Facility Design and CGMP Facility Design and CGMP Considerations for Cell Considerations for Cell

Therapy ProductsTherapy Products

James CrimJames CrimHHS/FDA/CBER/OCBQ/DMPQHHS/FDA/CBER/OCBQ/DMPQ

ISCT- 6ISCT- 6thth Annual Symposium Annual SymposiumSeptember 25-27, 2006September 25-27, 2006

SCOPESCOPE

Regulatory OverviewRegulatory Overview Current Good Manufacturing Practices (cGMPs) - Current Good Manufacturing Practices (cGMPs) -

Expectations During DevelopmentExpectations During Development Basic facility considerationsBasic facility considerations

- Facilities/Personnel- Facilities/Personnel - Environmental Monitoring- Environmental Monitoring

Contamination and cross contamination controlContamination and cross contamination control- Aseptic Processing- Aseptic Processing

Regulatory ConsiderationsRegulatory Considerations

IND regulations (21 CFR 312) - patient safetyIND regulations (21 CFR 312) - patient safety

and clinical trialsand clinical trials Biologics regulations (21 CFR 600s) – Biologics regulations (21 CFR 600s) –

licensing requirementslicensing requirements CGMPs (21 CFR 211s) – current good CGMPs (21 CFR 211s) – current good

manufacturing practices for drugs/biologicsmanufacturing practices for drugs/biologics Combination products (21 CFR 800s)Combination products (21 CFR 800s)

CGMP Continuum: Expectations CGMP Continuum: Expectations During DevelopmentDuring Development

GMPs expected throughout clinical studies, GMPs expected throughout clinical studies, though level of control and validation will though level of control and validation will vary on the process and critical nature of the vary on the process and critical nature of the issueissue

Documented control over the facility, Documented control over the facility, equipment, and processequipment, and process

Expect control to increase as product moves Expect control to increase as product moves from one phase to the nextfrom one phase to the next

Consider some of the following Consider some of the following elements of CGMP: elements of CGMP:

Facility design to control operationsFacility design to control operations Adequate documentation/recordsAdequate documentation/records Production and process controlsProduction and process controls Quality control/assuranceQuality control/assurance Validation/process controlValidation/process control Equipment calibrated/qualifiedEquipment calibrated/qualified Personnel training and certificationPersonnel training and certification Environmental monitoringEnvironmental monitoring

Facility DesignFacility Design

Manufacturing areas designed for aseptic processing Manufacturing areas designed for aseptic processing – smooth, easily cleaned surfaces, etc.– smooth, easily cleaned surfaces, etc.

Designed to control the manufacturing environment Designed to control the manufacturing environment (personnel and process)(personnel and process)

Adequate and separate areas, for various activities Adequate and separate areas, for various activities (receipt of materials, testing, manufacturing)(receipt of materials, testing, manufacturing)

HEPA-filtered air in manufacturing areas; higher HEPA-filtered air in manufacturing areas; higher control (classification) for critical manufacturing control (classification) for critical manufacturing stepssteps

Facility DesignFacility Design

Product type and makeupProduct type and makeup Stage of manufacturing Stage of manufacturing Scale of manufacturingScale of manufacturing Material and personnel flows designed to maximize Material and personnel flows designed to maximize

efficiency and minimize product mix-upsefficiency and minimize product mix-ups Concurrent vs. campaigning – impact on HVAC, Concurrent vs. campaigning – impact on HVAC,

cleaning and personnelcleaning and personnel

Facility Design considerations: Product Facility Design considerations: Product IssuesIssues

Will the entire manufacturing process be performed Will the entire manufacturing process be performed in the facility?in the facility?

Nature of the starting material – cell culture vs. Nature of the starting material – cell culture vs. recombinant cell linerecombinant cell line

Nature of the process – open vs. closed systems; Nature of the process – open vs. closed systems; fermentation/cell culture, purification, etc.fermentation/cell culture, purification, etc.

Multi-product or patient manufacturing?Multi-product or patient manufacturing? Facility intended to be licensed or limited to IND Facility intended to be licensed or limited to IND

products?products?

Facility Design: Multi-Product IssuesFacility Design: Multi-Product Issues

Campaign vs. concurrent production will Campaign vs. concurrent production will impact on design and operation of the facilityimpact on design and operation of the facility

Commercial vs. investigational product Commercial vs. investigational product manufacturingmanufacturing

Dedicated vs. shared equipmentDedicated vs. shared equipment Multiple patient cellsMultiple patient cells

Facilities/PersonnelFacilities/Personnel Personnel practice universal precautions when Personnel practice universal precautions when

processing biological materials such as cells or processing biological materials such as cells or tissuestissues

Unidirectional flow of personnel and processed Unidirectional flow of personnel and processed materialmaterial

Temporal segregation of processing activities, if Temporal segregation of processing activities, if possiblepossible

Gowning program designed to protect the product Gowning program designed to protect the product from contamination and keep airborne particulates from contamination and keep airborne particulates away from the product and prevent the transfer of away from the product and prevent the transfer of particulates from one manufacturing environment to particulates from one manufacturing environment to another environment of higher classificationanother environment of higher classification

Environmental MonitoringEnvironmental Monitoring

PurposePurpose To demonstrate that environment quality is consistently To demonstrate that environment quality is consistently

within specified levels.within specified levels. To provide a timely and sensitive warning if the To provide a timely and sensitive warning if the

environmental quality or its control is becoming or have environmental quality or its control is becoming or have become unacceptable.become unacceptable.

To initiate a timely, comprehensive planed course of action To initiate a timely, comprehensive planed course of action whenever environmental monitoring results are indicative whenever environmental monitoring results are indicative of unacceptable environmental quality or control (i.e., of unacceptable environmental quality or control (i.e., “excursion” or OOS).“excursion” or OOS).

Environmental MonitoringEnvironmental Monitoring

How much environmental monitoring is needed and when?How much environmental monitoring is needed and when?

Routine dynamic monitoring of the “clean”Routine dynamic monitoring of the “clean”environment and operations is important to insure thatenvironment and operations is important to insure thatmodes of bioburden introduction are under control. Themodes of bioburden introduction are under control. Therecommendation is to at least monitor viablerecommendation is to at least monitor viableparticulates during aseptic processing and understandparticulates during aseptic processing and understandthe airflow in the hood and pressure differentials inthe airflow in the hood and pressure differentials inareas of operations as the pressure differentials may provide anareas of operations as the pressure differentials may provide anindication that the area is suitable for use.indication that the area is suitable for use.

Environmental MonitoringEnvironmental Monitoring

The main goal is to protect the product by The main goal is to protect the product by demonstrating that the class 100 environment has demonstrating that the class 100 environment has been maintained.been maintained.

• Should have qualified Biosafety Cabinets of appropriate air Should have qualified Biosafety Cabinets of appropriate air classification and on a maintenance plan for filter testing.classification and on a maintenance plan for filter testing.

• Should routinely monitor (if even settling plate) during Should routinely monitor (if even settling plate) during processing of patient cells or tissues to ensure no additional processing of patient cells or tissues to ensure no additional microbial contamination.microbial contamination.

• Should be working towards process simulations to ensure Should be working towards process simulations to ensure aseptic processing.aseptic processing.

• Operators should be trained and practice due diligence with Operators should be trained and practice due diligence with regard to aseptic manipulations.regard to aseptic manipulations.

Examples of operations that may be performed in classified areas

Class/(ISO equivalent) Example of operation

Class 100/ ISO 5 open manipulations (see below) aseptic connections

Class 1000/ ISO 6Class 10,000/ISO 7 surround Class 100 (bioburden control)

centrifugation location of incubators and closed systems

Class 100,000/ ISO 8* surround Class 10,000 (areas requiring

moderate control) centrifugation and labware storage location of incubators and closed systems

* If additional microbiological controls are required the procedure should be performed in a Class 10,000 area

An example of a floor An example of a floor planplan

Class 10,000++

BSC (Class 100)

BSC (Class100)

Class 100,000Gowning Room

+

Personnel and Material

Controls for preventing contamination Controls for preventing contamination and cross contamination:and cross contamination:

Controls for preventing contamination Controls for preventing contamination and cross contamination:and cross contamination:

Campaign manufacturing and area/equipment Campaign manufacturing and area/equipment clearanceclearance

Labeling systemLabeling system Segregation and Tracking of Patient MaterialSegregation and Tracking of Patient Material Use of Sterile Transfer Connecting DevicesUse of Sterile Transfer Connecting Devices Cleaning and SanitizationCleaning and Sanitization Flow of Product and Waste MaterialFlow of Product and Waste Material Gowning ProgramGowning Program Preventing microbial contamination (Aseptic Preventing microbial contamination (Aseptic

Processing)Processing)

Aseptic ProcessingAseptic Processing

What is aseptic processing (technique)?What is aseptic processing (technique)?

The ability of personnel to manipulateThe ability of personnel to manipulatesterile preparations, sterile packagingsterile preparations, sterile packagingcomponents, and sterile administrationcomponents, and sterile administrationdevices in a way that excludes thedevices in a way that excludes theintroduction of viable microorganisms.introduction of viable microorganisms.

Aseptic ProcessingAseptic Processing

Where does aseptic processing start?Where does aseptic processing start?

It may depend on the process, it may have aIt may depend on the process, it may have a

sterilizing step prior to filling or some products sterilizing step prior to filling or some products

can not be sterilized so aseptic processing occurscan not be sterilized so aseptic processing occurs

from beginning to the end. from beginning to the end.

Critical input elements to successful Critical input elements to successful aseptic processing:aseptic processing:

Personnel performance (gowning and technique)Personnel performance (gowning and technique) Environmental quality and controlEnvironmental quality and control Validated, controlled sterilization of all product and Validated, controlled sterilization of all product and

added ingredients, container/closures, equipment, added ingredients, container/closures, equipment, utensils, and product-contract surfacesutensils, and product-contract surfaces

Media Challenge – worse case scenarios, routine Media Challenge – worse case scenarios, routine dynamic environmental monitoring, equipment and dynamic environmental monitoring, equipment and environmental capabilities, sterility needs for environmental capabilities, sterility needs for supporting process stream contact materialssupporting process stream contact materials

In Summary….In Summary….

FDA recognizes changing nature of clinical FDA recognizes changing nature of clinical studies; need for sliding scale approach to studies; need for sliding scale approach to meeting cGMPsmeeting cGMPs

Key production steps, equip. and facilities Key production steps, equip. and facilities need to be under documented controlneed to be under documented control

Patient safety cannot be compromisedPatient safety cannot be compromised Testing alone does not assure a quality productTesting alone does not assure a quality product QC/QA needed at early stagesQC/QA needed at early stages

In Summary….In Summary….

Suggest facility be designed to accommodate Suggest facility be designed to accommodate current and future needscurrent and future needs

Suggest facility be designed to be as flexible Suggest facility be designed to be as flexible as possible as possible

Suggest that the facility be designed, operated Suggest that the facility be designed, operated and controlled to the highest level possible and controlled to the highest level possible (room classifications, pressure differentials, (room classifications, pressure differentials, monitoring, etc.)monitoring, etc.)

Special thanks to…Special thanks to…

Jay Eltermann – OCBQ/DMPQJay Eltermann – OCBQ/DMPQ

Laurie Norwood – OCBQ/DMPQLaurie Norwood – OCBQ/DMPQ

For more information….For more information….

Reviews/meetings with DMPQ:Reviews/meetings with DMPQ:

(301) 827-3031, (301) 827-3536 fax(301) 827-3031, (301) 827-3536 fax Technical issues:webmaster@cber.fda.govTechnical issues:webmaster@cber.fda.gov Manufacturers assistance: matt@cber.fda.govManufacturers assistance: matt@cber.fda.gov CBER SOPP for meetings:CBER SOPP for meetings:

http://www.fda.gov/cber/regsopp/81011.htmhttp://www.fda.gov/cber/regsopp/81011.htm