Particulate Containment Validation

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

2. 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

4. 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

5. 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

6. 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

8. Example of Laminar Flow Booth Surrogate Monitoring

9. 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

10. 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

11. 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

12. 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

13. 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.

14. 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.

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

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