multi product issues

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Copyright 2002, Barbara W. Unger,Don Hill & Associates Inc.

1

Regulatory Compliance for

Multi-Product Facilities

Barbara W. Unger

Don Hill & Associates Inc.,

317.582.1504

[email protected]

Licensed Solely for Use in Conjunction with the 2002

ASME Bioprocess Technology Seminar



2

T opics

Unique Characteristics of BiotechProducts

Design Considerations

Plant Systems

Equipment

Validation

± Master Plan

± Cleaning

System Inspections



3

T ypes of Multi-Use

Multiple Products, Similar Stages of Manufacture

Single Product,Multiple Lots, VariousStages of Manufacture

Common Areas / Equipment forPotentially Infectious vs. Inactivated

Process Streams

Different Products, Campaign Basis



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Concerns for Multi-Use

Contaminants Difficult to Identify /

Detect

± Adventitious Agents Known

Unknown / Novel

± Product Stream Cross-Contamination

Intermediates API

Associated Impurities



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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 MULT IP LY

ComplexMolecules

± Large

± Heterogeneous ³Family´

Amino Acid Substitutions

Variability in - Terminus

Glycosylation



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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

Characteristics of Biotechnology Products



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Means of Establishing CON T ROL

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 ProductMix and Processes

± ³flexibility´ adds $$$$



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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



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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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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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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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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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Equipment Consider ³Cost´ of Disposables

Dedicated vs.. Shared

± Cleaning

± Changeover Procedure

± Unique Identification

± Status Tags

± Maintenance and Calibration

± Use Logs



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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

³Routine´ Sampling at Facility Entry

Used for:

± Bacterial Fermentation if PW Quality Not Necessary

± Initial Equipment Rinse

± Source Water for Purified Water Production



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Purified Water

Prepared by ion-exchange, reverse osmosis orother 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 Reliablethan 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) forMoist Heat Sterilization

± Clean Steam, No Additives

± Condensate Meets WFI Quality Attributes

Separate Systems for Decontamination Dry-Heat Ovens for Depyrogenation

Double Doors AssistMaterial Flow

SterileMaterials Cool Down Under Controlled

Air Validation Should Include:

± Empty Chamber Studies

± Load Validation



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Waste T reatment

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

PreventiveMaintenance

± 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 andManagement

Commitment to the Validation Program A ³living´ 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 ClinicalDevelopment

30-40% of 2001 WL to APIM

fgrs IncludeCleaning 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, +/- ³Field´ Biennial Inspections, Team Biologics

(1992)

± Specially Trained, National Experts

± The ³Best´ of Both Centers

± Reports to ORO Headquarters



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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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³ System´ Audit 2 orMore Systems, Coverage of Quality

System isMandatory

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

DocumentM

anagement 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



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Facilities and Equipment

Facilities

± Flows and Air Handling Systems

± Sanitation and Maintenance

± Change Control

± Water

Production Equipment Cleaning



39

Facilities and Equipment

Cleaning

± Procedures, Validation, Logs

Adequacy of Design, Size, Location

Controls to Prevent Contamination

Calibration andMaintenance

IQ/OQ Identification

Change Control



40

Conclusion

Spend Time on Planning

Allow Sufficient Space for Storage

Know ProductMix

Design Controls Rather than Procedural

Stay Current with Regulatory Agency

Expectations

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