An often overlooked but critically important step along the path from bench to bedside, Process Performance Qualification (PPQ) often results in delays and potential non-compliance issues without proper planning. PPQ is a pivotal moment in the product lifecycle, when a manufacturer must demonstrate that a process—in the intended facility, with qualified equipment and trained staff—can operate reliably to achieve consistent product quality at commercial scale. PPQ represents the final stage of formal process validation before routine commercial manufacturing begins. This step is especially challenging in cell and gene therapy (CGT) manufacturing since batch sizes are small, starting materials and product attributes can be highly variable, and processes are very complex.

“The inherent variability in biological materials can make it difficult to achieve the consistency and reproducibility you need for successful PPQ,” says Hiren Patel, senior quality manager at MilliporeSigma’s viral vector CDMO in Carlsbad, CA. “It’s not always practical to do the three-run validation that manufacturers would traditionally expect. Instead, you need a robust master plan, a proactive regulatory communications strategy and an analytics-driven approach to create a compelling PPQ campaign.”

PPQ for CGTs are complicated by the fact that regulatory frameworks are still evolving. Regulatory agencies have signaled an increasing willingness to consider platform data and results from statistical models in process validation, while also giving sponsors greater latitude in the number of lots required. The FDA recently announced a more flexible approach to overseeing CMC requirements for CGTs, including case-by-case tailoring of PPQ requirements based on individual process and product characteristics. While this flexibility is good news for manufacturers, it makes early and frequent dialogue with regulatory agencies even more important for successful process validation.

Validating CGT manufacturing processes will always involve complexity and uncertainty, but choosing the right CDMO partner gives sponsors access to specialized expertise, helping to mitigate these risks and streamline the path to commercialization.

Three Ways to De-Risk PPQ

If stakeholders approach PPQ with a “check the box” mentality, late-stage delays and complete response letters (CRLs) are more likely, especially for biologics and CGTs. Here are three ways developers can avoid these hurdles.

1. Plan for PPQ early and intentionally.

Creating a Process Validation Master Plan is a best practice, but sponsors should aim to define their overall PPQ strategy as early as possible. Setting clear objectives makes it possible to set specific requirements for stakeholders and deliverables across the entire process. When sponsors and CDMOs have aligned their expectations about responsibilities and documentation from the start, PPQ execution will be much more streamlined.

It’s also critical to make process characterization studies as comprehensive as possible, Patel says. “The more thoroughly you assess the inherent variability in your process, the more robust you can make your control strategy to ensure consistent product quality. This is true of PPQ in general—the more detailed work you do early on, the better you’ll perform later.”

Many of the issues most likely to derail PPQ can be anticipated. Supply chain disruptions, for instance, are not uncommon, and when they occur, it can be difficult to secure the raw materials needed to complete validation runs.

“Prepare for the worst-case scenario,” says Patel. “Stock enough raw materials and supplies to support more runs than you had initially planned.”

2. Emphasize process quality and continuous improvement.

A robust process control strategy is essential for successful PPQ. Critical quality attributes (CQAs) and critical process parameters should be defined in accordance with Quality by Design (QbD) principles. Your CDMO partner should be able to demonstrate that process parameters have been appropriately classified and that the most critical parameters are being actively monitored.

A strong quality management system (QMS) helps ensure that clear policies, standard operating procedures (SOPs) and oversight mechanisms are in place across the process. An effective QMS also supports well-designed change control, supplier management and employee training programs, providing assurance that operations are safe, compliant and consistent.

“CGT manufacturers should conduct a Failure Mode and Effects Analysis (FMEA) early on,” says Patel. “This allows teams to identify potential points of failure in the process and take mitigation steps before problems arise. FMEA is a critical tool for risk management and improving process reliability.”

As regulators become increasingly open to post-approval criteria adjustments, they are placing greater emphasis on ongoing continuous process verification (CPV). To prepare, CGT manufacturers must monitor their processes with an eye toward making improvements over the long term.

“You should be constantly monitoring your process parameters, so that you can investigate root causes as soon as you notice any kind of shift in the process,” Patel explains. “At MilliporeSigma, continuous improvement is central to our culture. We encourage our technical teams to speak up about potential quality improvements and are always looking for ways to do better. This mindset contributes directly to PPQ success.”

3. Leverage data and analytics throughout process validation.

Your CDMO partner should use statistical tools to analyze available process data and assess variability to provide greater confidence in process performance.

“In cell and gene therapy manufacturing, relatively few batches are produced,” Patel says. “Because of this, it’s especially important to extract as much insight as possible from the data you do have. At MilliporeSigma, we’ve invested heavily in technology to boost our data integrity compliance. We’re constantly evaluating digital tools that help improve data integrity and generate deeper insights, because we believe that this data will be key for regulatory approval.”

CGT manufacturing processes and analytical methods are still maturing, so limited historical data and platform knowledge are available to draw upon in designing a PPQ strategy. This gives manufacturers a certain freedom at a time when opportunities to engage in discussion with regulators are also increasing.

“It’s becoming more common to have conversations about why certain decisions were made,” Patel says. “Why did you choose a certain number of runs? Why did you define your process validation master plan the way you did? Why did you establish a particular PPQ protocol? When you can answer these kinds of questions—and you have the right documentation—it’s easier to meet regulators’ expectations.”

By selecting a CDMO partner with deep expertise in process validation—one that has made major investments in people and technology—late-phase developers can reduce the stress and uncertainty that PPQ would otherwise bring.

“Our Process and Analytical Department has the latest technology and state-of-the-art equipment so that we can conduct cutting-edge research and deliver exceptional results,” says Patel. “Our expert teams bring the same focus on quality to tech transfer and manufacturing. Our site prioritizes staying up-to-date with the latest regulatory changes so that processes can continue to meet compliance requirements.”

MilliporeSigma has been a leader in viral vector manufacturing for more than 30 years and has supported four commercially-available viral vector-based gene therapies. As a viral vector CDMO, MilliporeSigma offers comprehensive regulatory support and specialized technical expertise to de-risk process qualification and make the transition from clinical to commercial manufacturing seamless.

Learn more about MilliporeSigma’s viral vector CDMO services.

MilliporeSigma is the U.S. and Canada Life Science business of Merck KGaA, Darmstadt, Germany.