Particulate Containment Validation By Prashant Kondragunta, ISS

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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

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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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Contract Manufacturing Scenario in 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.

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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_at_issehs.com)

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