The document discusses the significance of particulate containment validation in reducing pharmaceutical exposure, particularly in India's rapidly growing contract manufacturing sector. It highlights challenges such as inadequate risk assessment, lack of occupational exposure limits, and insufficient analytical methods, while presenting a validation procedure that involved monitoring four isolators. Results showed that exposure levels were mostly below the containment performance target, but surface contamination exceeded thresholds, leading to key recommendations for improving containment practices.

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Particulate Containment
Validation: An Effective Tool in
Reducing Pharmaceutical
Exposure in Emerging Economies
Prasanth.Kondragunta
International Safety Systems,
Vadodara, India
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Agenda
• Introduction
• Contract Manufacturing (CM) sites scenario in India
• Challenges at CM sites
• Particulate Containment Validation
• Validation Procedure
• Results
• Conclusion

3. Introduction – Pharmaceutical Industries
• Pharmaceutical manufacturing is growing at 14% to 17% per
year in emerging economies, specifically China and India
• Outsourcing of work to Contract Manufacturers (CM)
expected to exceed $53 Billion
• Active Pharmaceutical Ingredient (API) manufacturing
– Bulk drug is manufactured
– Large volume handled potential solid exposure risk is high
• Formulation or Dosage Form
– Solids and liquid pharmaceuticals are made
– Potential solid API exposure risk is high
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4. Contract Manufacturing Scenario in
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India
• Third party/Contract Manufacturing (CM) sites are increasing
rapidly:
 low labour costs,
 large existing pharmaceutical manufacturing base,
 sizable patient population
 large number of qualified pharmacists and chemists

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Challenges at CM sites
• Safety professionals or occupational physicians practicing IH
• Limited sensitivity of site professionals to degree of hazard of
Active Pharmaceutical Ingredients (APIs).
• No risk assessment and evaluation through industrial (or
occupational) hygiene assessment to determine potential
exposure of APIs to workers.
• Occupational Exposure Limits (OELs) are not available for
large number of APIs and intermediates.
• Validated analytical methods are not available for large
number of APIs
• No accredited laboratories are available in India for API
analysis

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Challenges at CM sites
• Categorizing (or “banding”) the API based on inherent potency
and toxicity, linking the category to safe handling practices
and control strategies
• Open handling of potent compounds
• High reliability on Personal Protective Equipment (PPE)
• No Segregated gowning and de-gowning areas provided with a
room airlock or anteroom.
• Limited knowledge and application of appropriate containment
and control measures to maintain exposures below acceptable
levels.

7. Particulate Containment Validation
• Surrogate monitoring – Lactose/Naproxen Sodium
• International Society for Pharmaceutical Engineering (ISPE)
• Standardized Measurement of Equipment Particulate Airborne
Concentration (SMEPAC) Committee
• ISPE Good Practice Guide: Assessing the Particulate
Containment Performance of Pharmaceutical Equipment
• Standardized method of measuring
– Performance of containment systems against specific
challenge
– Establish an agreed and valid method that can be used to meet
the requirements of practitioners and supplier organizations
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Example of Laminar Flow
Booth Surrogate Monitoring

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Validation Procedure
• Certified Industrial Hygienist (CIH) reviewed the containment
systems installed in an ABC company and provided a draft
particulate containment validation plan.
• Surrogate monitoring was carried out for four numbers of
stainless steel negative pressure rigid isolators:
 Dispensing
 Compounding
 Unloading from Vacuum Tray Drier
 Sifting, Milling and Pack Off
• Containment Performance Target (CPT) was 1 μg/m3

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Methods
• Lactose was chosen as surrogate – Limit Of Quantitation
(LOQ) of 2.5 nanograms
• Personal, area/static samples and wipe samples were
collected as per ISPE protocol.
• Three Iterations were considered for performance
verification.
• 25mm, 1 micron Teflon® filters ; sampling flow rates were
approximately 2 L/Min.
• 100 cm2 surfaces of the equipment and surrounding areas
using swabs and distilled water as a wetting agent.
• AIHA accredited laboratory analyzed the samples

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Results
• Dispensing Isolator:
 Personal Breathing Zone - 0.07 μg/m3 to 0.33 μg/m3
 Area Static - 0.01 μg/m3 to 0.17 μg/m3
 Wipe/Swab – 0.127 μg/100 cm2 to 7.54 μg/100 cm2
• Compounding Isolator:
 Personal Breathing Zone - 0.03 μg/m3 to 0.23 μg/m3
 Area Static - 0.01 μg/m3 to 0.72 μg/m3
 Wipe/Swab – 6 μg/100 cm2 to 23.3 μg/100 cm2

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Results
• Vacuum Tray Drier Isolator:
 Personal Breathing Zone - 0.03 μg/m3 to 0.24 μg/m3
 Area Static - 0.01 μg/m3 to 0.06 μg/m3
 Wipe/Swab – 1.11 μg/100 cm2 to 3.44 μg/100 cm2
• Sifting, Milling and Pack off Isolator:
 Personal Breathing Zone - 0.09 μg/m3 to 0.34 μg/m3
 Area Static - 0.01 μg/m3 to 0.8 μg/m3
 Wipe/Swab – 0.05 μg/100 cm2 to 4.3 μg/100 cm2

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Recommendations
• Although air sample results were below CPT of 1 μg/m3,
surface contamination results exceeded 10 times the CPT of 10
μg/cm2 and hence following recommendations were provided:
 Rectify the containment breach near glove port
 Cleaning of spills immediately with wet wipes
Wet wiping of the poly bag outer surface before taking out
the bag into Rapid Transfer Port (RTP) canister
 Ensure use of High Efficiency Particulate Air (HEPA) filter
equipped vacuum cleaner for the cleaning and
housekeeping activities.
 Ensure operators take shower to decontaminate the full
body suit after use and before removing the suit to avoid
potential exposure to API while removing contaminated
suit.

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Conclusion
• Particulate Containment Validation process was effective in
identifying exposure and contributing factors.
• The results of the particulate containment review of the
isolators indicated that all the four isolators can be operated
with API containment level below 1 μg/m3 .
• The Contract Manufacturing site leadership team recognized
the importance of particulate containment validation review to
determine the overall potential occupational health risk.

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References
• www.gpcmevent.com
• www.pharmaceutical-technology.com
• www.pharmoutsourcing.com

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Questions?
Prasanth.K
(prasanth.k@issehs.com)
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