Determining Particulate Containment

Through Surrogate Monitoring at

Pharmaceutical Companies in India

May 18, 2011

Ganesh Desai

+91 9327547481

Ganesh.Desai@issehs.com

Agenda

• Background

• Approaches adopted

• Exposure Sources

• Recommendations

• Lessons Learned

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Pharmaceutical Companies in India

• India is identified as most desirable country for

supplying dosage form and API to Pharmaceutical

corporations

• More than 200 contract manufacturers (CM) in India

• India has the most US FDA approved manufacturing

sites outside the USA.

• Driving Forces:

– Low cost of production and pool of scientific talents

– Price control

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Objective of Studies

• Surrogate monitoring was conducted in a small scale

manufacturing facilities of Company A, Company B and

Company C.

• Determine the degree of individual exposure with the current

containment to surrogate and relate to potential Active

Pharmaceutical Ingredient (API) exposure levels

• Recommend exposure controls to reduce exposures to API below

OEL

• Determine contribution of work practices in overall exposures

• Determine the need and type of respiratory protection to be used

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Sampling Protocol and Analytical Methods

• ISPE Good Practice Guide Assessing The Particulate

Containment Performance of Pharmaceutical Equipment

• Standardized Measurement of Equipment Particulate

Airborne Concentration (SMEPAC) committee

• Sampling Methodology and Instrumentation

– Air sampling pump - flow rate ranging 2 liters/min to 5 liters/min

– Primary Calibrator

– Sampling media – 1 micron 25 mm diameter PTFE filter and Swabs

• Analytical Methods

– American Industrial Hygiene Association (AIHA) accredited laboratory

analyzed the sample

– High Pressure Liquid Chromatographic and an Electrochemical

detector

– Limit of Quantification: 2.5 nanograms

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Surrogate Specifications • Lactose was selected as surrogate

• Factors considered in selection of Lactose:

– Particle size of target Active Pharmaceutical Ingredient (API)

– Detection sensitivity

– 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)

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Surrogate Sampling Locations

• Area samples – 5 and ½ feet above the floor.

• Transfer points – Within 6 inches (15 centimeters) of a

pass in/pass out transfer point.

• Personal Breathing Zone (PBZ) Samples– On 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

• Swab Samples – As per the ISPE protocol

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Unit Operations Dispensing

Sifting

Granulation

Drying

Milling

Blending

Compression

Coating

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Equipment Tested

• Isolator

• Down flow booth

• Sifter

• Rapid Mixer Granulator

• Fluid Bed Dryer (FBD)

• FBD with in-line mill

• Co Mill

• Bin Blender

• Compression Machine

• Coating Machine

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Findings

• Exposure monitoring results were found to be

above the company established occupational

exposure limits in Company A, Company B

and Company C.

• Containments or engineering controls are not

effective when safe work practices are not

followed

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Exposure Sources: Dispensing

• Isolator (Company A)

– Emissions from the connections of the hicoflex bags

• Laminar Flow Booth (Company B and C)

– Over filling of Scoop

– Rubbing of hands to remove Lactose adhered on the gloves

– Shaking of bag to remove leftover Lactose

– Spilled Lactose not cleaned immediately

– Adherence of Lactose on the secondary gown and gloves

– Visible particles seen on the outer side of the bag

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Exposure Sources: Sifting

• Isolator (Company A)

– Particulate emission seen from the discharge point

• Vibratory Sifter (Company B and C)

– Tapping of sieve

– Spilled surrogate was not cleaned, which became airborne

after the sifter was turned ON

– Poly bag with blend away from charging area resulting in

spillage and particles becoming airborne

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Exposure Sources: Granulation

• Rapid Mixer Granulator (Company A, B and C)

– Addition of blend manually in the RMG

– Opening of RMG during the granulation to scrap the

powder from the side walls of the RMG

– Manually pushing the left over blend in the discharge

point of the RMG

– Particulate emission seen from the discharge point

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Exposure Sources: Drying

• Ultima Pro 75 (Company A) – Spillage observed while opening the transfer valve

– Traces of dust particles coming out while removing the Hicoflex® bag from the discharge point, Small gap between two docking joints resulting in leakage of particles

– Tapping of the Hicoflex® bag to ensure smooth flow

• Fluid Bed Dryer (Company B and C) – Scrapping of blend from the walls of the IBC resulting in

particulate emissions

– Particulate emissions seen while manual scooping of blend in the poly bags

– Exposure were low during the first iteration as vacuum transfer system was used.

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Exposure Sources:

Milling

• Particulate emissions seen

from the charging point

when the co-mill was

switched ON

• Particulate emission seen

from the discharge point

as the bag was held

loosely

Blending

• Spillage during charging of

blend in the blender

• Spillage on the bin not

cleaned resulting in dust

particles becoming air borne

while bin was rotated

• Shaking of bags to remove

leftover blend

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Exposure Sources:

Compression of Tablets • Reach height for charging above shoulder height resulting in

Lactose spillage

• Compressed tablets taken without de-dusting for hardness

testing

• The powder on the tablets was removed by tapping on the

tablets, making the powder airborne.

• Sample tablets collecting bin was kept uncovered

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Exposure Sources: Coating of Tablets

• Leaks seen from the rubber lining of the door of the coating

machine

• Spillage of tablets while loading them in the coating pan

• The coating machine was modified to accommodate tablet

filling chute which resulted in sealing of the door becoming

inefficient to control the exposure

• Particulate emissions when the coating machine door was

opened to adjust the spray pattern

• The employee had to remove the tablets blocked on the

discharge point manually

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Common 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 Bulk Container (IBC)

• Manual scooping in the Mill instead of vacuum transfer

• Emissions observed from the rubber lining of the door of the

coating machine.

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Common 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.

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Recommendations

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Crimping

Recommendations

• Upgrade respiratory protection to Full face-piece Air

Purifying Respirator and Powered Air Purifying Respirator

(PAPR), until the controls are placed and exposure is

confirmed below the required OEB.

• Consider providing flexible containment for the equipment

such as sifter, RMG and the mill.

• Using Intermediate Bulk Containers (IBCs)

• Use crimping process to reduce the exposure during

discharging and handling of plastic liners.

• Clean spilled blend immediately by wet mopping or by a

vacuum equipped with HEPA filter.

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Recommendations

• Ensure the local exhaust ventilation system is

operational before commencing the coating activity,

• Ensure the rubber lining on the door of the coating

machine provide effective sealing to reduce emission,

• Keep a portable local exhaust ventilation near the

transfer points,

• Raise employee awareness on health hazards of APIs

and the importance of following safe work practices

and using recommended respiratory protection. Include

safe work practices in the operating procedures.

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Strengths of Surrogate Monitoring 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

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Limitations of Surrogate Monitoring Study

• Conditions are simulated and are not the actual

working conditions

• It 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

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Lessons Learned

• Surrogate monitoring 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

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Thank You

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