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2008 PharmaConsult Us Inc.

Presentation to

Occupational and Patient Protection from Exposure

© 2009 PharmaConsult Us Inc.

Agenda Powder Explosion

• The Specialists View, fear is the key• A simpler approach• West and TWA 800 as case studies• The FAA solution to the same problem the

Pharmaceutical industry faces• Examples

Flexible versus Rigid the never ending debate• Disposable• Reusable


Dust explosion kills six, destroys West Pharmaceutical Services plant, Kinston, NC, Jan. 29, 2003.


BasicsFor a fire or an explosion to occur, three conditions must be met:

A combustible substance must be present An oxidizing agent must be present; usually this is atmospheric oxygen A source of ignition of sufficient energy must be active.

If and only if these three conditions prevail at the same time, fire or explosion are possible.Eliminate one of the above and explosion cannot occur


A Dust Explosion

Confinement

Oxygen

Ignition

Combustibility Dispersion


Explosion Pentagon

Oxygen to support Combustion normally atmospheric 2% O2 for Solvent 5% for Dust

Ignition could be electrostatic discharge, Electrical Equipment should be rated if removal of ignition is the chosen route

Dispersion Requires energy to produce cloud, (could be initiating explosion) (West)

Confinement to achieve concentration could use ventilation to achieve dilution below concentration

Combustible has to be combustible but low mass high area dusts are combustible (Aluminum)


Make it easy; Loose the Oxygen

TWA 800 The crash killed all 230 people on board the flight from New York to Paris. NTSB officials

hope that the hearings may help clarify the circumstances surrounding one of the most

mysterious air disasters in US history


Explosion Pentagon TWA 800

Oxygen to support Combustion normally atmospheric 2% O2 for Solvent 5% for Dust

Ignition Electrical, chafed wiring Dispersion Requires energy sat in hot sun

for 4 hours. Confinement Closed fuel tank Combustible aviation fuel heated by sun


Solution Nitrogen by Filtration

2008 PharmaConsult Us Inc.

Examples of Inerted Isolators


Key Features Low nitrogen flow rate 1-2 ACH O2 Sensor Isolates electrical supply when

out of range and alarms Room is not involved not rated O2 Sensor must be protected from

environmental O2 use closed loop peristaltic or venturi vacuum.

Inertion is very dry


Small scale API in an Isolator


Results

GENERAL AREA BACKGROUND SAMPLES – Set No. 1(Collected while Kilo Lab #1 was occupied, before the original containers

of naproxen sodium were transferred from the Stokes Vacuum Oven to the QC Lab)b

Start/ Finish

grams m3

Kilo Lab #1 (Room 122)Collected on the front of the Isolator, outside of Chamber #1, between

the right and center Isolator panels, 89 inches above the floor.

1018/1125 <0.003.7

Kilo Lab #1 (Room 122)Collected on the rear of the Isolator, outside of Chamber #1, between

the left and center Isolator panels, 87 inches above the floor.

1018/1125 <0.003.7

Main Corridor, outside of Kilo Lab #1Collected at the top of Electrical Panel LRP-2, 68 inches above the

floor and 45 inches to the right of the entrance door to the Lab.

1020/1127 <0.003.7


Results

GENERAL AREA BACKGROUND SAMPLES – Set No. 2(Collected while Kilo Lab #1 was primarily unoccupied, after the original containers

of naproxen sodium were transferred from the Stokes Oven to the QC Lab)c

grams m3

Kilo Lab #1 (Room 122)Collected on the front of the Isolator, outside of Chamber #1,

between the right and center Isolator panels, 89 inches above the floor.

1150/1313 0.0071

Kilo Lab #1 (Room 122)Collected on the rear of the Isolator, outside of Chamber #1,

between the left and center Isolator panels, 87 inches above the floor.

1150/1313 0.015

Main Corridor, outside of Kilo Lab #1Collected at the top of Electrical Panel LRP-2, 68 inches above

the floor and 45 inches to the right of the entrance door to the Lab.

1152/1315 0.014

Start/finish


Results

GENERAL AREA BACKGROUND SAMPLES – Set No. 3(Collected throughout the three iterations of the naproxen sodium handling

procedures)

grams m3

Kilo Lab #1 (Room 122)Collected on the front of the Isolator, outside of Chamber #1,

between the right and center Isolator panels, 89 inches above the floor.

1344/1601 <0.001.8

Kilo Lab #1 (Room 122)Collected on the rear of the Isolator, outside of Chamber #1,

between the left and center Isolator panels, 87 inches above the floor.

1344/1601 <0.001.8

Main Corridor, outside of Kilo Lab #1Collected at the top of Electrical Panel LRP-2, 68 inches above the

floor and 45 inches to the right of the entrance door to the Lab.

1345/1603 <0.001.8

Start/finish


Results

GENERAL AREA SAMPLE – INSIDE OF THE ISOLATOR(Collected throughout the three iterations of the naproxen sodium handling procedures)

grams m3

Isolator – Chamber #2Collected on the corner of the oven section,

approximately 15 inches above the inside floor of the isolator.

1346/1605 6,400

OPERATORS’ BREATHING ZONE SAMPLES (Shift Equivalence Exposures)(Collected throughout the three iterations of the naproxen sodium handling procedures)

1 1347/15151532/1600

0.018 TWA 0.004.35

2 1347/15161532/1600

0.026 TWA 0.006.33

Start/finish


Oven Isolator


General Purpose Isolator

This isolator has two baffle plates at either end and a top 12” TC for Vacuum transfer, it also has planks for general purpose uses and for staging. This isolator is an adaptable workhorse that has even been adapted to control slave isolators attached to it


Mill


Filtration and Vacuum Tray Drying with 500 gallon Vessels in a Safelab unit


Formulation


Equipment Integration Development Scale in a Box


Bench Top Chemistry Dilution


200 L High Shear Granulator Issues

• Charging• Layering• Sampling• Heel retention• Wet Milling• Cleaning• Ergonomics


The Flexible Solution GPCG 5

The original concept was a sketch drawing showing the GPCG, mill and granulator

An ergonomic model was built to evaluate the issues, and the process was run. The cage was made from water pipe and the GPCG was modified so that the bowl slid out without using the cart.

Concept to reality 6 weeks


Flexible Film SolutionActual Performance Using API

Summary of Industrial Hygiene Monitoring ResultsJanuary 5 and 6, 2005

Activity (ug/m3) Av. Max.Granulation 0.013 0.010 0.019

0.0190.0080.0060.0060.008

Fluid Bed Drying 0.017 0.022 0.0700.0700.0110.0110.0110.012

Milling 0.590 0.284 0.6600.3900.6600.0170.0200.025

Decontamination of the glovebag 1.300 1.433 1.800

1.2001.800

Cleaning equipment 1.100 4.267 10.000

The bag project took 6 weeks and showed that in normal operation the bag provided reasonable protection, The problem came in disassembling the bag and cleaning the equipment, because the bag had limited transfer capability and because cleaning a flexible film is difficult and finally because of the size and weight of the objects to be cleaned the results were not a good as expected and so the decision to provide a fully engineered rigid solution was made Personal Samplers


“Hot” Replacement of the Bagging Tube


Bagging Out

Object topass in

Object topass Out

Object topass in

Cut between Crimps with Pipe cutters Isolator Boundary

Isolator BoundaryIsolator Boundary

Isolator Boundary

Isolator Boundary

1 The Start Poition

2The Object to pass Out is placed

3The Lay flat is extended

4The Pass out items are pushed out. Two crimps are placed and a pipe cutter is used to cut the pass out away

6The Bagging tube is ready for the next event

Bagging Out Technique


Bagging In

Object topass in

Object topass in

Object topass in

Waste from bag in and any other waste

Cut between Crimps with Pipe cutters

Isolator Boundary

1 The Start Poition

2The Object to pass In is placed

3The Lay flat is extended to allow a crimp to be placed

4 The crimp on the isolator side is cut away allowing the object to pass in

Isolator Boundary Isolator Boundary

Isolator Boundary

Isolator Boundary

Isolator Boundary

5 The waste tube and any other wastes are compressed and pushed out. Two crimps are placed and the waste is bagged away

6The Bagging tube is ready for the next event

Bagging In Technique


Crimp and Cut Uses readily available

tools, Uses readily available

lay flat tube, the basic material of PE Bags

Effective and cheap


Rapid Transfer Port/ Bag

RTP port and bag Can be a bagging ring to

allow canister or bag transfer Tool shown is used to open a

Beta port without an Alpha port, can only be used with a clean bag or in an emergency with the correct precautions


FIBC Transfer


FIBC Transfer Issues Cost of Bag Port recovery, or greater cost with disposable port Prevention of powder on seals Can be Split Butterfly valve, but the cost is higher

for the passive and recovery is essential, there are no disposable SBV’s currently

Consider Hycoflex


Laboratory Disposable Canopy Isolator

Canopy about $ 1,000 but would be cheaper in volume

Airflow issues due to disposable filters

User acceptance issues Performance was below 0.1

mcg/m3/duration


Access to V Blender

Development Batch 5 cu ft PK blender Mobile platform and

disposable bag isolator Tubular removable frame Lay flat tube connection to

manways $ 7,000 and 4 Weeks Stellar performance below

limit of detection


5 cu ft V blender

Sampling left and right Front and back Top, Middle Bottom 3 Sample sets 30

samples 3 Batches Mock up adapter and

bagging ring on V bleneder, added to an existig 5 cu ft PK Blender


Tablet Press, De-Dust and Test


Press in a Bag

Occupational exposure data showed that the active bonded to the excipient so successfully that an API with an OEL of 0.07mcg/m3/10hrs. Resulted in exposures without the bag below the required limit

The bag was dispensed with.


Development OSD in a Flexible Film


Laboratory Isolators


Issues with Flexible Film Solution

The air flow in the isolator was low due to the type of filter and the absence of an air handling system… It was tied to the dust collector

Was prone to the high physical demands caused by the handling requirement

Handling was an issue even with a slide for the FBD Bowl

Accidental over pressure on the bearing caused explosive discharge from the granulator

The IH results were good in operation but during cleaning and removal but the risks were considered too high


Baffle Plate Equipment Multi Use Isolators


Occupational v Product ExposureRisks and Opportunities

Breakdown the EH&S/ Quality and Compliance Silos

Great opportunity for CIH to leverage into a position that is core Quality

Differences between Occupational and Product Exposure data

Multi product high hazard facilities will have to conduct risk assessment

Current study using surrogate and placebo batches OSD and Parenteral formats and typical IH sampling at the same time to address the perception of cross contamination

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