Recently approved cell and gene therapies are delivering impressive results for patients who otherwise have exhausted all treatment options or have had no options available to them. The combination of these results, along with a deeper understanding of the underlying biology, is fueling explosive growth within the industry as evidenced by robust pipelines.
While these new modalities are generating significant excitement among patients and caregivers, cell and gene therapy manufacturers are experiencing growing pains. The rapid growth and continued momentum of the industry has led to the issuance of new guidance. The US FDA finalized the guidance for several aspects of development of gene therapies in January 2020.This previous lack of clarification and the current novelty of the guidance contributes to the complexity and risk of advancing these novel therapeutics. Success in the complex and highly competitive cell and gene therapy space requires managing uncertainties and risks related to manufacturing. This imperative can prove especially challenging when operating with compressed regulatory timelines and a sense of urgency to address significant unmet patient needs.
In this article we share insights for navigating within a novel and complex regulatory environment, mitigating risks posed by raw materials and implementing proper risk assessments during manufacturing. We also share our perspective on optimizing communication and ensuring transparency when working with a contract development and manufacturing organization (CDMO).
Adopting a Risk-Based Approach
Regulations related to cell therapy were initially put in place more than a decade ago and focused on somatic and unmodified cells. Fast forward to today, and it is clear that development and manufacturing of highly sophisticated gene and gene-modified cell therapies continues unabated as regulatory guidance evolves. In this fast-paced environment, close communication with regulatory authorities and a risk-based approach is essential. A risk-based approach should be leveraged for every aspect of manufacturing. Manufacturing should be carried out under a mature quality system to ensure adequate and consistent product quality. In determining the appropriate measures to address the identified risks, priority should be given to patient safety; the greater the risk to the patient, the greater the amount of characterization that should be conducted. A best practice is to leverage a quality by design (QbD) strategy in which a significant amount of data is collected to support risk-based decisions. Principles of International Council on Harmonization (ICH) Q9 can be followed to perform a risk assessment and ensure that level of effort and documentation is commensurate with the level of risk as:
- A product not demonstrated to have mitigated risks to patient safety may not receive approval for clinical studies
- A weak quality system may also compromise the approval of the clinical trial if the safety of trial subjects is at risk
- With a cell or gene therapy, this data collection should be accompanied by early, open and routine dialogue with regulators to avoid any surprises – on both sides.
Ensuring the Quality of Raw and Starting Materials
With many gene and gene-modified cell therapies being developed under accelerated timeframes, it is imperative for companies to think about their raw materials, starting materials and supply chains early in the process. This proactive approach provides the time needed to establish the proper controls and have supply chains qualified early, so there will be no delays when the time comes to move into clinical development.
Raw Materials
Unlike the processes used to manufacture monoclonal antibodies in which the protein therapeutic is subject to many purification steps prior to formulation as the final product, with cell-based therapies, there is little opportunity to remove impurities or do a terminal sterilization. Because the cells are the product, anything introduced into the culture such as media, buffers, microcarriers, enzymes and growth factors, can alter or modify the cells or their function such that safety or efficacy are affected. For example, if the cell culture medium is not chemically defined, and/or contains supplements such as serum, it becomes difficult to have exact specifications for it; the resulting lot-to-lot variability can affect the cell growth and in turn the performance of the cellular therapeutic.
An increasing number of suppliers are now manufacturing these raw materials and cell culture media, historically used for research purposes, under good manufacturing practices (GMP) to reduce variability, ensure traceability and ensure supply robustness. Use of GMP under a quality management system (e.g., ISO 9001) ensures high lot-to-lot consistency and the documentation to help users with their risk assessments and align with regulatory guidelines. GMP and a mature quality management system ensure suppliers have standard operating procedures and a corrective and preventative action (CAPA) methodology in place to rapidly and effectively address any quality issues. To further protect processes and patients, we recommend creating a supply agreement between the user and suppler which establishes:
- Technical specifications
- Quality specifications
- Change management details
As animal origin components pose a risk of microbial and viral contamination, their use is discouraged by regulatory agencies globally. Animal or human origin materials that are not manufactured under a quality management system and used at a stage in the manufacturing process where there is no opportunity for clearance pose the highest risk to patient safety. However, if their use cannot be avoided adequate risk mitigation should steps should be put in place. Fortunately, several steps can help ensure critical raw materials are not contaminated by adventitious agents:
- Source from well-known, safe geographies and use screened donors
- Test for species-relevant contaminants
- Inactivate by validated methods using heat, irradiation and filtration
- Use of at least two orthogonal mitigation methods for high-risk material
Starting Materials
In addition to the vector and virus stocks, patient, donor and producer cells are critical to the final product quality. For allogeneic applications, we recommend using a two-tiered cell bank system manufactured under GMP with procedures to:
- Ensure preventive principles to provide reasonable assurance of the absence of contamination and to provide a reliable source of the cell substrate
- Avoid cross contamination by other cell types and to avoid microbial contamination
- Freeze under defined and controlled conditions, stored in the vapor phase of liquid nitrogen
- Protect from catastrophic events using redundancy in the storage containers, back-up power, automatic liquid nitrogen fill systems and storage at different sites.
The two-tiered cell bank system starts with a master cell bank (MCB) which serves as the starting material for the overall production process. The MCB is the collection of cells of uniform composition derived from a single source prepared under defined culture conditions and fully characterized for microbial and viral contaminants. The working cell bank (WCB) is derived from one or more vials of cells from the master cell bank, which are expanded by serial subculture. The pooled cells are dispensed into individual vials and cryopreserved to form the WCB. Table 1 summarizes how master and working cell banks can be characterized to ensure quality.
Opening the Lines of Communication
In addition to engaging in regular dialogue with regulatory authorities, we recommend close and proactive communication with your CDMO who should create a multidisciplinary team to support the project. The team should include members from project management, process development, manufacturing, technology transfer, supply chain, regulatory and quality.
Among the key conversations to have with the CDMO are the possible expedited designations the company is expecting to receive such as fast track, breakthrough therapy, PRIME or regenerative medicine advanced therapy (RMAT). These designations can have an impact on the commercialization strategy. Previously planned timelines can become significantly
compressed. Activities such as manufacturing clinical lots, characterizing the product and manufacturing process performance qualification (PPQ) batches may overlap and require additional resources and close management to progress quickly.
Even slight changes to a process may necessitate a pause in clinical manufacturing; this may include execution of a non-GMP engineering batch to ensure the impact of changes can be identified and implemented within the Quality System before proceeding. Timely communication with the CDMO will enable the setting of reasonable timelines for possible multiple revisions of the batch records during the PPQ process.
Close communication and transparency with your CDMO are also essential for a successful inspection and review process as they will participate in the process. Both sides must be in complete alignment in terms of the approaches used and data generated to avoid any missteps in front of the regulatory authorities.
Conclusion
Gene and gene-modified cell therapies are offering remarkable results for patients with unmet medical needs. The manufacturing of these modalities, however, is much more complex than biologics such as monoclonal antibodies and the industry must continually break new ground, operating in an environment of constant change. As we collectively seek to replace complexity and uncertainty with clarity, a number of considerations should remain top-of-mind for gene and gene-modified cell therapy manufacturers as they position themselves and their drug candidates for success:
- A risk-based approach to the manufacture of these therapies is recommended.
- Adventitious agent control, traceability, supply security and control of lot-to-lot variability of raw materials is key to product quality.
- Well-characterized cell banks and vector lots are required by global regulatory bodies.
- Seamless, proactive communication with your CMDO helps minimize surprises and helps the innovator company succeed with an accelerated timeline.
