GMP Principles in iPS Cell Line Development: A Key Foundation for Advancing Therapeutic Applications

Introduction

The manufacture of Advanced Therapy Medicinal Products (ATMPs) requires the generation of high-quality starting materials, specifically cell lines, to ensure the safety and efficacy of the final product. One of the key advantages of iPSC allogeneic cell therapies is the creation of a master cell bank for the lifetime of the commercial product. The creation of this cell bank is performed once and relies on lengthy small-scale reprogramming and gene editing processes. The GMP principles, as defined by the European Medicines Agency (EMA) in the guideline EMA/246400/2021, provide a framework for manufacturing starting materials from biological origin, particularly for products involving gene transfer. These guidelines form the foundation of the Quality Management System (QMS) implemented by Cellistic for Cell Line Development,aligning with the International Council for Harmonisation (ICH) Q7 guideline regarding starting materials for biological manufacturing.

Current regulatory Standards in GMP for ATMP Manufacturing

The EMA’s GMP principles for starting materials used in the production of ATMPs establish minimal manufacturing requirements. These principles, while aligned with ICH Q7 guidelines, focus specifically on the preparation of cell lines for gene transfer processes, which are central to the creation of ATMPs. Notably, these principles differ from traditional GMP or current Good Manufacturing Practice (cGMP) in key areas (Table 1).

Table 1: Comparison of GMP Principles vs. cGMP

GMP Principles in Cell Line Development at Cellistic

Cellistic’s GMP principles, embedded in its Quality Policy, provide the foundation for ensuring the quality of cell lines used in the production of ATMPs described in Figure 1.

Figure 1: Schematic Overview of Cellistic iPSC-based Allogeneic Cell Therapy Manufacturing Workflow

These principles are designed to address the unique challenges of iPS Cell Line Development, including the selection of donors, isolation of donor cells, reprogramming, gene editing, and the creation of seedbanks. The GMP principles encompass a risk-based approach tailored to each of these processes and emphasize the need for consistent quality monitoring and improvements.

The principles guide the management of critical aspects such as personnel training, vendor qualification, and environmental controls. Additionally, a comprehensive documentation system ensures traceability and accountability for all processes.

Key Elements of GMP Principles in CLD at Cellistic

The GMP principles applied by Cellistic to its cell line development activities include several crucial components that ensure high standards of safety and quality in the production of ATMP starting materials:

• Quality Management System: A robust QMS defines responsibilities, quality objectives, and ensures continuous monitoring and improvement across the entire manufacturing process.
• Risk-Based Approach: Risk assessments are conducted to identify and mitigate potential hazards related to environmental monitoring, manufacturing techniques, and raw material use.
• Personnel Training and Qualification: Comprehensive training programs ensure that staff are proficient in GMP practices, including adherence to specific gowning procedures and cleanroom behaviors.
• Vendor Management: Thorough selection and qualification of vendors based on the criticality of materials and services provided ensures compliance with GMP standards.
• Documentation Practices: Detailed record-keeping and documentation, including batch records, specifications, and testing results, maintain traceability and accountability.
• Environmental Control: Continuous monitoring and management of environmental parameters (e.g., temperature, humidity, air quality) ensure consistency during critical manufacturing steps.
• Cleanroom Design and Management: Design and operational protocols focus on personnel and material flows, cleanliness, and contamination prevention through strict air quality and temperature control.
• Cleaning and Sanitization Protocols: Regular cleaning and sanitization protocols for equipment and facilities minimize contamination risks and support a sterile environment.
• Material and Equipment Management: Material and equipment qualification processes ensure their suitability for manufacturing activities and compliance with GMP procedures.
• In-Process Controls: Ongoing in-process controls and release testing guarantee the identity, purity, and quality of products at every stage of production.
• Continuous Improvement: Regular reviews and updates to manufacturing processes are conducted based on new information, technological advancements, and regulatory updates to improve product quality.
  

By rigorously applying these principles, Cellistic ensures that its cell lines meet the highest quality standards, contributing to the safe and effective development of ATMPs.

Conclusion

Adherence to GMP principles in cell line development is a critical foundation for the successful manufacturing of Advanced Therapy Medicinal Products (ATMPs). Through a robust quality management system, risk-based approaches, and stringent controls, Cellistic is committed to producing high-quality starting materials for gene therapies. By maintaining comprehensive documentation, ensuring environmental control, and employing continuous improvement practices, Cellistic ensures the safety, efficacy, and traceability of its cell lines, contributing to the advancement of innovative therapeutic applications.

Sources:

1. European Medicines Agency. (2021). EMA/246400/2021: Starting Materials of Biological Origin Used to Transfer Genetic Material for the Manufacturing of Advanced Therapy Medicinal Products (ATMP).
2. International Council for Harmonisation (ICH) Q7: Good Manufacturing Practice for Active Pharmaceutical Ingredients.
3. Cellistic Quality Policy Document.
4. EU Regulation (EC) No 1394/2007 on Advanced Therapy Medicinal Products.

Authors: Vincent Ernst and Eric Mathieu