Navigating the Life Cycle for Cell & Gene Therapies

Designing these standards requires agile approaches—similar to the agility essential for the strategic development, manufacturing, supply chain, and distribution that bring these disruptive innovations to patients worldwide. Successful quality standards creation also requires collaboration between regulators and pharmaceutical companies, which must all work together through uncharted waters and move swiftly to bring these therapies to market.

Regulators’ Role

In a 2019 interview,2 Peter Marks, MD, PhD, Director of the US FDA Center for Biologics Evaluation and Research (CBER), stressed the part that regulators play in this collaboration:

We have an important role in providing regulatory clarity to innovators. Our job as regulators is to set the bar in accordance with statutory authorities for the degree of uncertainty that we are comfortable accepting for our society in reaching product-approval decisions.

In support of innovation, agencies have created pathways to help product developers increase the speed of development. For example, the CBER Advanced Technologies Team (CATT) has created the Initial Targeted Engagement for Regulatory Advice on CBER producTs (INTERACT) program to encourage early engagement between gene and cell therapy developers and the FDA. This collaboration provides enhanced flexibility and guidance for products requiring accelerated review paths, such as products that might receive the breakthrough or regenerative medicine advanced therapy (RMAT) designation as per section 3033 of the 21st Century Cures Act.3

In the EU, the development pathway for cell and gene therapies involves the EMA Committee for Advanced Therapies (CAT), which is responsible for assessing the data and preparing a draft opinion on the quality, safety, and efficacy of the advanced therapy medicinal products (ATMPs). Additionally, the EMA Committee for Medicinal Products for Human Use (CHMP) issues an opinion recommending (or not) the authorization of ATMPs by the European Commission, which has the final decision.4 ^,5

However, industry and regulators still have a ways to go on the journey to designing quality standards for the agile development and commercialization of these therapies. By collaborating with regulators and building strong partnerships, leveraged from professional and industry associations invested in the development of guidances, pharmaceutical companies can have a great impact on these standards.

Preparing for Submission

Companies developing cell and gene therapies must involve health authorities early on to drive collaboration. Company representatives should plan presubmission meetings throughout the development process with all health authorities that will receive the submission. During these meetings, representatives should use available data to provide an up-to-date overview of the product—including information about the disease state, product attrib-utes, the clinical and nonclinical data set, labeling, and safety—and preemptively discuss concerns, such as any potential issues that need to be resolved prior to submission.

Because of the unique nature of personalized medicine therapies, where one size does not fit all, companies need to ensure:

• All studies are tailored based on risk assessments related to the route of administration, viral vectors, target tissues, indications, and other factors.
• Product development complies with all good laboratory practices (GLP).
• Safety endpoints in disease models, including cytotoxicity and potency tests, are considered.

Companies also must ensure they will be able to respond quickly to regulators’ questions. Onsite GMP inspections are not solely for evaluating quality systems and auditing the process; they also enable health authority representatives to deepen their knowledge about cell and gene therapies and chemistry, manufacturing, and controls (CMC) processes.6 As the reviewers on the inspection team more frequently augment the preapproval inspection team, these inspections also provide the opportunity for company representatives to answer deficiency questions. A question database can help a company expedite and facilitate responses to questions from health authorities. Ensuring a quick response to regulators is also necessary during any periodic meetings with agencies and for requests point filing. During the COVID-19 pandemic, industry has experienced an increase volume of questions coming from regulators, as a means to fill in the gap of not being able to directly inspect sites. Some health authorities also performed remote inspection; in the virtual setup, the pace of questions and in depth reviews were heightened.

Process Design

In commercial manufacturing of cell and gene therapies, meeting patient and physician needs must be balanced with end-to-end product and process robustness. For example, because hospitals and collection centers are key contributors to incoming material variability (e.g., patient sample or donor), it is essential to provide clear requirements around cell collection protocols or to establish human cell collection programs at the collection centers, whichever best fits the design space based on the development experience of the product.

The organization must develop and implement decision-making processes that are aligned with the organization’s quality systems while providing mechanisms to manage the complexity and variability of personalized medicines. Where possible and applicable, consideration should also be given to process and analytics automation to reduce process and throughput times and increase overall process robustness by controlling variability (e.g., using flow cytometry for incoming and final product characterization with automated cell classification and enumeration).

Because traditional GMP approaches do not always work in processes for cell and gene therapies, organizations should challenge the “whys” of every decision, while ensuring compliance and flexibility are maintained during the product release testing that confirms the safety, identity, strength, purity, and quality of each personalized patient batch. The extent of the patient material characterization should be commensurate to the process design and requirements to minimize unnecessary steps.

Product Specifications

For cell therapies, important usual attributes include viability, purity, and other functionality-related parameters that are product specific. Although defined on a case-by-case basis, these attributes are part of a release specification that is created in a phase of the development process when there is a still limited understanding of critical quality attributes (CQAs). Defining these specifications is further complicated by limited manufacturing experience and difficulties in characterizing the drug product, drug substance, and in-process materials. Furthermore, incoming cell characteristics are difficult to identify due to the complexity of the disease state and human genetics. In other words, there is no genetic match between two human beings.

Final product release, in this context, is an interesting example of the balance required between rigor in documentation and the urgency of the medication. Achieving this balance may require exceptional release pathways, which is another reason to maintain an ongoing dialog with health authorities. In many cases, these therapies are treating unmet serious conditions, and therefore, releasing product that does not meet the approved specification may be acceptable for compassionate use—the benefits of use may outweigh the risks.

From development to commercialization, cell and gene therapy companies should also consider:

• How, given the limited manufacturing experience, the organization will adequately define meaningful specifications that capture the true attribute ranges of acceptable quality, safety, and efficacy
• Which analytical methods are appropriate and fit for intended use
• How to appropriately set the acceptance criteria (e.g., upper and lower numerical limits)
• The inherent variability of the assay versus the variability of the product due to the variability of incoming starting material (i.e., incoming cells)

For example, if number of patients at the time of filing for an advanced therapy is small, the organization may have very limited manufacturing experience as it approaches the clinical pivotal phase. Therefore, the approach to setting process parameters and specifications should be conservative.

Although it would be ideal to design and conduct studies that identify and confirm the associations and relationships of attributes and process parameters to drug substance CQAs, this strategy is not always possible. Comparability runs will inherently be full scale and highly complex in terms of established acceptance criteria around process parameters and specifications (target values versus ranges).

The high variability of the cellular starting material—which is unique for each patient and affected by different treatment protocols—may have additional impact on the consistency of the manufacturing process. It may generate out-of-specification or trend results that cannot be fully characterized for the final product.

This high variability in cellular starting material is why organizations must focus on the continuous control of variability in process and analytical methods during development and post-approval. It also reinforces the importance of close collaboration between industry and regulators so time-sensitive decisions in the interest of saving patient lives can be made.

In sum, when developing and manufacturing cell therapies, it is paramount to communicate with regulators as early as possible, build systematic approaches for constantly evaluating process performance, and improve understanding of the relationship between established CQAs and process robustness and consistency.

US FDA regulations, for example, bring clear expectations around safety testing. Sterility, endotoxin, and identity testing must be performed on samples from the final drug product stored in the final container. The sample strategy should accommodate this requirement, although it will not meet the “final container” requirement. Companies must be sure to validate the rapid methodology and demonstrate comparability to traditional methods, such as rapid sterility.

Supply Chain Considerations

To ensure continued supply of cell and gene therapy products and a reliable supply chain during product development, alternative approaches and analytical pathways must constantly evolve. Supply-related issues may range from the need for waivers for local import testing to standardizing primary container labels to reduce handling of drug product and specific shipping validation that need to be executed.

Additionally, major CMC changes prompted by new sourcing for raw materials, such as viral vectors,7 ^,8 certain expansion media components, and others, must be carefully evaluated, as the newly sourced materials may require a comparability study and report. Companies can consider using im-pact-based comparability assessments—a risk-based approach that applies the concepts of ICH Q119 —even if the variations are not directly in scope. Company representatives should be sure to discuss the planned changes or studies with the health authorities prior to implementation—and to establish appropriate controls along with second sources for all critical materials.

These considerations—along with other elements and the complexity of cell and gene therapies—have resulted in regulatory agencies shifting from prescriptive industry guidance to pharmaceutical companies being responsible for properly justifying the approach they adopt for sampling plans, batch disposition, retention samples, and provision to patients.

In the 2019 interview mentioned earlier,2 Marks said:

In some ways, this can be likened to a razor-and-razorblade model. In instances where there is something that we have seen before—the razor—we might have an established set of expectations. We could then focus our attention on the razorblade: the unique and different aspects of a particular product compared to all the others that we have seen.

For cell and gene therapies, there are products that use a common set of technologies—such as some of the vectors, closed systems, and bioreactors. Collaborating across the industry and with regulators in these areas may bring more comfort as more products use the same underlying technologies, equipment, and processes. When the underlying technologies are nearly identical, there is no need to reinvent the wheel with each new product. Standard practices already exist in cell counting, measuring flow cytometry, and assuring cell viability. Collaborating on approaches that can be validated and highly characterized may streamline how therapies are brought to market and lead to increased assurance on behalf of the industry, regulators, physicians, and patients.

Conclusion

Like other pioneers, gene and cell therapy companies must continually learn, and be prepared to course correct when necessary. As the regulatory guidance on risk identification and mitigation for advanced therapies evolves, long-term safety and efficacy data on such therapies must be collected via long-term follow-up of clinical trial participants. Additionally, data from patient registries can play an important role in monitoring the safety and efficacy of cell and gene therapies, so ongoing discussions and guidelines are needed in this space.10 The EMA initiative for patient registries launched in 2015 is one step in this direction.11  This initiative and other efforts to promote regular discussions with registry holders, patient groups, marketing authorization holders, and agency representatives should be encouraged.

The possibility of enrolling postmarketing patients in existing disease registries with secondary use of data must be explored. Risk management should focus on risks related to quality characteristics, storage, and supply chain distribution of finished product—along with risks involving the donor, administration procedures, third-party transmission, and issues related to the use of viral vectors (immunogenicity, insertional mutagenesis, viral latency, and reactivation, etc.).

Great strides will be made if industry and regulators work together to continuously pursue advanced manufacturing and analytical technologies, develop strategies to provide robust and efficient pathways for manufacturing innovative therapies, and create sufficient flexibility in standards to support the innovation.

• 2 a b vMcKinsey and Company. “Helping to Accelerate Cures: Regulating the Rapidly Evolving Field of Cell and Gene Therapies.” January 22, 2019. https://www.mckinsey.com/industries/pharmaceuticals-and-medical-products/our-insights/helping-to-accelerate-cures-regulating-the-rapidly-evolving-field-of-cell-and-gene-therapies
• 321st Century Cures Act. US Pub. L. no. 114-225 (2016). https://www.congress.gov/114/plaws/publ255/PLAW-114publ255.pdf
• 4European Parliament. Regulation (EC) No. 1394/2007 of the European Parliament and of the Council of 13 November 2007 on Advanced Therapy Medicinal Products. November 2007. https://www.legislation.gov.uk/eur/2007/1394/introduction
• 5European Parliament. Regulation Commission Directive 2009/120/EC of 14 September 2009 Amending Directive 2001/83/EC of the European Parliament and of the Council on the Community Code Relating to Medicinal Products for Human Use as Regards Advanced Therapy medicinal Products. September 2009. https://www.legislation.gov.uk/eudr/2009/120/contents
• 6US Food and Drug Administration. “Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs): Guidance for Industry.” January 2020. https://www.fda.gov/media/113760/download
• 7US Food and Drug Administration. “Recommendation for Microbial Vectors Used for Gene Therapy: Guidance for Industry.” September 2016. https://www.fda.gov/media/94200/download
• 8US Food and Drug Administration. “Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-Up: Guidance for Industry.” January 2020. https://www.fda.gov/media/113790/download
• 9International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. “ICH Harmonised Tripartite Guideline Q11: Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities).” May 2012. https://database.ich.org/sites/default/files/Q11%20Guideline.pdf
• 10US Food and Drug Administration. “Long Term Follow-Up After Administration of Human Gene Therapy Products: Guidance for Industry.” January 2020. https://www.fda.gov/media/113768/download
• 11European Medicines Agency. “Patient Registries.” Accessed February 16, 2021. https://www.ema.europa.eu/en/human-regulatory/post-authorisation/patient-registries