Risk-MaPP A cGMP Driver for Contained Equipment and Facility

Report
Paul Richards
CRB Consulting Engineers
PharmaForum 2011 - Portland, OR
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I am not an Industrial Hygienist
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I am a Chemical Engineer who is PASSIONATE about containment
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Senior Process Engineer for CRB Consulting Engineers
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23+ years in chemical and pharmaceutical industries
◦ Formerly Sr. Principal Engineer with Pfizer (11+ years)
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Extensive capital project experience in API and OSD manufacturing
facilities
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Designed, installed, and tested many successful containment systems
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Steering Committee - ISPE Containment CoP
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Board of Directors – ISPE New England Chapter
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BS Chemical Engineering / MS Management
PharmaForum 2011 - Portland, OR
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What is Risk-MaPP
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How Risk-MaPP relates to Containment
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Practical solutions
PharmaForum 2011 - Portland, OR
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A guide to managing risks
associated with cross contamination
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ISPE Baseline Pharmaceutical
Engineering Guide
◦ Rolled out in Fall of 2010
◦ Six years in development
◦ FDA and EMA reviewed and approved
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“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
 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
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Protecting the PATIENT through
quality systems to manage the
risk of cross contamination
PharmaForum 2011 - Portland, OR
PharmaForum 2011 - Portland, OR
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Mix-up
◦ Cross contamination by using wrong API, excipients,
product contact materials, equipment, etc…
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Equipment Retention / Residue Carryover
◦ Material that remains in product contact after cleaning due
to failure or inadequate cleaning
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Mechanical Transfer
◦ Particulate transfer on clothing/feet from operators and
equipment alternating between 2 or more processing areas
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Airborne Transfer
◦ Cross contamination via airborne migration of particulates
PharmaForum 2011 - Portland, OR
PharmaForum 2011 - Portland, OR
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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?
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How do you validate containment if it is a
cGMP control?
PharmaForum 2011 - Portland, OR
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Sterile Manufacturing
◦ RABS
◦ Isolators
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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
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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
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Clean to set limits
◦ Base limits on science, risk assessment, statistical
analysis
◦ Cleaning validation
◦ Equipment designed for CIP
◦ On-line monitoring / PAT
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Disposable product contact parts
Dedicated product contact parts
PharmaForum 2011 - Portland, OR
PharmaForum 2011 - Portland, OR
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Limit transfer of compounds between suites
◦ ie. High Shear Granulation, Milling, and Drying in same suite
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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
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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
• 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
PharmaForum 2011 - Portland, OR
PharmaForum 2011 - Portland, OR
OEB I
OEB II
OEB III
OEB IV
OEB V
OEL (μg/m3)
10,000
1,000
100
10
50
1
0.1
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)
0.01
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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
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La Calhene
Applied Containment Engineering
Central Research Labs
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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
Primary Vendors
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GEA Buck Valve
Charge Point
Glatt
Andocksysteme
Types of Split Butterfly Valves
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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
PharmaForum 2011 - Portland, OR
PharmaForum 2011 - Portland, OR
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Perform risk assessment to identify steps and controls,
prioritize level of risk, and determine corrective actions
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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
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Multiply each factor for a resulting risk priority number (RPN)
◦ S x O x D = RPN
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Set limits for RPNs
◦ Acceptable
◦ Investigate and remedy
◦ Requires immediate attention
PharmaForum 2011 - Portland, OR
PharmaForum 2011 - Portland, OR
PharmaForum 2011 - Portland, OR
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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”
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There are many common engineering controls to reduce risks
of potential cross contamination and operator exposure
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Understand and document your risks and your controls
PharmaForum 2011 - Portland, OR
PharmaForum 2011 - Portland, OR

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