results
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• Corridor Air Samples and Wipe Samples for API (Partial)
Wipe samples Range (µg/100 cm2)
On the handle inside compression room 30.15
On the handle inside coating room 0.9
On the handle inside IPC room 7.04
On the recording table inside IPC room 2.47 and 9.4
Wipe samples outside the process rooms (23
samples)
< 0.6 to 1.19 (22 samples) and 16.9 (1
sample-on the handle compression room)
Air samples Range (µg/m3)
Corridor (22 samples) < 2.47 (below the Reporting Limit)
The operator took tablet samples with hands (disposable Nitrile gloves worn). Touching
of contact surfaces (e.g., door handle) with contaminated gloves contributed to the high
results of the swabs.

16. Recommendations to reduce
exposures
• Evaluate feasibility of providing in-situ cleaning of the glove box used for
QC sampling.
• Raise employee awareness on health hazards of API and the importance
of following safe work practices through initial and refresher training
programs.
• Include the particulate containment devices, such as isolator and split-
butterfly valves into the preventive maintenance program and ensure
the devices function properly.
• Evaluate feasibility of collecting rejected tablets and tablets for QC in a
contained system. If plastic bags have to be used, ensure all connections
are tight to reduce particulates emissions.
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17. Recommendations to reduce spread
of API Contamination
• Define Red Zone (potentially contaminated area such as API handling
areas), Yellow Zone (less contaminated where PPE is removed) and
Green Zone (not contaminated such as corridors).
• Use shoe covers and disposable coveralls. Remove potentially
contaminated gloves, shoe covers and coveralls, place them into double
plastic bags and discard them into a waste container located in Yellow
Zone.
• Separate air locked entry and exit for operators and separate airlock
door/window/corridor for taking equipment in and out.
• Wipe clean potentially contaminated equipment and materials such as
cart before taking it out of the API handling area.
• Develop and implement procedures to use two pair of gloves. Replace
outer pair, when contaminated.
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18. Lesson Learnt
• Surrogate monitoring is indicative and not confirmative of the API
particulate containment and exposures.
• Variability in personal exposure results for surrogate and API was
significant. Relying of surrogate monitoring results to determine API
exposure is questionable.
• API exposure monitoring is needed to confirm particulate containment
and employee exposures.
• Variability in static air monitoring results for surrogate and API was not
significant and hence surrogate monitoring results are indicative of
containment efficiency for API
• As expected, work practices contribute to the high personal exposures
and surrogate – API result variability
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19. Thanks you.
Any questions?
Shaobo Chen, Senior Industrial Hygienist
Bob.chen@issehs.com
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