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Analysis of Exposure Monitoring Results and

Lessons Learned – Pharmaceutical Unit

Operations

Maharshi Mehta, CSP, CIH

Prasanth K., CIH, Gopal C.

International Safety Systems, Inc.

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Pharma Forum 2016

AIHCE, Baltimore, May 25

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Objectives

Analyze API and surrogate monitoring results

Identify exposures at unit operations

Identify effectiveness of exposure controls

Identify exposure contributory factors

Reduce future exposure monitoring

Implement exposure controls based on lessons learned

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This study is beginning of long term study of

10000+ sampling results

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Results Origin

~ 5500 results of API and surrogates

100+ workplaces

21+ countries

Over a period of last 7 years

Personal and area sampling

APIs and surrogates

Only air samples considered, not wipe

11 ISS professionals were involved in collecting data

Only ISS collected data is considered at this time

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USA

Canada

Mexico

Brazil

Columbia

Argentina

Results Origin: Americas

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Results Origin : Asia

India

China

Singapore

Indonesia

Japan

Australia

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Austria

Germany

Netherland

France

Ireland

Portugal

Italy

Spain

UK

Results Origin: Europe

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Challenges

Result variability – GSD

Work practices dependent

Engineering controls and particulate

containment variability

Weight of API/surrogate

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Methods – API/Surrogate Sampling

and Analysis

Only validated methods from AIHA accredited lab with

pharma analytical expertise used and anlyzed

Written protocol for sampling used

– Sample flow rates/volume

– Media

– Avoiding cross contamination

– Each sample in zip-lock plastic bag

ISPE protocol used for surrogate monitoring

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Method – Data Analysis

Sampling notes entered in result sheets in Excel® was

available workplaces

Result sheets were standardized

– Sample id,

– Sample duration,

– Unit Operations

– Weight of API/Surrogate

– Controls provided

Results were sorted

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Unit operations for statistical

analyses

As a first stage of the analysis, unit operations with less

variability selected

– Laboratory scale weighing with controls (VBSE, or laboratory

fume hoods) and without controls

– Weighing dispensing in isolator

– Charging/discharging with split butterfly valve

– Weighing and dispensing in Laminar Flow Booth

– QC sampling

500 + results separated for above unit operations and for

weight of API/surrogate

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Statistical Analysis Tool used

IHSTAT®

– From AIHA Exposure Assessment Committee

IHData Analyst® (Bayesian Data Analysis)

Results for the unit operations were entered

Results were separated for weight range

95th%tile point estimate and GSD were determine

Lognormal distribution was determined

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Results and preliminary

conclusions – Qualifiers

The results are indicative and not confirmative

The conclusion from the results and lessons learned are

also indicative and not confirmative

Additional study is needed

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Personal exposure: Laboratory Scale

weighing in VBSE

Sample size: 10

Range of results: < 0.04 – 0.41 μg/m3

Sample Duration: 27 - 34 Minutes

Sample Weight: < 1 gram

GSD: 2.59

95th%ile – 1.57 μg/m3

Lognormal distribution hypothesis is

not rejected

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Personal exposure: Laboratory

weighing- no exposure controls

Sample size: 12

Range of results: 0.078 – 3.84 μg/m3

Sample Duration: 5 – 15 minutes

Sample Weight: < 1 gram

GSD – 4.48

95th%ile – 4.21 μg/m3

Lognormal distribution hypothesis is

not rejected

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Comparison of laboratory scale weighing

results

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Lessons Learned-Laboratory

Weighing

Initial Indication – For < grams of weighing

– OEB 5 (< ug/m3) and low OEB 4 (>1 ug/m3 and < 10 ug/m3)

compounds may require isolator

– VBE could be used for OEB 4 compounds coupled with sound

work-practices and PPE

Work-practices contributing to high exposures

– Using brush to clean surfaces

– Removing API container and other tools out without wipe

cleaning and without double plastic bags

All size and types of enclosures are used – use only

VBSE that meets specifications

– HEPA filter

– Port for removal of waste

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Personal exposure: Dispensing inside Isolator

(Weight Range 20 Kg – 40 Kg)

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Sample size: 16

Range of results: 0.025 μg/m3 –

4.6 μg/m3

Sample Duration: 30 – 60

minutes

Sample Weight : 20 – 40 Kg’s

GSD: 4.3

95th%ile exposure: 3.15 μg/m3

Lognormal distribution

hypothesis is not rejected

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Between the two glove ports of main dispensing

chamber (Weight range: 20 – 40 Kg)

Sample size: 9

Range of results: < 0.004 μg/m3

– 0.58 μg/m3

Sample Duration: 30 – 60

minutes

Sample Weight : 20 – 40 Kg

GSD: 3.84

95th%ile: 1.62 μg/m3

Lognormal distribution

hypothesis is not rejected

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Adjacent to RTP/Pass box (Weight range: 20

Kg – 40 Kg)

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Sample size: 18

Range of results: 0.055

μg/m3 – 2.43 μg/m3

Sample Duration: 30 – 60

minutes

Sample Weight : 20 – 40

Kg

GSD: 2.9

95th%ile: 1.88 μg/m3

Lognormal distribution

hypothesis is not rejected

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95th%ile for Dispensing inside Isolator (for

weight range of 20-40 Kg)

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Lessons Learned-Isolator

Do not assume exposure will be below OEB 4-5 APIs as

isolator is used.

Best of isolator would not reduce exposures if work

practices are not followed:

– API container when received has no contamination outside?

– In double plastic bags?

– Isolator integrity test before being used?

– Make-shift or real isolator?

– Disposable spatula and tools used? Wiped and in double plastic

bags before removing?

Develop detailed SOP on selecting, validating and using

isolator 21

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Personal Exposure: Charging/Discharging

using SBV (15 Kg – 60 Kg)

Sample size: 21

Results range: 0.028 μg/m3 - 4.26

μg/m3

Sample Duration: 30 – 90

minutes

Sample Weight: 15 kg – 60 kg

GSD : 4.17

95th %ile : 7.69 μg/m3

Lognormal distribution hypothesis is

not rejected

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Area Sample: Charging (weight range: 15 Kg –

60 Kg)

Sample size: 44

Results range: 0.032 – 21.6 μg/m3

Sample Duration: 30 – 90 minutes

Sample Weight 15 kg – 60 kg

GSD: 3.7

95th %ile: 3.53 μg/m3

Lognormal distribution hypothesis is

not rejected

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95th %ile results: Charging with SBV

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Lessons Learned - SBV

Don not assume installation of SBV will reduce

particulate emissions below OEB 4/5 OELs.

Selection, installation, use/misuse and maintenance of

SBV resulted in to high area concentrations

Carefully select supplier – initial cost may be high – long

term cost savings and exposure reduction benefits could

be significant

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Personal exposure: API Dispensing Inside

LFB (Weight: 500 grams – 1.5 kg )

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Sample size: 14

Results range: 0.077 μg/m3 - 128

μg/m3

Sample Duration: 15 – 60 min.

Sample GSD : 7.09

95th %tile : 94 μg/m3

Lognormal distribution hypothesis is

not rejected

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Personal exposure: API QC sampling inside

LFB (60 grams) (results from single site)

Sample size: 14

Results range: 0.108 μg/m3 –

15.9 μg/m3

Sample Duration: 15 – 30

minutes

GSD : 5.11

95th %ile: 21.1 μg/m3

Lognormal distribution

hypothesis is not rejected

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Personal exposure: API QC sampling inside

LFB (10-100 grams) – Multiple site data

Sample size: 23

Results range: 0.108 μg/m3 –

196 μg/m3

Sample Duration: 15 – 30

minutes

GSD : 8.05

95th %ile: 147 μg/m3

Lognormal distribution

hypothesis is not rejected

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Lessons Learned during

Dispensing/QC sampling under LFB

Focus on QC sampling same or even more than weighing and

dispensing

– Although API weight sampled is much lower than

weighing/dispensing, exposure is likely to be high

– Opening of containers for sampling – opening and closing of poly

bag and breathing zone near bags during QC sampling

– Standardization of exposure controls (LFB) is important

What pharma IH community believed is confirmed

– API exposure is not likely to be below < 50 μg/m3 during

weighing/dispensing in LFB

– Work practices significantly contribute to higher exposures

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Summary: 95th %ile personal exposure results

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Summary

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Limited sampling results analysis of the selected unit operations

identified:

– Personal exposure levels likely to occur

Additional data analysis and professional judgement would assist in

implementing controls and work-practices that would reduce

exposure below target levels

Add required data collection

– Sample weight

– Name/brand name/picture of controls

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Summary

PPE and RPE are standardized across all pharma sites for

some companies

– Same approach is needed for pharma containment

equipment also

Installation of equipment is not enough; SOPs, training

and maintenance are even more critical

Participate in exposure control selection process

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Plans

Invite IHs from other companies and form a group

Conduct similar data analyses with larger sample size

Address lessons learned from this limited study

– Weight range

– Specific details on engineering controls

Peer review

Publish

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Recognition

Terry Lane from Merck for review

Perry Logan for insights on analysis using BDA tool

Current and previous ISS team who diligently conducted

exposure monitoring

Ankit Sharma, Gopal and Prasanth from ISS who

complied and summarized results

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Volunteers participate in

rigorous study? Publication of

papers?

Thank you

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