Solving the Challenges of Containing an Existing Compression Process using Hard-wall and Flexible Containment (A Work in

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

3. 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. Introduction

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

6. 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 <10 μg/m3 (Potentially <1 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

7. 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).

8. 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 IBC’s 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

10. 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 SBV’s total compounding/compression).

12. 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

13. 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)

14. 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

15. 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

16. 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.

17. Conceptual Drawings

18. Conceptual Drawings

19. Conceptual Drawings

20. Conceptual Drawings

21. Mock-ups Cone with connection for drum liner Glove Ports Flow Control Valve

22. Mock-ups

23. Surrogate Testing of Mockups

24. Surrogate Testing Results - 1st Mock Up

25. 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

26. Sketches for Prototype

27. Manufacturing Drawings/Sketches for Prototype

28. Manufacturing Drawings for Prototype

29. Prototypes

30. Prototypes

31. Testing Short Video of Surrogate Testing Played at This Point

32. Surrogate Testing Results – 2nd Mock Up

33. 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) - couldn’t see through it Leaks in the glazing panels on isolator Surrogate Testing Results - 2nd Mock Up

34. 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

35. 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

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

37. 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

38. 3rd Mock Up IH Testing Results Placebo contained 67.4% lactose

39. 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 can’t 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.

40. 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

41. 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

42. 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)

43. 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% Compression Containment Cost Considerations

44. 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 <10µ/m3 with the potential for 1 µg/m3 should be readily achieved for final product

45. Any Questions? Contact Details Robert Mc Cafferty North American IH Manager Teva Pharmaceuticals, Inc. Tel: 201 930 3411Fax: 201-930-3316Mobile: 201-312-7522 E-mail: rmccafferty@barrlabs.com Hari Floura President Floura LLC. Tel: 609-259-7136Fax: 609-249-5541Mobile: 908-896-1698 E-mail: hari@flourallc.com