ISPE Guide: Advanced Therapy Medicinal Products – Allogeneic Cell Therapy cover image

ISPE Guide: Advanced Therapy Medicinal Products – Allogeneic Cell Therapy

Published:January 2024

Pages:144

Advanced Therapy Medicinal Products (ATMPs) are based on genes, cells, or tissues delivered to patients to provide a therapeutic benefit based on a specific target of interest. For ATMPs, the therapy is cells, engineered tissues, or the manipulation of the patient’s genome. This is in contrast with traditional manufacturing processes for compounds that are synthetically derived (i.e., small molecule) or proteins or peptides expressed by cellular systems (i.e., large molecule biopharmaceuticals). The development, regulatory path, facility design, qualification, and manufacture of ATMPs present significant challenges to manufacturers, engineers, and suppliers. The GMP regulations are evolving as novel processes are presented and manufacturing paradigms are being tested. This Guide addresses facility engineering issues that are most applicable at the time of publication, as based on the experience of the authors.

This Guide focuses primarily on allogeneic cell therapies, specifically manufacturing facility development and design. Allogeneic cell therapies have unique challenges due to the small manufacturing scale, limitations in scale-up, the need to manufacture multiple lots of products concurrently, and the need for flexibility to accommodate a varied and evolving product portfolio. This Guide covers common challenges with allogeneic cell therapy facilities, design concepts specific to allogeneic cell therapy facilities, and GMP layout and architectural design development. Key aspects of the allogeneic cell therapy manufacturing process, including sampling, QC, and process understanding, are presented.

Not included in the scope of this Guide are the following areas:

  • Manufacture of allogeneic cell therapies for non-parenteral use
  • Tissue-based allogeneic products
  • Processing or manufacture of ATMPs in a clinic/hospital setting
  • Manufacture of medical devices or components used in combination devices that involve ATMPs

While this Guide focuses on allogeneic cell therapies to the greatest extent possible, the authors recognize a significant amount of content is applicable to other types of ATMPs, particularly around regulatory compliance, technology transfer, utilities, HVAC, and supply chain. The framework of this Guide has been built upon the ISPE Guide: Advanced Therapy Medicinal Products – Autologous Cell Therapy in order to create cohesive content between thetwo modalities that have significant overlaps.

  • 1 Introduction
  • 1.1 Background
  • 1.2 Scope and Purpose
  • 1.3 Structure of the Guide
  • 1.4 Manufacturing Process Overview
  • 2 GMP Compliance and Quality Risk Management
  • 2.1 Introduction
  • 2.2 Application of Quality Risk Management to ATMP Facilities
  • 2.3 Contamination Control Strategy (CCS)
  • 2.4 Identification of Critical Aspects (Including Critical Quality Attributes and Critical Process Parameters)
  • 2.5 GMP Design Requirements
  • 2.6 Multi-Product Processing
  • 2.7 Aseptic Processing Requirements
  • 2.8 Cleaning, Sanitization, and Environmental Monitoring (EM)
  • 2.9 Qualification and Validation
  • 2.10 Quality Assurance and Quality Control
  • 3 Technology Transfer
  • 3.1 Introduction
  • 3.2 Regulatory Considerations
  • 3.3 Quality Considerations
  • 3.4 Scale-out and Scale-up Considerations
  • 3.5 CMC Framework
  • 3.6 Control Strategy
  • 3.7 Technology Transfer Process and Points to Consider
  • 4 Allogeneic Cell Therapy Manufacturing Process
  • 4.1 Introduction
  • 4.2 Process Closure
  • 4.3 Sampling and QC
  • 4.4 Process Understanding
  • 5 Allogeneic Cell Therapy Facilities
  • 5.1 Introduction
  • 5.2 Common Challenges with Allogeneic Cell Therapy Facilities
  • 5.3 Design Concepts Specific to Allogeneic Cell Therapy Facilities
  • 5.4 Development of GMP Layout and Architecture (Part I – Design Philosophy)
  • 5.5 Development of GMP Layout and Architecture (Part II – Layout Development)
  • 5.6 GMP Support Spaces
  • 6 Utilities
  • 6.1 Introduction
  • 6.2 Process Utilities
  • 6.3 Mechanical Utilities
  • 7 HVAC
  • 7.1 Introduction
  • 7.2 Typical Allogeneic Process Critical Environmental Parameters
  • 7.3 Process Knowledge, Risk, and HVAC Design
  • 7.4 Facility Layout and HVAC Design
  • 7.5 Environmental Monitoring System
  • 7.6 Qualification of HVAC Systems
  • 7.7 Cost Considerations
  • 7.8 Cleaning and Maintenance of HVAC Systems
  • 7.9 Biosafety Containment
  • 8 Supply Chain
  • 8.1 Introduction
  • 8.2 Input Material
  • 8.3 On-Site Considerations
  • 8.4 Outputs
  • 8.5 Other Considerations
  • 9 Appendix 1 – Additional Information: Regulations and Guidance Documents
  • 9.1 General
  • 9.2 Technology Transfer/Scale-out
  • 9.3 Risk-Based Approach
  • 9.4 HVAC
  • 10 Appendix 2 – References
  • 11 Appendix 3 – Glossary
  • 11.1 Acronyms and Abbreviations
  • 11.2 Definitions
  • Jose Caraballo-Oramas, Kite, a Gilead Company, USA
  • Pinar Cicalese, PhD, Immatics, USA
  • Norman Goldschmidt, Genesis AEC, USA
  • Komal Hatti, NCARB, LEED AP (Co-Lead), IPS, USA
  • Niranjan Kulkarni, PhD, CRB, USA
  • Ian Moy (Co-Lead), Catalent, USA
  • Emilie Pelletier, Orchestra Life Sciences, USA
  • Erik Steffensen (Co-Lead), Spot-on Pharma Consulting, Denmark
  • Daniel Swanson, PE, IPS, USA
  • Biana Torres, Encoded Therapeutics, USA

The goal of this Guide is to provide current best practices addressing the key design and operational challenges for the commercial manufacture of allogeneic cell therapy products. The rapid pace of change within the Advanced Therapy Medicinal Product (ATMP) space is unprecedented in the industry. Science and regulatory guidance are being expanded and challenged continuously. Ongoing innovations in the product pipeline create opportunities for life-changing therapies along with significant challenges that must be addressed.

On behalf of ISPE, the Biotechnology and ATMP Communities of Practice (CoPs), and the members of this Guide team, we hope this document becomes a reference for those entering the allogeneic cell therapy space and continues to expand the industry’s knowledge of this life-changing therapeutic platform.

The framework of this Guide has been built upon the ISPE Guide: Advanced Therapy Medicinal Products – Autologous Cell Therapy published in 2021. The Autologous Cell Therapy Guide was leveraged for facility design and operational aspects that are common to both modalities; however, this Guide focuses on discussing the challenges unique to allogeneic cell therapy manufacturing.

The body of knowledge for this therapeutic area is relatively new for the industry. The Guide reflects the current state of biotechnology. In the coming years, as the industry evolves, we foresee a need to update this Allogeneic Cell Therapy Guide to reflect significant technological breakthroughs.