Risk- MaPP A cGMP Driver for Contained Equipment and Facility Design Risk -Based Ma nufacture of P harmaceutical P

1. Risk-MaPPA cGMP Driver for Contained Equipment and Facility DesignRisk-Based Manufactureof Pharmaceutical Products Paul Richards CRB Consulting Engineers PharmaForum 2011 - Portland, OR

2. Who am I? • I am not an Industrial Hygienist • I am a Chemical Engineer who is PASSIONATE about containment • Senior Process Engineer for CRB Consulting Engineers • 23+ years in chemical and pharmaceutical industries • Formerly Sr. Principal Engineer with Pfizer (11+ years) • Extensive capital project experience in API and OSD manufacturing facilities • Designed, installed, and tested many successful containment systems • Steering Committee - ISPE Containment CoP • Board of Directors – ISPE New England Chapter • BS Chemical Engineering / MS Management PharmaForum 2011 - Portland, OR

3. Topics of Discussion • What is Risk-MaPP • How Risk-MaPP relates to Containment • Practical solutions PharmaForum 2011 - Portland, OR

4. What is Risk-MaPP? • A guide to managing risks associated with cross contamination • ISPE Baseline Pharmaceutical Engineering Guide • Rolled out in Fall of 2010 • Six years in development • FDA and EMA reviewed and approved • “meant to assist pharmaceutical manufacturers in the design and construction of new and renovated facilities that are required to comply with the requirements of the US FDA.” PharmaForum 2011 - Portland, OR

5. Intent of Risk-MaPP • Risk-MaPP provides a scientific risk-based approach, based on ICH Q9, to manage the risk of cross contamination in order to achieve and maintain an appropriate balance between product quality and operator safety. • Focus on science based risk analysis to design and operation versus emotional reactions PharmaForum 2011 - Portland, OR

6. cGMP Focus of Risk-MaPP • Protecting the PATIENTthrough quality systems to manage the risk of cross contamination PharmaForum 2011 - Portland, OR

7. FDA Focus on Sound Risk Assessments PharmaForum 2011 - Portland, OR

8. Exposure Routes • Mix-up • Cross contamination by using wrong API, excipients, product contact materials, equipment, etc… • Equipment Retention / Residue Carryover • Material that remains in product contact after cleaning due to failure or inadequate cleaning • Mechanical Transfer • Particulate transfer on clothing/feet from operators and equipment alternating between 2 or more processing areas • Airborne Transfer • Cross contamination via airborne migration of particulates PharmaForum 2011 - Portland, OR

9. Proper Control is Critical PharmaForum 2011 - Portland, OR

10. Risk-MaPP and Containment • cGMP versus Industrial Hygiene • Patient versus the Operator • Different exposure routes / pathways • IH monitoring targeted at worker exposure not cross contamination • How do you meaningfully correlate IH data from an air sampling pump and filter? • How do you validate containment if it is a cGMP control? PharmaForum 2011 - Portland, OR

11. The Relationship Exists between cGMP and Containment • Sterile Manufacturing • RABS • Isolators • Highly hazardous (potent) compounds • Containment is effective to protect workers as well as to reduce risks of cross contamination via mechanical transfer or airborne transfer PharmaForum 2011 - Portland, OR

12. Reducing the Risk of Cross Contamination from Mix-up • Redundant electronic verification of materials • Redundant manual checks • Color coding • Bar coding and RFID of materials & equipment • Locked cages to store APIs with chain of custody • Transfer and utility connect technologies that are unique to the process • Process Analytical Technologies (ie. NIR) • Separate dispensary areas • Separate raw material staging areas PharmaForum 2011 - Portland, OR

13. Reducing the Risk of Cross Contamination from Residue Carryover • Clean to set limits • Base limits on science, risk assessment, statistical analysis • Cleaning validation • Equipment designed for CIP • On-line monitoring / PAT • Disposable product contact parts • Dedicated product contact parts PharmaForum 2011 - Portland, OR

14. Health Based Cleaning Limit PharmaForum 2011 - Portland, OR

15. Reducing the Risk of Cross Contamination from Mechanical Transfer • Limit transfer of compounds between suites • ie. High Shear Granulation, Milling, and Drying in same suite • Segregate work areas to a single product • Contain at the Source • Close process systems • Room airflow • Airlocks • Gowning procedures • Wipe down protocols for mobile equipment • Clean mobile equipment in processing room • Misting showers • Cleaning bays with dirty / clean pass through PharmaForum 2011 - Portland, OR

16. Reducing the Risk of Cross Contamination from Airborne Transfer • Contain at the Source • Close process systems • Room airflow • Airlock separation to corridor • Gowning procedures • Wipe down protocols • Misting showers • Room differential pressures • High room air change rates PharmaForum 2011 - Portland, OR

17. Containment Design 101 • Contain at the source • Avoid technique dependant systems • Focus on transfer systems • Design below the OEL / ADE • Consider ergonomics, cleaning, sampling, waste, material compatibility • Provide redundancy / secondary containment • Engineer out the reliance on PPE

18. Containment at the SourceDispensing PharmaForum 2011 - Portland, OR

19. Avoid Technique Dependent Systems

20. Focus on Transfer SystemsThe Key to Success PharmaForum 2011 - Portland, OR

21. Typical Containment Levels OEB I OEB II OEB III OEB IV OEB V OEL (μg/m3) 1,000 100 10 1 0.1 0.01 10,000 50 Local exhaust ventilation Crossflow booth Downflow booth Cone Valve Split Butterfly Valves HicoFlex / EziDock CSV4 Split Butterfly Valves with air extraction Bag Technology Split Butterfly (Glatt SKS / Buck TC) Rapid Transfer Ports (RTPs)

22. Rapid Transfer Ports (RTPs) • Well proven in industry • Performance: < 0.1 μg/m3 • Consists of an alpha (active) port attached to an isolator and a beta (passive) port connected to the portable container • The beta is docked and locked to the alpha by rotation before the door can be opened • Requires an isolator • Vendors • La Calhene • Applied Containment Engineering • Central Research Labs

23. Rapid Transfer Ports (RTPs)

24. Rapid Transfer Port Demo

25. Rapid Access Port (RAP) • Same basic technology at RTP, but passive attaches to equipment • Active fitted with a purpose made glove bag • Active made in HDPE to keep light weight • Passive flange or bolted • Adapt passive with sight glass • Pressure cap provides 6 bar-g design • Active $12,000 • Passive $ 6,000 (SS) • Vendor – Heaton Green Containment

26. Rapid Access Port (RAP)

27. Split Butterfly Valves • Primary Vendors • GEA Buck Valve • Charge Point • Glatt • Andocksysteme • Types of Split Butterfly Valves • Standard • With air extraction shroud • Air or Liquid Wash systems • Pressure rated or not • Primary concern with split butterfly valves! • material on the faces of the valves after undocking

28. Split Butterfly Valves

29. Split Butterfly Valve Demo PharmaForum 2011 - Portland, OR

30. Flexible Solutions to Reduce Risk PharmaForum 2011 - Portland, OR

31. Risk AssessmentFailure Modes Effect Analysis (FMEA) • Perform risk assessment to identify steps and controls, prioritize level of risk, and determine corrective actions • FMEA format for risk assessment • Severity – the impact on the patient • Occurrence – how often this effect takes place • Detection – how easily the failure can be detected • Multiply each factor for a resulting risk priority number (RPN) • S x O x D = RPN • Set limits for RPNs • Acceptable • Investigate and remedy • Requires immediate attention PharmaForum 2011 - Portland, OR

32. FMEA Risk Scoring Example PharmaForum 2011 - Portland, OR

33. FMEA Example PharmaForum 2011 - Portland, OR

34. Summary • The FDA is on board with Risk-MaPP • The regulations have not changed, but the FDA will expect all manufacturers’ to “Show us your scientifically sound assessment” to prevent cross contamination and to “justify the level of controls” • There are many common engineering controls to reduce risks of potential cross contamination and operator exposure • Understand and document your risks and your controls PharmaForum 2011 - Portland, OR

35. Questions? PharmaForum 2011 - Portland, OR