Design, Qualification, and Operation of a Gene Therapy

Design, Qualification, and Operation of a Gene Therapy Facility

Michele LevensonSr. Program Manager / Pharmatech Associates, Inc

AIA Quality Assurance

The Building Commissioning Association is a Registered Provider with The American Institute of Architects Continuing Education Systems (AIA/CES). Credit(s) earned on completion of this program will be reported to AIA/CES for AIA members. Certificates of the Completion for both AIA members and non-AIA members are available upon request.

This program is registered with AIA/CES for continuing professional education. As such, it does not include content that may be deemed or construed to be an approval or endorsement by the AIA of any material of construction or any method or manner of handling, using, distributing, or dealing in any material or product.

Questions related to specific materials, methods, and services will be addressed at the conclusion of this presentation.

BCxA Conference – Chicagoland, IL – 2019 2

Learning Objectives

BCxA Annual Conference – Chicagoland, IL – September 2019 3

• Background• Gene Therapy Overview• Design Elements• Qualification on a Mission Critical Project• Good Practices During Routine Operations• Conclusion

Drug Lifecycle


• Attrition rate is high!

100's of cmpds made

12s of cmpds 2

1 2 3

1Preclinical Evaluation

Phase

1) 20-50 healthy volunteers: Is it safe? What dose is needed?2) 100-500 patient volunteers: Does it work?3) 500-3000 patients: Does it work as well or better than SOC?

Drug Manufacturing Facilities


* Reference: http://rmcpharmanews.blogspot.com/2012/12/the-cost-of-pharmaceutical-facilities.html

http://rmcpharmanews.blogspot.com/2012/12/the-cost-of-pharmaceutical-facilities.html

Different Types of Pharma Manufacturing


Biotech Manufacturing Facility

* Reference: https://cranecpe.com/chem-energy/processmap/biotech-process-map

Tablet Manufacturing Facility

* Reference: http://www.pharmtech.com/role-powder-characterization-continuous-manufacturing

https://cranecpe.com/chem-energy/processmap/biotech-process-map

http://www.pharmtech.com/role-powder-characterization-continuous-manufacturing

Gene Therapy Overview


• Viruses introduce their genetic material into cells

• In gene therapy, viral vectors are used to deliver genetic material to cells for a therapeutic effect w/out making patients sick Although created from viruses, viral

vectors are modified so they can no longer self-replicate

Minimizes the risk of handling and no longer considered a virus

• Gene Therapy has the promise of delivering, in as little as a single administration, the missing gene.

Typical Gene Therapy Facility


Facility Design


Potential Employee Exposure:

Features of a BSL2 Facility


Compliance Differences


HVAC Design


• Single pass air• Pressurization schemes• Airlock design and philosophy• Exhaust moved to the roof drives

down risk of cross-contamination• Prevailing wind patterns must still be

demonstrated• Environmental Monitoring program

will have to demonstrate there is no cross-contamination

• Response to containment envelope breach

HVAC Automation and Facility Controls


• Implementation of sophisticated automation• BMS and/or EMS to handle alarming & remote notifications• Requires a clear plan on how the data will be used:

Quality Metrics Process Validation Stage 3 What kind of data? How will it be monitored? 21 CFR Part 11

• Intelligence associated with these facilities is really high…and, we have the ability to monitor almost every aspect!

HVAC Risk Assessment


Options System Description Details Cost Delta ($)

Baseline Current Budgeted System

• 10 ton packaged unit and 12,000cfm air handler • 80%Re-Circulated Air/20% Single Pass Outside Air • HEPA filtered Air • No Redundancy

$424,610

0

Option1 100% Single Pass Outside Air

Engineering and Permits Packaged Unit abd Pre-Heater Supply Duct and HEPA Filtration Insulation Exhaust Fan and Duct with Low Wall Registers Controls Zone Heaters (Electric) Air Balance

Total Cost

$ 35,000 $145,000 $155,000 $ 15,000 $ 40,000 $ 70,000 $ 30,000 $ 20,000 $515,000

90,390

Option 2 100% Single Pass Outside Air, 4 Fan Wall Separate Condenser Unit


Total Cost

$ 35,000 $192,000 $155,000 $ 15,000 $ 40,000 $ 75,000 $ 30,000 $ 20,000 $562,000

137,390

Option2+ 100% Single Pass Outside Air, 100% Air Redundancy, 100% Condenser Redundancy


Total Cost

$ 35,000 $284,770 $155,000 $ 15,000 $ 45,000 $ 75,000 $ 30,000 $ 20,000 $659,770

235,160

HVAC Risk Assessment, cont’d


Options System Description Considerations/Risks Technical Regulatory Operating

Baseline Current Budgeted System

• No room isolation • Does not meet FDA or EMA Expectations

• Potential for cross contamination

• Lowest operating cost

Option1 100% Single Pass Outside Air

• Achieves Room Isolation

• No fan redundancy

• Meets FDA and EMA Expectations

• Eliminates potential for cross contamination.

• Higher operating cost because to control temperature of singe pass air

Option 2 100% Single Pass Outside Air, 4 Fan Wall Separate Condenser Unit


• Fan redundancy • Separate Condenser

(low failure risk- 4 compressors)



• Higher operating cost than baseline, because to control temperature of singe pass air.

• Slightly higher Qualification costs

• Slightly lower operating cost than Option 1

Option2+ 100% Single Pass Outside Air, 100% Air Redundancy, 100% Condenser Redundancy


• Fan redundancy • Condenser

redundancy



• Highest operating cost • Lowest facility

downtime risk • Higher Qualification

Costs

Project Team Dynamics


Time FLIES when you’re having…a schedule!

The race to production can be even more intense in gene and cellular therapies than it is in ‘emergency’ tech transfer in traditional pharmaceuticals.

Commissioning & Qualification


• Fast paced project that requires efficiencies!• Specification and Submittal Review• FAT/SAT/AT Review• Commissioning Test Plan finalization and PQ development• Equipment relocation (where applicable)• Portable and COTS equipment• CTP and PQ (where applicable) Execution

Classical Validation Paradigm


User Requirements (URS)

Functional Requirements

(FRS)

Design Specifications(DS)

Commissioning

Installation Qualification (IQ)

Operational Qualif ication

(OQ)

Performance Qualif ication

(PQ)Verifies

Verifies

Verifies

Validation V Model

Risk Based Validation


• Approach to validation based on risk factor of the functions of the system or equipment

• The goal is to determine the impact, likelihood, and detectability of a failure to establish the overall risk of each scenario

• Risk is assessed using system impact assessment where each function requirement of the system is weighted and tested as appropriate

• Classic validation would test each functional requirement of the system equally

Classical versus Risk Based Validation


HVAC & Isolator/BSCs PQs


• Coordination of EM sampling requires close communication between the various groups.

• Maximum room capacities influence the level of room cleanliness.

• Specific sampling points on risk-based qualification.• Operations should be simulated per current procedures during

dynamic testing.• Sequence of cleanings/equipment hold times, static and

dynamic sampling must be planned ahead of time.

HVAC Commissioning versus IOQ and PQ


Commissioning Installation & Operational Qualification Performance Qualification

AHUs and associated EF’s tested

Room particle tested

Balancing/ACPH data review

Smoke Testing, etc.

System functionality & system features are tested

* Pre-requisite: Commissioning

Baseline data collection for Environmental Monitoring (EM) program.

Rooms tested typically under static & dynamic conditions

* Pre-requisite: IOQ, facility GMP cleaning

Allogenic versus Autologous Manufacturing


One to a bigger one One to many ones

Qualifying equipment for a scaled-up process can be more challenging than for one that has been scaled out

vs.

Facility Flow


Segregation


• Biggest concern – the risk of cross contamination!

• Training for the operators – aseptic gowning, aseptic techniques

HVAC Stability Strategy


• Must be able to demonstrate that all controlled areas (classified and unclassified) for temperature, humidity and pressure must remain in a state of control

• Emergency generators must back up all critical operations within the suite

• General operations (offices, canteen, etc.,) can go on energy savings or be turned off during non-use hours.

Conclusions


• Segregation of each step of the manufacturing process is key to prevent cross-contamination. Virus particles are on the nanometer scale and can easily pass through a 0.1 micron

“sterile barrier” filter, posing a high risk for environmental contamination.

• Best way to avoid the common failure points build them into the design and reviewed by a cross-functional team.

• Must understand how the facility and equipment will be used to successfully qualify and operate the facility.

Michele LevensonSr. Program ManagerPharmatech Associates, [email protected]

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Design, Qualification, and Operation of a Gene Therapy