Containment 101

1
Presenters Hari Floura Robert Mc Cafferty
December 2009
Solving the Challenges of Containing an Existing
Compression Process using Hard-wall and Flexible
Containment (A Work in Progress!)
2
Presentation Plan

• Project History
• Existing Conditions
• Challenges
• Goals and Criteria
• Potential Solutions Issues
• Charging
• Compression
• Product Reconcilliation
• Drawings, Pictures/Video
• Mock Up Testing and Results
• Summary and lessons Learned
• Next Steps
• Questions

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Introduction

• Project Initiated at Barr, Pomona, NY Facility in
  May 2008.
• Stakeholders Involved To Discuss Need For
  Containment Of Compression Processes at the Site.
  
• The Following Slides Summarize the discussion on
  Compression Machine Containment Retrofit Design
  Project.

4
Existing Process Conditions

• Charging and compression of potent compounds in 4
  separate manufacturing suites (Many Legacy
  Processes)
• Post hoists fitted with drum cones are used to
  charge compression machines
• Double lined drums are used for product
  containers
• PAPR/PPE/LEV/Work practice controls and Muller
  caps are used to provide operator protection
• The maximum concentration of API in the compounds
  to be compressed 2.5
• OEL for API 40 Nanograms Per Meter Cubed (Eight
  Hour Time Weighted Average)
• Similar processes equipment at other sites

5
Challenges

• Hand charging of compression machine feed hopper
  prior to connection of the drum cone
• Connection of product drum to compression machine
  feed hopper
• Drum changes
• Trouble shooting during the process
• Cleaning of compression machine and integrated
  De-duster/product recovery and associated
  containment solution
• Equipment dimensions/layout varies in each
  manufacturing suite

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Project Goal Criteria

• Goal Implement most effective containment
  solution with minimal cost and least impact to
  production schedules/productivity, and validation
  
• Criteria
• Reduce operator exposure to lt10 µg/m3
  (Potentially lt1 µg/m3) Per Meter Cubed (Eight
  Hour Time Weighted Average)
• Use existing equipment with minimal modifications
• Able to be reversible for non-potent compounds
• Easily transferable
• all manufacturing suites and other sites

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Project Goals Criteria

• Criteria
• Cost of implementation to be low-moderate
• Operability of solution must allow the operators
  to continue utilizing PPE procedures if necessary
• Minimal impact to operability and clean-ability
  of equipment/process
• Applicable in Compounding as well as compression
  (drum lift glove box).

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Solutions Discussed - Charging

• Use Split Butterfly Valves with drum liners to
  charge press
• Issues
• High cost to implement - large number of valves
  required
• Additional post hoist modifications needed for
  charging of drums/containers fitted with split
  valves and drum liners
• Cleaning and storage of containers (If IBCs Used
  instead of lined drums)
• Decision Discard
• Buy new contained tablet press
• Issues
• New Contained Press would be as well as
  validation costs to transfer to new presses for
  existing processes.
• Decision Discard

9
Solutions Discussed - Charging

• Use flexible split valve to charge compression
  machine
• Issues
• High operational cost
• Unsatisfactory experience with drum sized
  containers
• Decision Discard

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Solutions Discussed - Charging

• Use bag over bag grooved contained transfer
  system to charge
• Issues
• Very high capital operational cost
• Safety concerns of operators working at an
  elevated height to make connections
• Decision Discard
• Integrate hard or soft wall isolator to feed port
• Issues
• Ergonomics and safety concerns of operators
  working at an elevated height to interface drums
  and charge machine
• Potential requirement for major post hoist
  modifications
• Decision Discard

11
Preferred Solution - Charging
Split Butterfly Valve technology was the
preferred solution. To reduce split valve
numbers, a hard wall isolator system interfaced
with the post hoist, using bag in bag out, to
allow interfacing of a drum. This solution would
require only one active and one passive valve.
(Approximately an 80 reduction in the number and
cost for SBVs total compounding/compression).
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Solutions Discussed Compression

• Hard Wall Containment Enclose machine in an
  isolator.
• Issues High cost, spatial requirements
  ergonomics
• Fit glove ports to access doors
• Issues Safety and ergonomics
• Investigate further

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Solutions Discussed Compression Containment

• Roll Up Rigid Isolator with flange connector to
  doors
• Issues Capital cost, cleaning, storage,
  ergonomics
• Soft Wall Containment Enclose Machine in an
  Isolator or hybrid replace doors with soft wall
  containment.
• Issues No Major Issues Flexible containment
  already successfully used at site. (Operational
  costs, disposal)

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Solutions Discussed Product Reconcilliation

• Change vacuum bags in soft wall or rigid
  isolators or down flow booths
• Issues Capital Cost, space
• Use better collection bags with 0.2 micron
  filters as well as police filter in front of HEPA
  
• Change using glove bag technology
• Use safe change disposable vacuum cartridges
• Issues Consumable costs and capital costs of
  the vacuums

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Solutions Discussed Product Reconcilliation

• Connect dust collector pot with Lay Flat Tubing
  Using Crimp Cut or SBV for desired containment
• Issues Cost, Space, HVAC capacity
• Already in use at some sites

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Conclusion of Discussion

• Based on Stated Goal and Criteria Floura LLC was
  tasked with Design and Development of The
  Following Solutions Hard wall drum lift isolator
  to allow bag in/out connection to split valve
• Flexible enclosure interfaced to compression
  machine doors
• Drum lift isolator to allow bag in/out connection
  to split valve.

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Conceptual Drawings
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Conceptual Drawings
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Conceptual Drawings
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Conceptual Drawings
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Mock-ups
Cone with connection for drum liner
Glove Ports
Flow Control Valve
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Mock-ups
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Surrogate Testing of Mockups
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Surrogate Testing Results - 1st Mock Up
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Conclusion of 1st Mock Up Testing

• Update design to incorporate operator comments
• Based on the experience test results, a report
  was prepared to document these results and the
  next steps
• Prepare Manufacturing drawings and specification
  drawings and issue for bid

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Sketches for Prototype
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Manufacturing Drawings/Sketches for Prototype
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Manufacturing Drawings for Prototype
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Prototypes
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Prototypes
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Testing
Short Video of Surrogate Testing Played at This
Point
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Surrogate Testing Results 2nd Mock Up
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Surrogate Testing Results - 2nd Mock Up

• Higher concentrations during sampling were caused
  by
• Holes in inner liner operator tore product bag
  with stainless steel scoop when subdividing
  lactose drums (prior to test start)
• Bungee cord used to secure outer liner on post
  hoist isolator failed
• Operator removed tablet reject verification bag
  (fitted to tablet reject chute) - couldnt see
  through it
• Leaks in the glazing panels on isolator

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Lessons Learned

• Drum Connecting Isolator
• Elastic cords not an effective solution to hold
  liners in position. Band clamp system as
  previously used will provide better liner seal
• Vision into the enclosure needs to be improved
• Addition/larger vent filter required to prevent
  pressurization of isolator
• Glazing panels to be caulked gasket installed by
  vendor was not effective

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Lessons Learned

• Flexible Enclosures
• Zippers on pass-in port not robust design needs
  improvement or substitution
• Integrated bungee would reduce setup time/need
  for 2 operators.
• Replace Allen screws on compression machine with
  hand or thumb wheels quick disconnects
• Improve reject verification, de-duster and
  finished tablet hopper containment/access

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Drum Lift Glove Box with SBV Contained
Kikusui Tablet Press During 3rd Mock Up
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3rd Mock Up

• Mock up ran for about 300 minutes
• 2 drum changes were performed as is reasonably
  typical for a shift
• 1 drum was full (about 80kg) and another nearly
  empty (about 14kg)
• An upper job was also initiated
• Feed frame was removed as well as several punches
• Most lessons learned from the 2nd mock up were
  incorporated into this trial
• Some were not due to cost constraints for the
  trial but will be incorporated into final design

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3rd Mock Up IH Testing Results
Placebo contained 67.4 lactose
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IH Sample Results Discussion

• The bag that was attached to the tablet de-duster
  came off and some tablets spilled on the floor
• They were vacuumed up immediately
• The operator tore a thumb in the tablet press
  glove box while removing a thumb screw
• The operator routinely uses latex and nitrile
  gloves for the same function and cant remember
  tearing those gloves ever before and they are
  much thinner gloves
• Some visible powder was observed on the SBV
  during disconnection
• Most likely more than usual as the drum was
  removed while full of powder.

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Lessons Learned from the 3rd Mock Up

• Drum Lift Glove Box Isolator
• Handling small quantities could be done in small
  drums or full drums with boxes in the bottom
• Not likely to happen but this will make it easier
  to reach
• Sealing the inner and outer bag is a 2 person job
• Clamps for both could make it a one person job
• The inner bag can be difficult to seal to the
  drum cone with a full drum of powder
• Use clamps to hold the bag out of the way on the
  bottom of the glove box instead of on the drum
  cone

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Lessons Learned from the 3rd Mock Up

• Tablet Press Isolator
• 2 glove ports are needed on the left side for
  cleaning
• Better access is needed for lower punch access
• May be a perfect place for a glove bag
• Design so feed frame slides instead of lifting
  out of the way
• Better ergonomically and reduces the front
  isolator door profile by 5 from over 13 ¾ to
  about 8 ¾
• Seal the upper glove box chamber to the die table
  so that both areas are separated
• Need to see where and how large the pass through
  needs to be based on the punch holder cases

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Current Status/Next Steps

• Drum lift Isolator and Compression Machine feed
  funnel design with lessons learned modifications
  has been sent out to bid
• Modify the tablet press door Isolator/glove ports
  design with lessons learned and perform ergonomic
  testing before finalizing the design and sending
  to bid.
• Make final decision regarding soft wall around
  existing doors or hybrid (some flexible with some
  rigid containment)
• Make improvements for containment/access for
  de-duster, rejects and finished tablets hopper
• Make business decision regarding product recovery
  solution
• Use cyclone with bag out collection or SBV
• Use contained HEPA vacuum (contained weighing/
  disposal)

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Compression Containment Cost Considerations

• Assuming each is just as effective from a
  containment and operational perspective a
  business decision needs to be made between the 2
  approaches
• Each tablet press produces about 200-250 batches
  per year
• Soft wall containment tablet press isolator is
  1300-1500 ea
• A batch campaign averages 5 batches per campaign
  so the average batch cost is 260-300
• Therefore the cost of consumables for the soft
  wall will run 52,000-75,000 per press per year
• Flanges and supports for the soft wall isolator
  can also be estimated at 5,000 per press
• Assuming a rigid isolator (glove box doors
  interlock upgrades) costs between 50,000-75,000
  per press
• 50k DPP 1.1-1.6 years, ROI 80-106, IRR 64-97
• 75k DPP 1.7-2.4 years, ROI 50-78, IRR 37-61
• Assuming 5,000 in consumables for rigid isolator
  hybrid
• 50k DPP 1.2-1.9 years, ROI 57-84, IRR 51-82
• 75k DPP 1.9-2.8 years, ROI 34-61, IRR 29-52

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Status on Goals/Objectives/Criteria

• We believe we have developed a concept for the
  most effective, least cost, least impact to
  manufacturing and validation solution for our
  processes (Met our target criteria)
• Need to implement lessons learned with tablet
  press isolator before finalizing design
• Finalize designs receive bids present to
  management for implementation
• Mock up testing shows IH target of lt10µ/m3 with
  the potential for 1 µg/m3 should be readily
  achieved for final product

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Any Questions?
Contact Details
Robert Mc Cafferty North American IH Manager
Teva Pharmaceuticals, Inc. Tel 201 930
3411Fax [phone]Mobile [phone] E-mail
rmccafferty_at_barrlabs.com
Hari Floura President Floura LLC. Tel
609-259-7136Fax [phone]Mobile
908-896-1698 E-mail hari_at_flourallc.com