Regulatory Compliance for

Multi-Product Facilities
Barbara W. Unger
Don Hill & Associates Inc.,
317.582.1504
bwunger@midlink.com

Licensed Solely for Use in Conjunction with the 2002

ASME Bioprocess Technology Seminar
Copyright 2002, Barbara W. Unger, 1
Don Hill & Associates Inc.
 Topics
• Unique Characteristics of Biotech
Products
• Design Considerations
• Plant Systems
• Equipment
• Validation
– Master Plan
– Cleaning
• System Inspections
2
 Types of Multi-Use
• Multiple Products, Similar Stages of
Manufacture
• Single Product, Multiple Lots, Various
Stages of Manufacture
• Common Areas / Equipment for
Potentially Infectious vs. Inactivated
Process Streams
• Different Products, Campaign Basis

3
 Concerns for Multi-Use
• Contaminants Difficult to Identify /
Detect
– Adventitious Agents
• Known
• Unknown / Novel
– Product Stream Cross-Contamination
• Intermediates
• API
• Associated Impurities

4
 Concerns for Multi-Use
• Source of Contaminants
– Cell Lines (murine, human, other)
– Animal Sourced Raw Materials
– People
– People Moving Among Products
– Inadequate Cleaning
– Poorly Characterized Materials
• Research Products
• Early Development
• Contract Operations
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Characteristics of Biotechnology Products
• Derived from Living Organisms / Tissues
– Inherent Variability
– Adventitious Agents MULTIPLY
• Complex Molecules
– Large
– Heterogeneous “Family”
• Amino Acid Substitutions
• Variability in - Terminus
• Glycosylation
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Characteristics of Biotechnology Products

• Most Parenterals so, Aseptic Processing

• More Difficult to Assay / Characterize
– Immunogenicity
– Adverse Events
• Growth Promoting Conditions
– Mostly Aqueous Solvents
– Physiological pH
– Moderate to Cold Temperatures
– Minimal Stress / Shear / Organic Solvents
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Means of Establishing CONTROL

• Employ a Combination of:

– Procedural Controls
– Temporal Controls
– Facility Design Controls

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 Facility Design
• Identify Shared Features
– Room(s)
– Equipment; all or some?
– Services as glassware washing, autoclave, column
pouring
• Identify and Establish Flows
– Facility uniform and shoes
– Single Corridor vs.
– Clean and Return Corridors
• Evaluate Product Mix and Processes
– “flexibility” adds $$$$

9
 Design Considerations
Regulatory
• Building Restrictions
– Extraneous Infectious Agents (Plasma
Fractionators)
– Spore Forming Organisms
– Live Vaccine Processing
– Penicillin, Cephalosporins
– Consider High Potency Compounds
– Don’t Mix Pharmaceutical and non-
Pharmaceuticals in Same Facility / Equipment 10
 Design Considerations
• Smooth Cleanable Surfaces
– Impervious to Sanitizing Agents
– Sealed Joints
– Coved Corners
• Minimize Exposed Piping
• Room Classification
– If so, ante-rooms for gowning / de-gowning

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 Design Considerations
Cell Expansion
• Room Classification: 10,00 or 100,000
– Lab coat / tyvek gown/ hair cover
– Sterile gloves / mask for open operations
• Open Operations in Biosafety Cabinet
– Class 100 conditions
– One Cell Line per Area at a Time
– Clean Between Cell Lines
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 Design Considerations
Logistics
• Sufficient Processing Space
• Separate, Well Defined Areas per Activity
– Pre and Post Virus Inactivation
– Segregation: temporal and procedural
• Storage…Storage…Storage
– In-Process Material
– Dirty Equipment
– Clean Equipment; Dedicated or Shared?
– Hallways aren’t Storage Areas
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 Design Considerations
Material(s) Flow
• Storage…Storage…Storage Continued
– Raw Materials and Components
– Released vs. Quarantine
– API
– Drug Product
• Logical Flow?
• Hard Piped Versus Transport

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 Design Considerations
Equipment
• Consider “Cost” of Disposables
• Dedicated vs.. Shared
– Cleaning
– Changeover Procedure
– Unique Identification
– Status Tags
– Maintenance and Calibration
– Use Logs
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 Design Considerations
Equipment Flow
• Segregate Clean from Used Equipment
– Remember the Status Tags
• Areas for Decon and Cleaning
– How to get it there?
• Storage…yet again
– NOT the Hallway

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 Plant Systems
• HVAC

• Water

• Sterilization

• Waste Treatment

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 Plant Systems
HVAC
• HEPA Filtration
• Defined Classification
– 100,000 vs.. 10,000 vs. 100
– Air Changes
• Pressure Differentials
– Gown Rooms, Process Rooms, vs. Hallways
• Single Pass vs. Recirculated Air
– Areas with Common Air Handler
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 Plant Systems
HVAC Continued
• Temperature and Humidity Control
– Elevated Temp and RH Increases Operator
Perspiration and Particle Shedding
• Operator Comfort
• Assure Environmental Quality
– > 60% RH: Increases rusting of equipment
– Low Humidity, 35%-50%, Limit Mold Growth
– Low Humidity, Enhances Electrostatic
Entrapment Capability of Filters
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 Plant Systems
Water
• Need to Consider and Evaluate Seasonal Variation
• Assume non-sterile API, Sterile Parenteral Drug
Product
• Water Nomenclature
– Potable
– Purified
– Highly Purified Water (Ph Eur, 2002)
– Water for Injection

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 Potable Water
• EPA Drinking Water Standards, 40 CFR
141
• OUS Site, Consider the Source
• Test Reports from Local Authority
• “Routine” Sampling at Facility Entry
• Used for:
– Bacterial Fermentation if PW Quality Not
Necessary
– Initial Equipment Rinse
– Source Water for Purified Water Production 21
 Purified Water
• Prepared by ion-exchange, reverse osmosis or
other suitable method;
• Bioburden Controls, 1 cfu / mL
• Endotoxin Controls, 2.5 IU / mL
• Used For:
– Fermentation if necessary
– Mammalian Bioreactors, if Acceptable
– Isolation and Purification
– Final Rinse if Same as Water Used

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 Highly Purified Water (EU)
• Same Quality Attributes as WFI
– Bioburden, NMT 10 cfu / 100 mL
– Endotoxin, NMT 0.25 IU / mL
• Method of Production Deemed Less Reliable than
Distillation
– Double Pass Reverse Osmosis
– + / - Ultrafiltration
• Used For:
– Mammalian Cell Culture
– Final Isolation and Purification
– Final Rinse if Same as Water Used

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 Water for Injection, WFI
• Method of Production
– Distillation Only (EU)
– Reverse Osmosis or Distillation (US)
• Used for:
– Final Purification Step
– Formulation
– Rinse, if WFI Used in Process

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 Sterilization Systems
• Autoclave(s) for Moist Heat Sterilization
– Clean Steam, No Additives
– Condensate Meets WFI Quality Attributes
• Separate Systems for Decontamination
• Dry-Heat Ovens for Depyrogenation
• Double Doors Assist Material Flow
• Sterile Materials Cool Down Under Controlled Air
• Validation Should Include:
– Empty Chamber Studies
– Load Validation

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 Waste Treatment
• Liquid Waste
– Capacity for Full Scale Catastrophic Failure
– Safeguards to Prevent Backflow
– Decontamination Validated?
• Solid Waste
– Separate Autoclaves
– Frequency of Removal form Mfg Area
– Space for Storage Before Contamination

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 Equipment
• Remember the Laboratories!
• Identify Critical vs. Non-Critical
• Unique Identifier
• IQ:
– Equipment is as Ordered and
– Installed Per Manufacturers Instructions
• OQ:
– Equipment Operates at Ranges as Required
– Have Protocol with Acceptance Criteria
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 Equipment

• Calibration
– Record Routine Calibration and Results
– If Contractor
• Qualify the Vendor
– Identify Standard
– Document Repair, QA Review
– Investigation of OOS results

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 Equipment
• Preventive Maintenance
– Record with Results
– Historical Information is Valuable
– May be More Frequent for Older Equipment
– Record Repairs with QA Review
– Contract Services
• Vendor Qualification
• Ongoing Oversite

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 Validation Master Plan

• Define Company’s Approach /

Philosophy and Management
Commitment to the Validation Program
• A “living” document, updated routinely
• High Level Overview of Validation
Program
• Remember to Include Re-validation

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 Cleaning Validation
• Determine Which Equipment to Share
• Cleaning Verification During Clinical
Development
• 30-40% of 2001 WL to API Mfgrs Include
Cleaning Observations
• Carryover Calculations
– Take into Account 1/1000th of Therapeutic Dose
– Type of Product Mix
– Pediatric Dosing

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 Cleaning Validation

• Consider: How Does Cleaning Time

Impact Facility Capacity?
• Validate Removal of:
– Product Residuals
– Cleaning Agents

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 Inspections
• CBER and PHS Act
• Pre-License Inspections Performed by
Headquarters, CBER, +/- “Field”
• Biennial Inspections, Team Biologics
(1992)
– Specially Trained, National Experts
– The “Best” of Both Centers
– Reports to ORO Headquarters

33
 System Based Inspections
• Rather than Inspection Focused on Specific
Product, Will Focus on Systems Across
Products.
– Quality Systems
– Facilities and Equipment System
– Materials System
– Production System
– Packaging and Labeling System
– Laboratory Control System

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 “System” Audit
• 2 or More Systems, Coverage of Quality
System is Mandatory
• Permits acceptability / non-acceptability
for all profile classes
• Categories established by subchapter
structure of the cGMPs

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 Quality System
• Review and Approval by QA
– Adequacy of Staffing
– Management Support / Ownership
• Document Management System
– Batch Record Review
– Deviations and Failure Investigations
– Procedures
– Specifications
– Out of Specification Results (OOS)
– Change Control

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 Quality System
• Vendor / Contractor Qualification
– Initial Qualification
– Ongoing Evaluation
• Complaints
– Medical
– Product
• Training
– GMP
– Measure of Effectiveness

37
 Facilities and Equipment

• Facilities
– Flows and Air Handling Systems
– Sanitation and Maintenance
– Change Control
– Water
• Production
• Equipment Cleaning

38
 Facilities and Equipment

• Cleaning
– Procedures, Validation, Logs
• Adequacy of Design, Size, Location
• Controls to Prevent Contamination
• Calibration and Maintenance
• IQ/OQ
• Identification
• Change Control
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 Conclusion

• Spend Time on Planning

• Allow Sufficient Space for Storage
• Know Product Mix
• Design Controls Rather than Procedural
• Stay Current with Regulatory Agency
Expectations

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