1. Flexible Containment Concepts in Real Application
Jon Gast
Steven Meszaros
PSG 2009

2. PSC Guideline Presentation Overview
RBEC History
Motivation
Scope
Strategy
Expectations
Gap Analysis & RBEC Checklists
Fixed Containment
Flexible Containment Solutions 2

3. PSC Guideline History OC Technical Guidelines - 1994
RBEC Guideline -1998, revised 2001
RBEC Interpretation Guideline
PSC Task Force 2003
PSC Guideline – EHS Policy 404
IH Policy 401
Containment Technology Matrix (CTM) – 2009 3

4. PSC Guideline: Motivation
Regulatory Requirements:
API Product Cross Contamination
Worker Health & Safety
Environmental – Air, Water & Waste - PNAEELs
Third Party Contractual Obligations & Liability
cGMP Harmonization - CS
OHC, OEGs and RBEC levels
Aligned with R&D & TO&PS Decision Gates 4

5. Historical PSC Risk Control Issues
Pre-RBEC Facility Designs & Equipment
Historical levels > 1,000 X OEG
Cross Contamination Potential
Pharmaceuticals In the Environment 5

6. Real Risks 6

7. PSC Guideline: Scope R&D API Manufacturing & Handling
Pharmaceutical Manufacturing
BioPharmaceutical Manufacturing
New Products Facilities and Areas
Renovated Facilities and Areas
Third Party Manufacturing
Requires project-specific RBEC Criteria interpretation - -The key is to design is to meet our OEG ! 7

8. Endorsement from TO&PS and R&D senior management
Rollout Strategy
Endorsement from TO&PS
and R&D senior management
Stakeholder meetings planned for:
TO&PS, R&D–CPD/PDC
GES, GSS, QA
Major Solid Dosage Sites
Key PSC manufacturing Sites 8

9. PSC Guideline: New Expectations
Responsibilities Defined
Timelines for Conformance Specified
cGMP Cross Contamination Harmonization of Engineering & EHS approaches
GAP Analysis
Short Term, Long Term Actions
Conformance Action Plans & Site Master Plans 9

10. RBEC: Risk Based Exposure Control
4-Tier Banding System
Aligned to OEG
Conforms to Pharmaceutical Industry
Hierarchy of Controls
Engineering Project Guidance
RBEC Criteria Tables
Containment Technology Matrix 10

11. PSC RBEC Criteria Table & Gap Checklist
Facility Design for Containment
Room & Work Surfaces
HVAC Systems
Local Exhaust Ventilation
Process Equipment
Unit Operations: milling, blending, sieving, etc.
Product Transfers
Maintenance & Cleaning
Medical Surveillance
Work Methods & SOPs
PPE & Respirators
Waste Containment & Disposal
cGMP & Regulatory conformance 11

12. PSC GAP Assessment
Facility Team: EHS, Engineering, management, and Quality Assurance.
RBEC Gap Checklist - For each API by area, process or unit operations.
RBEC 3 Gap Checklist
Facility:
Unit Operation / Area:
Prepared By:
Date:
Parameter
Criteria
PSC Gap
Actions
Priority
Yes No
S-M-L
Containment and Control of API Processing Area
No special containment or control strategies are required for handling or processing API.
cGMP requires that separate space be provided for the processing, manufacturing and laboratory testing.
cGMP requires space not be shared with non-API processing or laboratory functions (e.g., offices or maintenance operations); (i.e., cGMP for nutritionals and nutriceuticals). 12

13. API Dispensing: Containment13

14. New Technologies: Bin Blending14

15. Surrogate Testing Protocol Containment Technology Matrix
Real conditions
Assume sub-optimal technique
Worst case operator shift 15

16. PDC CONTAINMENT PROJECT
AN OVERVIEW 16

17. Facility: Airlocks Added17

18. Facility: Expansion of Process Areas18

19. Equipment Modifications/Containment Hardware
Flexible Containment Systems Summary
Process Equipment
Equipment Modifications/Containment Hardware
Tablet Press
SMI MiniPress MII
Mobile device support cart with integral enclosure attachment flange, bag-in canister, product staging table and external enclosure support frame
Korsh XL100 PRO
Press attachment flange, Bag-in canister on mobile stand with integral product staging table, Enclosure external support frame
Fluid Bed Gran
Glatt GPGC2
Cabinet attachment flange, Bag-in Canister mounted on left side filler plate, Enclosure external support frame
Extrusion
Nica E140
Cabinet attachment flange with rigid tray containment box, Bag-in canister on mobile stand with integral product staging table, Enclosure external support frame
Spheronization
Nica S450
Cabinet attachment flange, Bag-in canister mounted on enclosure external support frame
Coating Pan
O'Hara LC M
Cabinet attachment flange around product and/or cleaning door, Bag-in canister on mobile stand with integral product staging table, Enclosure external support frame
Blender
GlobePharma
Fluid Bed Drier
Strea 1 Pro
Column base and cabinet flanges for enclosure attachment, bag-in canister, utility pass through ports and external enclosure support frame
Wet Granulation
Procept Mi-Pro 1900
Vessel base with enclosure attachment flange, bag-in canister, utility pass through ports and external enclosure support frame
10 L collette standard high shear 
Granulator cabinet mounted enclosure attachment flange, Bag-in canister on mobile stand with integral product staging table, Enclosure external support frame
25 L collette high shear
Roller Compactor
Gerteis Mini-Pactor
Compactor cabinet mounted enclosure attachment flange, Bag-in canister on mobile stand with integral product staging table, Enclosure external support frame
Milling
LB Bohle Cone mill
Enclosure attachment canisters (two), Bag-in canisters (two) mounted on mobile stand with integral staging and collection container tables. 19

20. Flexible Containment Concept Designs
SMI Press
O-Hara Coater
LB Bohle Cone Mill
Korsch XL100 & De-duster
Gerteis Mini-Pactor
Glatt GPGC2
10L/25L Collette
In-Process Isolator
Nica E140
Nica S450
Strea 1 Pro
Note: Glove-ports in not shown in all concept sketches.
Blender and Mi-Pro & SMI system not shown 20

21. Transfer Systems
All the isolator systems provided with a Bag in/out canister to allow contained transfer in and out of materials. The canister is 11.73” internal diameter.
This canister also serves a duel purpose of allowing connection of the In-Process Isolator to them. Canisters are mounted at standard height to allow easy connection.
The only isolators that the In-Process isolator can not connect to directly are the Extruder and Spheronizer systems (due to height issues.). A connection can be made using a length continuous liner if it is required. 21

22. In-Process Isolator
The In-Process Isolator is a general purpose piece of equipment designed to allow any number of tasks to be carried out. It can be used independently or connected to other flexible isolator systems as shown. 22

23. Typical Process Flow A Subdivision/Weighing:
In-process isolator can be directly connected to Granulator or Blender or used independently. Place materials & tools required into In-process isolator using pass in ports and carry out subdivision & weighing process. After process is complete pass materials directly to granulator or blender (if connected) or out via bag out port.
Granulation
Pass weighed materials/tools required into granulator isolator using pass in ports and process. After process is complete pass materials out via bag out port.
Blender
Pass weighed materials/tools required into blender isolator using pass in ports and process. After process is complete pass materials out via bag out port.
Mill
Pass weighed materials/tools required into Mill isolator using pass in ports and process. After process is complete pass materials out via bag out port. 23

24. Typical Process Flow A B Extruder/Spheronizer FBD
Pass materials/tools required into FBD isolator using pass in ports and process. After process is complete pass materials out via bag out port.
Extruder/Spheronizer
Pass materials/tools required into Extruder or Spheronizer isolator using pass in ports and process. After process is complete pass materials out via bag out port.
Roller Compaction
Pass materials/tools required into Roller Compactor isolator using pass in ports and process. After process is complete pass materials out via bag out port.
Mill
Pass materials/tools required into Mill isolator using pass in ports and process. After process is complete pass materials out via bag out port. B 24

25. Typical Process Flow B END Compression
Pass materials/tools required into Compression isolator using pass in ports and process. After process is complete pass materials out via bag out port. The In-process Isolator can be connected for testing of tablets and for use as a staging area for tools, etc.
Coating
Pass tablets/tools required into Coating isolator using pass in ports and process. After process is complete pass materials out via bag out port. The In-process Isolator can be connected for testing of tablets and for use as a staging area for tools, etc.
O-Hara Coater
END 25

26. Extruder & Spheronizer Design Progress
Flange Mock Up
Flanges Installed
Finalized 3D Design Drawing
Enclosure Installed December2008 26

27. Glatt GPCG1 Design Progress
Finalized 3D Design Drawing
Ergonomic & Flange Mock Up
Enclosure Installed December 2008 27

28. Korsch Design Progress
Finalized 3D Design Drawing
Enclosure Installed December 2008 28

29. Enclosure Installed December 2008
Procept & SMI Press
SMI Press Flange Installed
Enclosure Installed December 2008
Procept Final Design 29

30. Finalized 3D Design Drawing for Flange
Strea Design Progress
Finalized 3D Design Drawing for Flange
Enclosure Installed December 2008 30

31. Roller Compactor Design Progress
Finalized Design Concept Final Assembly Shipped to Newbridge December 2008
Gerteis Mini-Pactor 31

32. Finalized 3D Design Drawing
Bohle BTS-100 Cone Mill
Finalized 3D Design Drawing
Enclosure Installed December 2008 32

33. Collette UltimaGral 10 – 25 Liter
Finalized 3D Design Drawing
Enclosure Installed December 2008 33

34. Installation Training
Training Carried Out January 2009 34