How To Leverage Platform And Process Characterization Data To Accelerate Cell & Gene Therapies

By BioPhorum

Streamlining the process development and validation activities for cell and gene therapy (CGT) products is highly beneficial to ensure the timely availability of therapies to patients and maintain sustainable product pipelines. Several mechanisms can contribute to an overall reduction in program timelines, primarily involving leveraging process development data and/or the use of process platforms to support manufacturing and validation.

This article provides points to consider on how companies can use prior knowledge and platforms to leverage process characterization to reduce the testing and/or studies required during process validation for drug substance (DS) and drug product (DP) manufacturing processes.

Regulatory Considerations

For developing and characterizing pharmaceutical production processes, and detailing the production process and its controls in regulatory dossiers, there is a well-established regulatory expectation that a commercial pharmaceutical manufacturing process is:

• defined
• characterized
• validated.

In a general sense, applicable to most therapeutic products regardless of their modality, the fundamental expectations for process characterization and validation are defined in guidance documents from the International Conference on Harmonisation, the European Medicines Association, and the U.S. FDA, among others. These requirements should form the basis of a regulatory platform for a systemic approach to the development of CGTs. Once the regulatory system and approach are established for one product, this should apply to subsequent products in development.

Business Considerations

An evaluation of regulatory considerations for creating and leveraging platform approaches to CGT product development would not be complete without considering the business environment for CGT product developers. Even for more established product categories, the concept of, and the potential strategic options around, “front loading” (investing earlier in process and analytical development and understanding) versus “back loading” (investing only at the time that the probability of therapy success is more likely) is an ongoing reflection. It requires a company to define its strategy, and each option has different cost/benefit balances and associated risks.

A decision is required by each product developer about which approach to take, whether to do what is necessary only at the required time, or to engage with (and resource) a more holistic effort. Certain realities of the CGT market also come to bear, such as:

• the number of products being developed by a company, i.e., are there opportunities for platforming if only one or two products are in development? and
• development agreements and partnerships, where different products may have different development partners, even within the same individual company portfolio.

What Is A Process Platform?

Process platforms in bioprocessing provide companies with an opportunity to streamline product development, validation, and commercialization based on accumulated prior knowledge of similar products and/or manufacturing processes. For CGT products, prior knowledge will likely be accumulated as internal knowledge grows from a company’s individual experience. External knowledge also will evolve as product and process knowledge increases within the industry over time.

With an established process platform, a better understanding of the relationship between process understanding, product quality, and process performance at a manufacturing scale creates an opportunity to leverage process characterization data to supplement process validation studies at a manufacturing scale. Leveraging platform processes has been successfully applied to other products, such as monoclonal antibodies, but establishing and applying platforms has not yet been widely applied to CGTs.

Platforms may comprise a common series of unit operations or be composed of standardized individual process steps, which can be combined in a product-specific manner based on needs (i.e., a modular approach). For some manufacturing processes, such as those for adeno-associated viruses, there may be significant differences in the approach taken by various companies (e.g., inclusion/omission of intermediate tangential flow filtration or viral retentive filtration steps). This could orient a platform toward a modular approach, where the individual process steps (but not the overall end-to-end process) could be platformed. This modular approach would still provide benefits in terms of leveraging and synergies from prior knowledge.

Considerations For Establishing A Platform

The first step to realizing the benefits of leveraging platform strategies is to identify and define the scope of a platform within a company’s pipeline and technology. Platforms will vary between companies, modalities, and therapeutic areas. Establishing a manufacturing platform does not require the entire process to be standardized; some individual unit operations may be highly amenable to replication across products and be good candidates for a platform, while others may be product-specific and require an individualized approach. The regulatory landscape for CGT products has a higher level of uncertainty than for other biologics and applying process platforms may not be immediately evident. In these cases, companies should focus on building a significant knowledge base (internal prior knowledge) in the early stages of program development that can be leveraged for future products.

When designing a manufacturing process, platforming considerations should be evaluated as early as possible in the product life cycle to plan for their future use. Though not all companies will have a multi-product portfolio upon start-up, scientific and engineering principles, and an understanding of the process, can inform potential platform applications in future processes and influence the design of the initial manufacturing process (and even the facility), creating possibilities for platforms for subsequent products.

Cell Therapy Platform Considerations

As cell therapies (CTs) advance toward commercialization, implementing robust and well-characterized production processes becomes increasingly important. Process characterization data have an essential role in accelerating the development of platform approaches while maintaining cell quality throughout all phases. The early identification and understanding of challenges are important during upstream operations, and particularly during downstream operations, such as harvesting, fill/finish, and freezing. During downstream processing, cells are maintained outside their ideal environment (without nutrients) and are subject to conditions that can result in losses in viability, activity, and potency.

CT products are heterogenous, which makes the general definition of a CT platform challenging. There is a general distinction between autologous and allogenic CT products, which differ mainly in the cell source that is used. While autologous therapies use and modify the cells from the patient, allogenic cells are derived from one donor and transplanted to multiple patients. This difference in donor source has a substantial impact on the platform process since it affects fundamental technical and economic factors such as timelines, nature of the manufacturing process and equipment, manufacturing scale, manufacturing location, or economy of scale.

Opportunities To Leverage Across Industry

While most leveraging opportunities will arise within a company’s technology platform, there may be some opportunities to leverage common studies across industry, e.g., with a given raw material or impurity. Studies applying to a range of product types and compositions, or that are product agnostic, may provide a valuable avenue to reduce the validation burden and sampling requirements for CGT products. These studies may be performed by a raw material vendor or through a cross-industry publication.

Considerations For Facility Design

Facility design should consider the ability to support standard platform technology used in CGTs through both the design of the facility layout and the utilities and services provided with the manufacturing spaces. The platform will vary based on the manufacturing modality. As an example, viral vector manufacturing using cell lines may be designed to include or require upstream cell expansion and harvest, downstream purification, and filling or packaging elements. This could necessitate dedicated production areas for each unit operation and a general utility layout in these spaces to support the required unit operations, agnostic of the equipment manufacturer. This supports future flexibility as technology evolves in the CGT space.

Phase-Appropriate Process Development And Characterization

We recommend that the manufacturing process is designed as early as the toxicological evaluation phase. This allows knowledge building and historical experience of the process and reduces the risk of comparability challenges later. Having a like-for-like process is often not possible, and changes are expected during product development as material needs and expectations change.

To ensure that the manufactured product meets regulatory expectations, it is crucial to understand the impact of the process parameters in each unit operation on both product quality and process performance. Designing, developing, and characterizing process parameters increases confidence that these requirements will be met. However, such an endeavor requires significant amounts of material, which is challenging and expensive to source or generate in the CGT development. CGTs may require a wide range of testing, which further increases costs, resources, and timelines. A phase-appropriate approach can help ensure a lower risk to product quality or inconsistency, while ensuring product efficacy and safety are maintained.

Considerations For Leveraging Development Or Laboratory-Scale Data

Laboratory-scale or development studies can provide a valuable tool for reducing and leveraging studies of the manufacturing-scale process, reducing time to clinical or commercial filings. Laboratory data may be used to bolster otherwise limited data sets, supporting the statistically meaningful assessment of manufacturing success during technology transfer or process consistency during validation.

Control Strategy

The control strategy is the consolidation of collective product, analytical, and process understanding designed to ensure that a product of the required quality will be produced consistently. It is a planned set of controls derived from current product and process understanding that assures process performance and product quality. The controls can include parameters and attributes related to DS and DP materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.

For CGTs, the approach to establishing a control strategy should not be different from other therapeutic product categories in terms of content, knowledge management, and regulatory requirements. Also, once the strategy, approach, and system are established, they should be leverageable for subsequent products. However, some specific considerations create challenges when establishing a control strategy for CGTs and leveraging this for use with multiple CGTs. These include:

• Limited product understanding (compared to other product types): A clear definition of critical quality attributes is needed that has a defined link to product safety, efficacy, and functionality. If this is not available, it can hamper identifying subsequent critical process controls if the effect of the process on the product is assumed (not known) or not well understood.
• Scale-down models: Especially for CTs, representative scale models for unit operations may be difficult or impossible to establish, substantially hindering the evaluation of the effect process parameters have on product quality at a small scale.

Data Management

While data accumulation starts from early drug discovery, not all data are included in the application for regulatory approval. For CGTs (and especially CTs), the molecule and process may go through several evolutions before the final molecule and/or process is locked. Besides adhering to current guidelines on data integrity, CGT developers should facilitate easy data retrieval to support the development of potential platform and/or prior knowledge strategies.

From the early stages of development, applying a systematic approach and appropriate data management tools to link process design and control to critical product quality attributes is invaluable to provide important primers for risk assessment during process characterization and validation in later stages. Data required to show representativeness, application, and qualification of a scale-down model may require in silico modeling or statistical analysis, which could require additional handling or modification compared to conventional biologics. In such cases, data from early development or historical data from platform products or processes become even more critical as the sponsor prepares for the launch of the product.

Conclusion

Platforms for developing manufacturing processes and analytical methods are well established for numerous therapeutic modalities. These enable significant efficiency gains in development programs by leveraging systems and approaches that were developed for earlier products, often by establishing platforms and aggregating and analyzing data across different development programs within the same modality to continuously increase understanding and insights. For well-established product classes such as monoclonal antibodies, platforms can significantly reduce the cost and time needed to bring new therapies to market.

This article summarizes some of the main points from a recent BioPhorum publication on the topic. To read more, including an appendix on leveraging process characterization data to accelerate validation benchmarking survey, check out the full paper, Leveraging platform and process characterization data to accelerate CGT validation and commercialization.