1. Paul Richards CRB Consulting Engineers
Risk-MaPP A cGMP Driver for Contained Equipment and Facility Design Risk-Based Manufacture of Pharmaceutical Products
Paul Richards
CRB Consulting Engineers
PharmaForum 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 Portland, OR

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

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

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

8. Exposure Routes Mix-up Equipment Retention / Residue Carryover
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 Portland, OR

9. Proper Control is Critical
PharmaForum 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 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 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 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 Portland, OR

14. Health Based Cleaning Limit
PharmaForum 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 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 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 Source Dispensing
PharmaForum Portland, OR

19. Avoid Technique Dependent Systems

20. Focus on Transfer Systems The Key to Success
PharmaForum Portland, OR

21. Typical Containment Levels
OEB I
OEB II
OEB III
OEB IV
OEB V
OEL (μg/m3)
10,000
1,000
100 50 10 1
0.1
0.01
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 Portland, OR

30. Flexible Solutions to Reduce Risk
PharmaForum Portland, OR

31. Risk Assessment Failure 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 Portland, OR

32. FMEA Risk Scoring Example
PharmaForum Portland, OR

33. FMEA Example
PharmaForum 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 Portland, OR

35. Questions?
PharmaForum Portland, OR