1. Exposure Control Validation at a
Supply Chain in India
Ganesh Desai and Toral Mehta, CIH
International Safety Systems, Inc.
Ganesh.Desai@issehs.com
www.issehs.com

2. Supply Chain In India-Pharma
Companies
 India identified as most desirable country for
supplying dosage form and API to Phrama
corporations
 Low cost of production and pool of scientific
talents
 More than 200 suppliers

3. Objective of Study
 Determine containment efficiency
 Determine the degree of exposure to the Active
Pharmaceutical Ingredients (APIs)
 Recommend exposure controls to reduce exposures to API
below OEL
 Determine type of respiratory protection needed
 Determine contribution of workpractices

4. Sampling Protocol
 ISPE Good Practice Guide Assessing The Particulate
Containment Performance of Pharmaceutical Equipment
 Standardized Measurement of Equipment Particulate
Airborne Concentration (SMEPAC) committee

5. Sampling and Analytical Methods
 Sampling Methodology and Instrumentation
 Air sampling pump - flow rate ranging 2 liters/min to 5 liters/min
 Primary Calibrator
 Sampling media – 5 micron 25 mm diameter PTFE fiter
 Analytical Methods
 American Industrial Hygiene Association (AIHA) accredited laboratory
analyzed the sample
 High Pressure Liquid Chromatographic and an Electrochemical detector
 Limit of Quantification: 5 nanogram
 Training of operators to explain objectives of study

6. Surrogate Specifications
 Lactose as surrogate
 Factors considered in selection of Lactose:
 Particle size of target Active Pharmaceutical Ingredient (API)
 Detection sensitivity (5 nanogram)
 Pharmacological activity (no effect on testing personnel or risk of cross-
contamination)
 Available particle size range giving a worst case of dustiness
 Ease of disposal (environmental consideration)
 Solubility in water (post-test cleaning)
 Stability (test material and sampled material storage)

7. Surrogate Sampling Locations
 Area – 5 feet, 6 inches above the floor.
 Transfer points – Within 6 inches (15 centimeters) of a pass
in/pass out transfer point.
 Operator (lead) – The lead operator, (i.e. the operator
performing the majority of the tasks). The preferred location is
attached to the collar as close to the breathing zone as possible
 Other operators – The other operators performing tasks for the
test provided with shift equivalence samplers.

8. Equipment Tested with Surrogate
Monitoring
 Sifter
 Rapid Mixer Granulator
 Fluid Bed Dryer
 Co Mill
 Bin Blender
 Compression Machine
 Coating Machine

9. Equipment Tested with Surrogate
Monitoring
Sifter Rapid Mixer Granulator
Fluid Bed Dryer

10. Equipment Tested with Surrogate
Monitoring Compression
Co-Mill
Bin Blender
Coating
Bin Blender

11. Personal and Emission Sample
20 Personal samples 27 Area samples

12. Findings
The Highest Personal Exposure was in the following activities
 Sifting
 Milling
 Compression of the tablets
 Compression machine cleaning

13. Contributory Factors - Containment
 Leakage from flange joints (sieve, mill)
 De-dusting and tablet filling area of compression without a local
exhaust ventilation (LEV)
 Significant emissions at all discharge points (Sieve, RMG, Mill,
Blender)
 Manual scooping in Compression machine instead of using an
Intermediate Bowl Container (IBC)
 Manual scooping in the Mill instead of vacuum transfer

14. Contributory Factors – Work Practices
 Material leaking from flange joints on Sieve, RMG, Mill
 Over filling of scoop while manual charging
 Shaking while emptying of Lactose with plastic bags
 Compressed air used for cleaning
 Dry sweeping in place of using a vacuum equipped with a
HEPA filter.

15. Recommendations
 Upgrade respiratory protection to Powered Air Purifying
Respirator (PAPR).
 Provide a Local Exhaust Ventilation with elephant trunk at
the discharging point
 Ensure all the joints are tightened and inspected by an
authorized person before commencement of the activity
 Avoid manual scooping of Lactose instead vacuum transfer
directly in to the mill

16. Recommendations
 Ensure all the flange joints are sealed using rubber
gaskets to avoid leakage.
 Use intermediate bowl container (IBC) for transferring
and collecting blend.
 Provide a plexi-glass cover that covers the de-dusting
and tablet filling area.
 Use a vacuum equipped with a HEPA filter.

17. Strengths of Containment Validation
Study
 Evaluate containment performance without potential exposures to
potent Active Pharmaceutical Ingredients (APIs)
 Evaluate containment performance in situations where an analytical
method has not been developed for the API of interest
 Extrapolate data for similar equipments and for multiple APIs with
similar characteristics
 Containment validation data applicable to the APIs for which
Occupational Exposure Limits are not established and analytical
methods are not developed

18. Limitations of Containment Validation
Study
 Simulated condition and not the actual working conditions
 Does not evaluate exposures to gases or vapors which may
escape the containment
 Employees work practices may be positively or negatively
biased knowing the purpose of the study
 Results are indicative and not confirmative

19. Lessons Learned
 Surrogate containment validation is effective in
determining degree of exposure
 Best of the containments or engineering controls
are not effective when safe work practices are not
followed
 Parent companies expecting suppliers to
demonstrate (through containment validation) that
API is exposure below OEL is the most effective
way of reducing exposure to API