®

cGMP, cGTP Facility Design for Production of Human Cells, Tissues and Tissue based

products

Presented by Kris Chatrathi at International Society for Pharmaceutical

Engineering-Midwest Chapter

October 11, 2011

www.burnsmcd.com/pharma

®

Introduction

• Regenerative Therapies Overview• FDA, cGMP, CGTP• Facility Introduction• CFD Evaluation of Room• Architectural Alternatives• HVAC Design

®

Regenerative Therapies

• Repair, replace, restore, regenerate damaged or diseased cells, tissues and organs:– Heart Muscle– Skin for Burn Victims– Spinal Cord Injury– Pancreatic Tissue to Produce Insulin

• Cell therapy, tissue engineering, biomaterials engineering, growth factors and transplantation science

®

Artificial Vessels

• Typically used for by-pass operations

®

Artificial Skin for Ulcers and Burns

®Replacement Cartilage

• Mimics usual cartilage environment– Cartilage cells– Collagenous scaffold

The close up image of cells in the replacement cartilage

®

Engineering Bone Grafts

• Change stem cells into bone cells – with proper growth

factors in cell culture media

A 3D calcium phosphate scaffoldFrom Becton Dickinson

®

Replacement Cells for Diabetes

In vivo Islet of Langerhans in Pancreas

®

A New Bladder

To make a bladder a scaffold, along with several different types of cells, are needed.

® Transplants That Match the Patient

1. Remove cells from patient.

2. Grow in culture with or without biomaterials.

3. Give appropriate chemicals to make cells do what is needed.

4. Replace into patient.

®

FDA

• CBER (Center for Biologics Evaluation and Research): vaccines, blood and blood products, human tissue/tissue products for transplantation, cell therapy, gene therapy, donor screening tests for blood and tissue safety, devices– Office of Cellular, Tissue and Gene

Therapies• Draft Guidance for Industry: Current Good

Tissue Practice (CGTP) and Additional Requirements for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)

®

cGMP

• Ensure Products are Manufactured by a Controlled Auditable Process

• cGMP elements– Facilities and Equipment– Personnel and Training– Documentation and Validation– SOP and Error Management– Process Control– Labeling– Auditing

®

cGMP/cGTP Focus

• Guidance recommendations are focused on preventing infectious disease contamination and cross contamination (including mix-ups) during manufacture

• Prevention of the introduction, transmission, or spread of communicable diseases

• Evaluate the type of area that a task would require in order to prevent contamination or cross-contamination

• Procedures must be established and maintained to prevent contamination or cross-contamination

®

Facility User Requirement Specification

• Scope• Facility and Process Description• User Requirements:

– Barriers, physical barriers to ensure particulate and microbial level do not exceed defined limits

– Construction, floors, walls, ceilings and finishes– Atmosphere, requirements for the monitoring

and control in classified areas– Processing Equipment– Auxiliary Services– Material Handling and Storage Requirements– Laboratory Functional Requirements

®CFD Objectives

• Objective of Baseline Analyses– Simulate flow in lab room– Examine flow environment near bio safety

cabinets• Understand impact of installation of

cabinet near returns• Determine if room air flows onto interior

work surface

® CFD Scope

•Scope of Baseline Analysis-Build room and cabinets using supplied data-Define model constraints and parameters

• Supply and return flows from TAB report• Balance of airflow exits through gaps

around doors-Run cabinet characterization simulation-Run full lab room simulation

®

CFD Results

• Results– Flow travels from supplies to returns; little mixing

occurs– Exhaust flow at cabinet is significant relative to

supplies– Air stagnates along wall opposite the returns– Location of cabinet near return creates bias at air

curtain• ISO-7 room air extends into cabinet on upstream

side• ISO-7 air region extends 19.7 inches into cabinet• Peak air speed at curtain is 80 FPM at center of

cabinet (20% reduction)– Increasing air changes/hr will likely increase bias at air

curtain

®

CFD Results Continued

• Other Considerations/Recommendations – Air passing by the cabinets has already passed over

the incubators, tables, and occupants – Very low air velocities near the incubators and along

the wall opposite the returns could likely be improved• Create an array of overhead diffusers and

install returns around perimeter

®

Contaminant Study – Comparison

Bio Safety Cabinet in Standard Room Bio Safety Cabinet in Lab Room

Room air extends 6.9” fromfront of unit @ 4” from sidewall

Room air extends 19.7” fromfront of unit @ 4” from sidewall

®

Conclusion

Kris Chatrathi

kchatrathi@burnsmcd.com

816-349-6731

Acknowledgements

David Leever, Burns & McDonnell

David Findlay, Burns & McDonnell