Addressing Challenges in Technology Transfer for Early-Phase Cell and Gene Therapy Products Strategies for Successful Transition from R&D to GMP Manufacturing

[Author’s note: This is the first article of a four-part series, focusing on the challenges and remediation strategies for companies that have developed products showing promising results in pre-clinical toxicity studies and are preparing to transition to GMP environments for Phase I/II manufacturing in collaboration with established CDMOs.]

The technology transfer of early-phase cell and gene therapy products from research and development (R&D) into current good manufacturing practice (GMP) environments presents a distinct set of technical, operational, and organizational challenges (1). These transitions are frequently complex and resource-intensive, often contributing to development delays and, in some cases, an inability to successfully scale to commercial manufacturing. Clear identification of common obstacles and practical mitigation strategies is therefore essential to improving the efficiency and robustness of technology transfer efforts, particularly when organizations engage Contract Development and Manufacturing Organizations (CDMOs) early in product development.

Key Challenges

Transitioning early-phase cell and gene therapy products into GMP manufacturing presents unique challenges that require meticulous planning and execution. These challenges include:

1. Transitioning from Lab to GMP Manufacturing
   The manufacturing of cell and gene therapies in GMP environments is governed by stringent regulations, including Code of Federal Regulations, Title 21 (21 CFR), Parts 210 and 211, which outline requirements for the manufacturing, processing, packaging, and holding of drugs to ensure their safety, purity, and efficacy (2,3).
    

   Laboratory processes are often documented informally, relying on notebook studies without formalized batch records or detailed instructions. This lack of documentation can complicate the transfer to CDMOs, as the process description, critical parameters, and ranges may be incomplete. Furthermore, laboratory equipment is frequently non-compliant with GMP standards, posing challenges related to equipment cleaning, electronic record maintenance (21 CFR Part 11 compliance), and scalability (4). These discrepancies can result in operational inefficiencies and delays during the technology transfer process.

 
2. Process Scalability
   Scaling up cell and gene therapy processes from laboratory batch sizes to Phase II and beyond introduces unique challenges, as the equipment and processes used in the laboratory may not translate seamlessly into a GMP environment. The sensitivity of certain products, such as cell-based therapies, can result in altered cell viability and density when transitioning from demonstration-scale bioreactors to larger Phase II equipment.
    

   Additional obstacles arise due to limited process documentation in early-stage development. Laboratory operations often rely on the implicit knowledge of a few individuals, without well-defined process parameters or robust documentation. This can lead to inefficiencies and failures during engineering runs, as CDMOs struggle to replicate the process consistently without clear guidance.

 
3. Regulatory Compliance
   In early-stage development, companies often prioritize process development, funding acquisition, and patient population identification over regulatory considerations. However, compliance with regulatory requirements is critical to avoid delays, recalls, or reputational risks. For example, the FDA’s Center for Biologics Evaluation and Research (CBER) has issued warnings to companies whose Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) fail to meet 21 CFR 1271.10(a) criteria (5).
    

   Companies in this phase often lack a comprehensive regulatory strategy, which can hinder their ability to meet compliance requirements and achieve timely market entry.

 
4. Phase-Appropriate Raw Material Testing and Supply Chain Management
   Securing the appropriate grade of raw materials and conducting adequate testing can create significant bottlenecks during the transition from laboratory to GMP manufacturing. According to PDA Technical Report No. 56 Application of Phase-Appropriate Quality System and cGMP to the Development of Therapeutic Protein Drug Substance and the International Council for Harmonization (ICH) guideline titled: Pharmaceutical Quality System, raw material testing requirements should follow a risk-based approach (7,12). While vendor certificates of analysis (CoA) and in-house identity testing may suffice for Phase I/II, more stringent specifications are required for advanced phases.
    

   However, companies frequently encounter challenges due to incomplete documentation or unqualified suppliers, which can result in delays stemming from supplier qualification, material testing, or sourcing new suppliers. These setbacks can extend timelines and strain financial resources.

 
5. Analytical Development and Transfer
   Validation and transfer of analytical procedures to CDMOs must adhere to regulatory standards, such as ICH Q2: Validation of Analytical Procedures, ICH Q14: Analytical Procedure Development, and other compendial requirements. Challenges often arise due to limited technical expertise and inadequate documentation of assay verification data during the R&D phase. Equipment used in laboratory environments may not meet GMP or Part 11 compliance standards, further complicating analytical transfer efforts.
    

   Additionally, the scarcity of material during early-stage development limits the opportunity for robust assay validation and hampers the ability to establish stable reference standards and procedures.

Impact of Challenges

The aforementioned challenges can lead to significant delays, financial strain, and inefficiencies, ultimately impacting the ability to deliver life-saving therapies to patients in a timely manner. From a funding perspective, these kinds of delays led to major setbacks with current and future investors. Some venture capitalists even lose their credibility because of an expanded timeline and delayed return on investment. For many patients, cell and gene therapies represent their last hope after exhausting conventional treatment options. Thus, addressing these obstacles is paramount for both companies and CDMOs to ensure the successful commercialization of these products.

Strategic Remediation Approaches

The following strategies can be implemented to mitigate challenges and facilitate a successful technology transfer process:

1. Early Familiarization with GMP Practices
   Introducing research teams and scientists to GMP regulations (1,3,6) early in the development process is crucial. This includes fostering a culture of good documentation practices (GDP) to ensure that process history, lessons learned, and changes are thoroughly recorded. Regular GEMBA and Data Integrity (DI) walks—on-site reviews of laboratory operations by quality and lab management—can promote adherence to safety, quality, data handling, and organizational standards. Such practices ensure smooth knowledge transfer to CDMOs, minimizing surprises during the transition.
 
2. Comprehensive Process Risk Assessment
   Conducting a process Failure Mode and Effect Analysis (FMEA) or similar risk assessment in collaboration with CDMO subject matter experts is essential. This joint effort allows for the identification of potential failure points, technical challenges, and risks early in the process. It also promotes transparency and facilitates the development of realistic, mutually agreed-upon timelines, enabling effective resource allocation and preventing unexpected delays. One valuable resource for this risk assessment is TR. No 54: Foundations of Quality Risk Management. This report — together with companion eLearning modules such as TR No. 54-2: Annex 1: Case Study Examples for Quality Risk Management in Packaging & Labeling and TR No. 54-4: Annex 3: Case Studies in the Mfg of Biotechnological Bulk Drug Substances, which focus on the practical application of quality risk assessment tools — provides detailed instruction on the effective use of methodologies like FMEA, PHA, and FTA (10,11).
    

   Challenges related to equipment compliance and scalability can be managed through partnerships with equipment manufacturers and the application of advanced technologies, including AI and machine learning.

 
3. Phase-Appropriate GMP Implementation
   To ensure the process remains robust during scalability studies, a phase-appropriate GMP approach should be employed. Overly stringent quality systems can hinder the progression of products through early phases of development. Instead, a flexible framework tailored to each phase of product development should be adopted, such as varying raw material specifications for Phase I/II versus Phase III and beyond. This approach is well illustrated in TR No. 56: Application of Phase-Appropriate Quality System and cGMP to the development of Therapeutic Protein Drug Substance and Phase-Appropriate GMP to Biological Process: Pre-clinical to commercial Production (9,12). It can help accelerate product release and support analytical method qualification and transfer (8).
 
4. Optimal Resource Utilization
   Efficient management of resources is critical for ensuring a successful transition to GMP manufacturing. Companies should focus on prioritizing product lines, leveraging clinical data effectively, understanding patient demographics, and conducting thorough stability assessments. Strategic allocation of limited funding can mitigate financial risks and improve outcomes for all stakeholders.
 

Conclusion

The challenges associated with technology transfer for early-phase cell and gene therapy products are significant, but they are not insurmountable. Through proactive and strategic collaboration between companies and CDMOs, along with the implementation of process risk assessments, phase-appropriate GMP strategies, and effective resource management, the transition from R&D to GMP manufacturing can be streamlined. By prioritizing knowledge sharing, transparency, and mutual trust, organizations can deliver high-quality therapies to patients who rely on these innovative treatments as their last hope for recovery.

References

1. Advanced Therapy Medicinal Products, (ATMP, 1497/2007/EC)
2. CFR Title 21, Parts 210: Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs
3. CFR Title 21, Parts 211: Current Good Manufacturing Practice for Finished Pharmaceuticals
4. CFR Title 21, Parts 11: Electronic Records, Electronic Signatures
5. CFR Part 1271: Human Cells, Tissues, and Cellular and Tissue-Based Products
6. Eudralex Volume 4: Guidelines on Good Manufacturing Practices Specific to Advanced Therapy Medicinal Products; Section 7, 2017
7. ICH Q10: ICH Guideline Q10 on Pharmaceutical Quality System; Annex 2, June 2008
8. ICH Q2: Validation of Analytical Procedures, August 2022
9. Phase appropriate GMP to Biological Process: Pre-clinical to commercial Production by Trevor Deeks, 2018
10. Technical Report 54: Foundations of Quality Risk Management
11. Technical Report 54-2 and 54-4: Practical Application of Quality Risk Assessment Tools
12. Technical Report 56: Application of Phase-Appropriate Quality System and cGMP to the development of Therapeutic Protein Drug Substance, 2016