A lifesaving biotherapeutic can help patients only after approval. To get approval from the U.S. Food and Drug Administration (FDA), bioprocessors count on experience and expert guidance. To learn about some of the best strategies to gain approval for a bioprocess, we talked with experts from three vendors—BIA Separations (recently acquired by Sartorius Stedim Biotech), Cytiva, and MilliporeSigma—and two contract development and manufacturing organizations (CDMOs)—Catalent Biologics and Lonza. These specialists reveal the key challenges and solutions.

Pete Gagnon
Pete Gagnon, BIA Separations

No matter what, the process is not easy. “For at least the last half century, there has been a not-funny joke cycling through the industry that anyone who manufactures therapeutics actually makes two products,” says Pete Gagnon, chief scientific officer at BIA Separations. “There’s the actual product, plus the documentation for the FDA.”

The challenge, he notes, applies to all stages of bioprocessing: upstream, downstream, analytics, development, validation, and clinical trials. “You can argue which is more difficult or more important,” he continues, “but the real challenge transcends any one of them.”

Much of the challenge arises in creating harmony between the steps in bioprocessing and the regulatory process all the way to market. To get such a wide range of steps in sync, it takes a philosophy that encompasses an entire company, as well as its suppliers. “The challenge,” Gagnon summarizes, “is compounded at all levels by the need to keep costs down, but the core remains the fundamental integration of technical and regulatory affairs.”

The regulatory challenge increases with the addition of anything novel, such as using new elements or manufacturing technologies. “These range from a new manufacturing cell line upstream or some improvement or change within the bioreactor, to modifications and updates to the downstream purification process,” says Andrew Bulpin, PhD, head of process solutions at MilliporeSigma. “All submissions to the regulators must contain a proper and full assessment of the entire process, especially as it relates to minimizing the risks of contaminants such as viruses and other biosafety risks.” Anything new will draw even more attention from the regulators. “In the worst case,” Bulpin points out, “supplemental studies might be requested which could negatively impact approval timelines and subsequent commercial availability.”

Taking a long view

The better that a bioprocessor understands a process, the easier it is to work with regulators. “The lack of process understanding can lead to a suboptimal control strategy that may hinder the ability to achieve tight specifications,” explains Claudia Berdugo, PhD, director of process development at Catalent Biologics.

Abdelaziz Toumi, PhD
Abdelaziz Toumi, PhD, Lonza

Also, instead of just focusing on the speed of developing a product, bioprocessors may take the long-term view and find that doing so works better. “The downside of timeline acceleration in early development is the risk that one may face the consequences of cutting corners,” says Abdelaziz Toumi, PhD, head of commercial solutions, Ibex™ Design and Develop, Lonza. Undesirable consequences, he says, include a “lack of cell line robustness and variable process performance, which are typically due to a lack of process understanding and control—and are often reviewed by regulatory authorities.”

Going too fast in the early stages could also create later difficulties in scaling up to commercial levels and even poor design of the product. “These issues,” Toumi continues, “can lead to the need to rework program stages, resulting in increased program cost and length, difficulties moving quickly to later stages or to pivotal trials, and even delays in regulatory approval.”

To save time at the start, a bioprocessor can opt to participate in CDMO programs, such as a program that Lonza has developed that can help small biotech firms go from a gene to an investigational new drug (IND) application. The process, Toumi says, can take just a year.

Catalent Biologics can also help a bioprocessor reduce regulatory risks. “[We offer] an outline of a comprehensive program that ensures no shortcuts are taken, [and we stagger] the work to accelerate timelines,” asserts Berdugo “This approach enables us to work toward improving our understanding of the process based on appropriately ranking critical process elements.” This method can lead to a better understanding of the risks and the creation of mitigation plans if needed.

Trying new tools

New approaches can also help CDMOs and bioprocessors work more quickly through specific steps. As an example, BIA Separations developed an anion exchanger that can used to purify large messenger RNA (mRNA) molecules. “It overcomes the longstanding problem of needing to heat the sample and column to recover the RNA,” Gagnon says. “This reduces the regulatory burden and cost by suspending the need for controlled high-temperature processing in preparative and analytical applications.”

The analytical version of the anion exchanger also provides regulatory benefits in upstream bioprocessing. “It enables fast characterization of in vitro transcription mixtures to document the quantitative impact of different reagents, relative amounts of reagents, and conditions on overall transcription efficiency,” Gagnon explains. “The preparative and analytical media together accelerate quality by design–based development of the entire manufacturing train, as well as their validation.

“Tools that are highly adapted to a particular application inherently reduce the paperwork burden. The smaller the number of process variables, the simpler it becomes to provide the FDA with precisely the kind of documentation it needs to be confident that a process can reproducibly yield a safe, effective product. Providing such documentation to the FDA as early as possible is a key to accelerating eventual approval.”

Another approach to accelerating approval involves the use of templated processes. “For well-established therapies such as monoclonal antibodies, vaccines, or blood products, the use of well-understood platform technologies in a templated process helps to speed the approval process,” Bulpin notes. “Indeed, the use of templated processes was reiterated in March this year by the ICMRA—the International Coalition of Medicines Regulatory Authorities—as a means of ensuring rapid approval for first-in-human trials of SARS-CoV-2 therapies.”

Although many bioprocessors would agree that templated processes and technologies can pave a smoother regulatory path, it’s not always the best path. For example, the templated approaches are the older ones, often decades old, and not necessarily very efficient. One example that Bulpin picks out is the characterization package for a manufacturing cell line that will be used for a Phase I study.

“The industry has long relied on in vivo models for the assurance of viral safety of their cell banks,” he says. “Unfortunately, these tests can take up to three months to provide the required data on viral risk.” To provide an alternative, Bulpin and his colleagues have worked for some time to replace some of the in vivo tests with “established molecular-based alternatives such as NGS—next-generation sequencing,” he continues. “However, it is the current pandemic situation that has driven a greater number of biopharma developers and manufacturers to adopt these alternatives.”

With NGS and the MilliporeSigma Blazar™ rodent panel—a rapid molecular-based detection assay that replaces the in vivo antibody-production test to screen for specific rodent viruses—the company can, asserts Bulpin, “effectively reduce the timeline for cell line characterization from three months to four weeks, facilitating vital therapies to enter the clinic faster.”

MilliporeSigma’s Blazar™
MilliporeSigma’s Blazar™ is a molecular detection platform that can serve as an alternative to in vitro detection assays and speed viral detection. It can also replace in vivo antibody-production tests. For example, it can screen for specific rodent viruses, reducing the timeline for cell line characterization from three months to four weeks.

With all the tools applied to the pursuit of regulatory approval for a biotherapeutic, a bioprocessor needs ways to keep track of data. As Michelle Stafford, Cytiva’s global enterprise marketing manager, says, “One of the biggest challenges facing biopharmaceutical manufacturers is data integrity and documentation.” Although advances in automation and digital solutions can provide the needed data processes, she points out that “many organizations lack the digital infrastructure needed for integrating data from disparate systems.”

If that’s a problem at the clinical trial stage, it expands in commercial operations. “Cytiva’s Figurate automation platform is designed to develop a standard platform at process design and grow with an organization from clinical to commercial manufacturing,” Stafford notes. Figurate, she adds, can create “standard platforms that streamline the transfer of information between and within facilities.”

Balancing speed and risk

As noted, new components and processes attract more regulatory attention. Bioprocessors need to find a balance in a precarious setting. “One major industry challenge is a Catch-22 situation where biopharma is highly motivated to produce therapeutics faster and more efficiently, ultimately reaching patients more quickly,” Bulpin notes. “However, there are real concerns about increased scrutiny, which could risk a delay in approval.”

Kee Cheung
Kee Cheung, Lonza

Other experts agree that this creates a complex challenge. “It is a delicate balance to provide speed, reliability, and quality biotherapeutic products to meet the regulatory requirements within time constraints,” says Kee Cheung, head of regulatory affairs, clinical development manufacturing, Lonza. To build in that balance, Lonza relies in part on experience. “Lonza has over 30 years in process development producing stable cell lines and reproducible processes for biotherapeutic products,” Cheung notes. “Lonza supported over 420 biotherapeutics in 2019, and over 40 are approved products.”

As the bioprocessing industry keeps moving, so must vendors and CDMOs. In some cases, vendors and CDMOs supply complete solutions. One example, Cheung points out, is Lonza’s Ibex Solutions. “At our new facility in Visp, Switzerland, we offer a complete product lifecycle through preclinical, clinical, and market supply,” she says. Building such a process, though, depends on tools and experience.

“There are several factors that contribute to Lonza’s ability to meet the timelines outlined in Ibex Design while minimizing the risk,” says Toumi. Part of this arises from substantial scientific expertise in developing processes. Other parts depend on tools. Here, Toumi refers to how a robust cell line construction process may be realized with the GS Xceed Expression System, which incorporates “a range of vectors, media, and detailed system knowledge to provide customers with a fully integrated package.”

In looking for a CDMO, a biotherapeutic maker can expect anything from specific steps being performed to a complete process. The best choice depends on the product and the customer. In any case, the CDMO should be able to provide plenty of examples of successes in the areas of interest.

The process of receiving regulatory approval for a new biotherapeutic will probably never be easy. When a bioprocessor endeavors to create new kinds of products and new production techniques, the regulatory path will always draw more attention and require a bioprocessor to provide more data and more assurances—whatever is required to ensure the highest levels of reproducibility, safety, and efficacy. By starting early—basically from the start—with an eye on making the regulatory process smoother, a bioprocessor can reduce some of the time and stress.

Working with experienced experts can further improve the outcome. In addition, new tools and techniques will continue to create novel ways to reduce risk. Although never risk-free, the regulatory path of a biotherapeutic can improve and support faster development. The right analytical tools and data management software will also help a bioprocessor keep track of advances in development, and the same data presentations will make it easier for regulators to assess the product and how it was made. Ultimately, it’s the complete process that determines if the regulatory path gets bumpy or stays as smooth as it can be.

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