The Secrets of Ensuring a Successful Process Validation Campaign at a CDMO

Pramthesh Patel, vice president of process development, Avid Bioservices.

Process validation is a critical step in the path to commercialization and is fraught with complexities. After offering how Avid, a contract development and manufacturing organization (CDMO), works with its partners, Pramthesh Patel offered three case studies of successful projects.

Avid is a dedicated CDMO with over 30 years of experience manufacturing biopharmaceuticals. It is a drug-substance company for both clinical-trial and commercial materials, with batch scales from 100 L to 2,000 L. Redundancies are built in to ensure that Avid can meet customer timelines. The fully disposable facility is designed to produce 20 kg/batch, and the management team brings a wealth of industry experience to all aspects of the organization.

In 2011, the FDA issued a revised guidance to industry for process validation based on general principles and practices. Process validation can be divided into three stages: process design (which Patel likes to call process understanding), process qualification, and process monitoring/continuous process monitoring. He noted that the industry has clear guidelines for stages 2 and 3, but that no clear guidelines exist for stage 1. What depth of understanding is needed, for example, for a process performance qualification (PPQ) study? The Avid group has developed a set of guiding principles for overall communication about process characterization, working to create a clear understanding of both the product and process. Setting a quality target product profile (QTPP), defining potential critical process parameters (CPPs), and determining process robustness all feed into an initial risk assessment.

A good scale-down model is an essential tool for process characterization work, which is needed to create a design space and control strategy. Following a detailed design of experiments (DoE) study, a company can update its risk assessment, start developing its initial control strategy, and then initiate a PPQ campaign. The finalized control strategy is filed with regulators, and once it is approved, the company can proceed to continued process verification, working with both the client company and with the regulators to implement process improvements.

CDMOs work with a complex mélange of client companies that different levels of experiences — from big pharma, to well-established and mid-sized biotechnology organizations and virtual or emerging companies. Mature clients might have reliable platform processes to enhance process understanding; virtual biotech companies have none of that. Some clients have mature, well-defined internal quality systems; others do not. A CDMO also works with clients with differing levels of risk tolerance and budgetary constraints.

Patel described four pillars for ensuring success in client–CDMO partnerships. He began with the importance of good, timely, and detailed communication. Avid appoints a dedicated project manager who encourages interactions between subject-matter experts (SMEs). Having a person-in-plant also supports timely communication.

The next two pillars are equipment and personnel —critical success factors. Patel’s slides showed Avid’s equipment offerings and highlighted staff experience, with a number of key directors having been with the company for more than 18 years (and with many previous years in the industry).

His fourth pillar for success is to create a solid management philosophy. It is extremely important to build trust with a client company, earning its respect through demonstrating a mutual desire for the product to succeed — in a sense, co-owning the product.

Patel’s three case studies began with a description of a scale-down model, which is critical to process characterization and development of a good control strategy. An example of a downstream model showed that material generated at large-scale was run on small-scale columns, maintaining the same column height and flow rate (therefore, a similar residence time). His second case study illustrated how Avid works flexibly with its partners. He explained how ongoing work with one partner has developed of a recombinant enzyme from 100-L to 300-L scale, then to a 1,000-L single-use bioreactor. His final case study evaluated continued process verification. His slide showed 15 consecutive batches that all fell within the defined limits.

Patel concluded by showing data of Avid’s “track record.” The company has made more than 200 commercial batches and is approved to manufacture marketed products in 90 countries.

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