Particulate Containment Validation: An Effective Tool in Reducing Pharmaceutical Exposure in Emerging Economies

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Particulate Containment
Validation: An Effective Tool in
Reducing Pharmaceutical
Exposure in Emerging Economies
Prasanth.Kondragunta
International Safety Systems,
Vadodara, India
www.issehs.com
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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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