Biotech Facilities: Regulatory and Design Approaches

Dr. Trent Carrier

Presentation Outline

Manufacturing Strategies Concept and Design Construction and Qualification Citation Examples Regulatory References

Manufacturing Strategies
New

manufacturing facilities can..

Be very expensive - costing tens/hundreds of millions of dollars Take a long time to construct, startup, validate & license

For

a new product, may require significant spending at risk

Having product supply ready at licensure requires spending before final clinical trial data May have uncertainties in product demand - but 3 have to build to a defined capacity

Product Profiles
Fermentation Vaccines (protein, polysaccharide)
- micrograms of API/dose, initial plus 1-2 booster doses - up to tens of million patients per year - bulk facilities at thousands of liters scale

Viral Vaccines
- tens of thousand of virus units/dose, initial plus 1-2 booster doses - up to tens of million patients per year - bulk facilities at hundreds of liters scale

Therapeutic Proteins (enzymes, antibodies)

- milligrams of API/dose, repeat administration (multiple doses/yr) - less than 1MM patients per year - bulk facilities at tens of thousand of liters scale

Cell Therapy & Gene Therapy (TBD)

Case Study: Style-ogen

Condition: Enzyme deficiency identified in professors. Linked with uncontrollable desire to wear brown polyester. Symptoms begin to appear around age 50. Product Profile: Injectable recombinant enzyme Timing: Launch the product in 2010 Dose: 5 mg/ml, 10 mg/70 kg body weight, 1 treatment per month Target Markets: US, EU, Japan Patient Population: 16MM Filled Product Requirements: 2,000 kg/yr Bulk Requirements: 5,000 kg/yr (adjusted for overage and losses) Process Scale: 2 fermentors at 5,000L scale (10 g/L titers)

Integrating with Product Timelines

What to build? When to start?

Facility Influences Begin Early

Competing Project Goals/Information...

Uncertainty in clinical data and market demand Must define project scope & facility capacity

Timely Licensure Launch product supply available

Defer capital spending as long as possible Minimize spending at risk

Robust GMP Manufacturing

Minimize capital spending

What Do You Need??? Options for Manufacturing

Outsource

Avoid capital spending Requires technology transfer to outside company

Launch/Pilot

Facilities

FDA guidance on use of pilot facilities Make validation/phase III/launch lots in small scale facility Transition to full scale mfg facility to meet supply needs

Final

manufacturing facility

Dedicated or multi-product? Scale/capacity?

Evaluate

ALL options before proceeding!

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Product: Style-ogen
Management decides that they want to build a manufacturing facility dedicated to this critically important product. Based on your experience, the project might cost ~ $30-60MM. When should we start?
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Typical Project YEAR Schedule

1 2 3 4 5 6
Phase III to start today Launch 2010 means we need APPROVAL Design Procurement Construction IQ/OQ Startup / Validation 100% % Spent APPROVAL

Scope

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Presentation Outline

Integrating Product and Facility Strategies Concept and Design Construction and Qualification Case Study Follow-up Regulatory References

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Concept and Design

Layouts Flows Classification Specifications Diagrams

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Links Between Regulations and Facility Concept and Design

Buildings of suitable size for cleaning, maintenance, and ops. Adequate space and flows for equipment and materials to prevent mixups -> Room size Premises laid out to allow production in logical order corresponding to sequence and cleanliness. -> Room organization and movement Equipment of appropriate design, size, constructed of non-reactive materials > Equipment specifications Measuring equipment of appropriate range and precision -> Instrument specifications Computer equipment has controls to ensure master production and control records are accurate -> Automation Equipment located to suit intended purpose-> Equipment layouts Control of ventilation temp, pressure, dust, microorganisms adequate for manufacturing -> Room environment

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Conceptual Plans
Process

Conceptual Plans

Inputs:
Research / development final process (Phase II clinical process?) Marketing Sales Forecast

Outputs:
Process Flow Diagrams (PFDs) with equipment sizes and mass balance Equipment List

Facility

Architectural Plans
PFDs and process equipment size estimates Utility and Material Handling / Storage Quality / cGMP Philosophy Staffing Plan

Inputs:

Outputs:

Cost

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Architectural Conceptual Plans

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Early Concepts Starting Point

Process Flow Diagrams
Step 1

Architectural Bubble Diagrams

People Mat In In Ferm Area Storage

Fermentation
Step 2

Step 3

Purification
Step 4

People In

Purif Area

Out

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Rules of Thumb
Process

Area vs. Total Building Area:

5%-10% 8%-17% 5%-15% 5%-15% 35%-50% 15%-20%

Process Support (Labs, Wash/Prep, Autoclaves) Building Circulation (Corridors and Airlocks) Personnel (Lockers, Offices, etc) Material Handling (Storage) Mechanical (HVAC, Utilities, Elec., Chases) Process Areas (Ferm, Purif., Buffer/Media)

Facility

Cost ~$1000 to $1500 / square foot

Style-ogen 7000 sq. ft. Process Area estimated (2 rooms of 3500 each) 7000 / 17.5% = 40,000 square foot building

1740,000 x $1250 = $50MM !!!!

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Building Architectural Plan

ort p p Su , s r ke c o L Ferm

f P ur i

vs

Ferm

h Mec

al c i n a

f P ur i

ical n a h ort c p e p M u S , s ker c o L

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Design
Process

Design

Piping and Instrumentation Diagrams (P&IDs) Equipment Specifications and Bid Packages Automation Functional Requirement Specifications

Facility

Design

Architectural Drawings with Equipment Facility Specifications (Finishes, Electrical, HVAC, etc.) All detail design drawings complete (CADD, 3D modeling, etc)

Cost

Estimate (+/- 10%)

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Process Scaleup From Lab

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Process Equipment Design

A P&ID is a representation of process elements
Pressure Control Vent Vent TI T Add Cln Stm TI T PI

TI

Sparge T

Tank

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Gas

FC Gas flow

TI T Agitator
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Equipment Functionality Via Design

Material Selection Material Charging Pressure Control

FT

Mix

M
Temperature Control

TT

PT

Discharge and Recirc

Pump

FT

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Suite Layouts Based on Equipment and Bubble Diagrams

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Room Classification Costs

Area classification remains topic of debate Balance of product quality risks vs. cost
Relative Cost ($/square foot)
100% 90% 80% 70% 60% 50% 40% 30% 20% <10%
Grade A Grade B Grade C Controlled Unclassified Uncontrolled Mechanical

Industry range

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Area Classification for Style-ogen Process Steps

Tank Fermentation Non Sterile Purification Buffer/Media Hold

Unclassified Space Closed Equipment Open Processing

Open Sterile Sampling Open Sterile Transfers
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Grade A

Solution Prep Equipment Assembly Sterile Purification

Classified Space

Open Aseptic Transfers

Lighter shading signifies more stringent area classification

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Presentation Outline

Integrating Product and Facility Strategies Concept and Design Construction and Qualification Case Study Follow-up Regulatory References

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Construction and Qualification

Fabrication and Assembly Fits/Finishes Installation Operation

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Links Between Regulations and Facility Construction and Qualification

Buildings of suitable construction for cleaning, maintenance, and operations -> Facility finishes, assembly Equipment installed in such a way to prevent risk of error or contamination -> Equipment fabrication Equipment designed to suit intended purpose. -> Qualification Input to and output from computer systems shall be checked for accuracy. -> Qualification

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Fabrication and Construction

Facility On-site

Assembly and Equipment Fabrication (Stick-built) Assemble piping, steel, walls, etc (off-site) Build elsewhere and ship to site

Modular Hybrid

approaches may be used

Facility stick-built on-site Process Equipment built at equipment vendor (Skids) Allows for concurrent facility and equipment construction

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Style-ogen Facility Assembly

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Styleogen Equipment Fabrication

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Style-ogen Process Area

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Qualification Steps

Factory Acceptance Testing / Site Acceptance Testing (FAT/SAT) ensures that equipment is fabricated according to engineering designs prior to IQ Installation Qualification (IQ) verifies that the equipment is the correct piece of equipment by design and has been installed properly. Operational Qualification (OQ) verifies that the piece of equipment will operate as designed, for example the valves open and close as designed, the agitator functions correctly, etc... Automation Qualification (AOQ) ensures that computer hardware and software systems used to automate processes, complete calculations, etc. can consistently perform their intended function. Performance Qualification Cleaning Validation Sterilization Validation Process Validation

Subject of another class

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Qualification Tiered by Product Impact

Temp controller Waste neutralization

ng i s Power station re a c n I tio a Air handlers c i al i f u fQ o l e Lev n

Fermentor

Water generator

Vacuum system

Autoclave

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Style-ogen Qualification
4 Process Steps / 12 Pieces of Equipment

6600 pages of IQ/OQ protocols + 9 months x 15 people equipment and testing

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Next Steps for Style-ogen

Validation Environmental Testing cGMP Operations

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Presentation Outline

Integrating Product and Facility Strategies Concept and Design Construction and Qualification Case Study Follow-up Regulatory References

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Style-ogen Follow-ups
Concept -> Design -> Construction -> Qualification

You finish the project and are happy to report that you were able to build the facility for $40MM, a savings of 20% on the initial estimate. Your boss asks how you were able to save so much? Concept Efficiencies through combining process areas Design Reducing area classifications and re-using equipment designs Construction Off-site fabrication of equipment at a new vendor Qualification Risk-based qualification approaches Your boss says that is a great story and suggests that your next project should be able to save 40% because you are so good.

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Style-ogen Follow-ups
Concept -> Design -> Construction -> Qualification

A production supervisor calls you and says that they cant get the pump to run at the flowrates they need. What happened? Design Perhaps the equipment specifications were wrong? Construction Perhaps the wrong pump was installed? Qualification Why didnt the qualification testing catch it? The specs were right, the right pump was installed, and the qualification did test the pump flowrate. You find that the wrong valve was installed in the pipe that caused a lower flowrate from the pump.

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Style-ogen Follow-ups
Concept -> Design -> Construction -> Qualification

An FDA inspector arrived to perform an audit of your new facility. They question how you know that your product is protected from microbes from outside. What are your safeguards? Concept People and material flows Design Area classifications and equipment designs Qualification Testing of the equipment The inspector is impressed with the thoroughness of your response and determines that your facility should be approved. and you get a raise!

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Conclusion

Regulatory guidance is major influence in facility design, but is open for interpretation. Facility design requires an integrated view of product, process, and operations. The lifecycle of a project is a progression of activities that build on each other. The successful completion of a manufacturing facility is a tremendous accomplishment

But its only the start.

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Presentation Outline

Integrating Product and Facility Strategies Concept and Design Construction and Qualification Case Study Follow-up Regulatory References

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Regulatory References

Guidance for Bulk Biologics

Facilities: CFR 211.42-211.58, 600.10; EudraLex Chapter 3 HVAC: 600.11, 211.46, EudraLex Chapter 3 Equipment: 211.63-211.72, 600.11, EudraLex Chapter 3 EU Annex 2 (WHO) ISPE Baseline Guide for Biopharmaceuticals (excludes vaccines) ASME-BPE 2002

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