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Process validation is an extension of biologics development processes.
When it comes to outsourcing process validation of biologics, Abel Hastings, director of process sciences at FUJIFILM Diosynth Biotechnologies, says that the relationship between a contract development and manufacturing organization (CDMO) and sponsor is key in ensuring successful process validation. “Customers that are open about their strategy, their data (good and bad), and their own strengths and weaknesses are most successful.”
Pharmaceutical Technology spoke with Hastings about the specific challenges that arise in the process validation of biologics.
PharmTech: What are the challenges of performing process validation during Phase III of biologics development?
Hastings: A primary challenge we see is viewing validation as phase-specific. Ideally, process validation should be an extension of the development and refinement processes. To support this, develop a long-term strategy for implementing some of the validation-readiness tools in simple versions early in development so that a transition toward validation is less a change in course and more an acceleration of the project.
PharmTech: What aspects of process validation should companies focus on when preparing to submit a biologics license application to FDA?
Hastings: As a CDMO, FUJIFILM Diosynth Biotechnologies has seen quite a variety of validation strategies. Some strategies are influenced by indication, regulatory designation, or client platform. Some common themes have shown themselves to aid in success of many of these projects. These themes include building clear attributeâparameter linkages, taking a systematic approach to validation, and leveraging data-driven risk management.
Clear attributeâparameter linkage begins with a fundamental understanding of the molecule attributes, the measurement systems, and the potential points of variation and ambiguity therein. This knowledge of the measurement can then be applied to the process control strategy including any ambiguity and interaction with other attributes. A team’s focus on required control becomes increasingly clear by applying a logically mapped linkage from attribute to the controlling parameters.
A systematic approach to validation that is based on consensus on both definitions and readiness criteria and is aimed at long-term commercial execution is recommended. We have refined our validation-readiness process to achieve a balance between lean efficiency and sustainability. This development required careful attention to details such as definition subtleties, systematic documentation linkage, quantitative assessment including leveraging previous data, and systematic manufacturing execution standards. This focus on mechanistically applying pre-built tools has proven to be successful with numerous clients efficiently driving their projects to success.
We also recommend building an iterative and logical risk-management program that is based on data-driven decisions. As progress continues toward validation, teams can often be influenced by process history (both recent and past), which can lead to decision making with unintended consequences. We push teams to iteratively refine risk-management documents when new data come available thereby allowing them to make decisions based on data, even in the ‘heat of the moment.’ To guide teams, we have built a series of risk-management tools that range from simple and focused on one problem to large and involved FMEA [failure mode and effects analysis]. This focus on regularly reviewing and documenting risk and data evolution has expedited project execution in a reliable manner.
PharmTech: What protocols or tools are used in process validation of biologics compared with solid-dosage drugs?
Hastings: Biologics, when compared with solid-dosage product, can be a sea of parameters and attributes, many with a high degree of variability. We have a systematic approach to process validation that draws on experience from more than 300 molecules; this allows us to focus attention on what matters most. We first begin with high-level process mapping intended to focus attention on parameter-attribute pairings. The next step, which includes smart use of a proprietary FMEA-like software tool, can help focus characterization and equipment adjustments to help improve process reliability. Finally, our platform quantitative assessment tool for parameter-attribute pairs confirms readiness for process validation. Taking this systematic approach, we have been successful in cutting through a large number of variables to reduce variation and ensure right-first-time success for validation campaigns with tight timelines.
PharmTech: How can the data obtained during process validation be used elsewhere in the production cycle?
Hastings: Process validation should be designed to demonstrate the capability of the process to support commercial manufacturing. To this end, the data generated during process validation should be the forerunner to the commercial control charts. A primary question when reviewing an initial set of commercial data should be: how do these data compare with the expected variation from my validation-preparation activities? Ideally, we expect commercial manufacturing to flow seamlessly from validation, but due to the artificial-perfection that can accompany validation, some changes are expected. Recognizing these subtle changes, and mitigating them as early as possible, can substantially improve long-term manufacturing reliability.
PharmTech: How can process validation help companies ensure their biologic’s supply chain is reliable?
Hastings: Process validation is not just about three batches in a row. It is about launching a reliable commercial process. This is why we design process validation campaigns around an expectation that sustained commercial supply must be planned for.
The quantitative pre-validation statistical guidelines and systematic tool-sets we use for validation-readiness have been developed and built around the expectations that projects must have data to support sustainable commercial success. Approaching statistical risk management with more pre-validation runs is a common practice for many companies, but our [process validation] philosophy extends beyond that to leverage a large body of pre-existing data and rigorous process-agnostic testing to augment process-specific data. To our clients, this means improved knowledge of their supply chain expectations prior to process validation.
Vol. 42, No. 1
When referring to this article, please cite it as S. Haigney, “Process Validation in Biologics Development," Pharmaceutical Technology 42 (1) 2018.