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Biologics have specific quality considerations that make fast tracking these drugs more difficult.
The COVID-19 pandemic put a spotlight on how the bio/pharmaceutical industry and regulators can work together to bring life-saving therapies to the market fast to safeguard and improve public health. The lessons learned from the pandemic should be evaluated and possibly applied to how regulators approve medicines and how manufacturers produce and deliver them to patients that need them.
Pandemic-related vaccines and treatments are not the only medicines that may be ushered quickly through approval and production processes. There are medications needed for a variety of diseases and conditions that are considered rare, unmet needs. Orphan drugs are one example. FDA defines an orphan disease as affecting fewer than 200,000 people in the United States. “Some diseases have patient populations of fewer than a hundred. Collectively, however, they affect as many as 25 million Americans, according to the National Institutes of Health (NIH), and that makes the diseases—and finding treatments for them—a serious public health concern,” according to the agency (1).
Regulatory agencies recognize the need for treatments for these conditions and have policies in place to ensure treatments are available for patients. FDA’s Fast Track designation process facilitates the development of medicines to treat serious conditions and/or fill unmet needs. The process also expedites the review of these drugs. Unmet medical need is defined by FDA as “providing a therapy where none exists or providing a therapy which may be potentially better than available therapy.” The process includes early and frequent communication between FDA and the sponsor company so therapies can be approved quickly (2).
In Europe, the European Medicines Agency (EMA) uses their priority medicines (PRIME) scheme to enhance development of medicines to fill unmet needs. The agency gives early and proactive support to PRIME drug sponsors so that robust data can be generated about the benefits and risks of medicines in development (3).
“In response to COVID-19, the Government of Canada wanted to build domestic capacity for rapid mRNA [messenger RNA] vaccine production to meet future potential outbreaks of infectious disease. As a modality, mRNA addresses a much broader range of diseases than only COVID-19. Some of these drug or vaccine candidates may be appropriate for an expedited approval process. For example, the science and technology are in place to use mRNA for therapeutic vaccines and other therapies to treat diseases like cancer and orphan conditions. We also have customers looking at mRNA vaccines for flu and other infectious diseases,” says Peter Ercoli, chief operating officer, Biologics, BIOVECTRA.
With the new interest in potentially shortening time to market for medicines using the lessons learned in the pandemic, industry and regulators may be looking to fast track large-molecule drugs. Biologics, however, are often more complex than their small-molecule counterparts and, therefore, may have specific quality considerations that make fast tracking these drugs more difficult. “As large organic molecules, biologics are inherently more complex and variable than small molecule drugs, creating challenges to manufacturing and quality control,” says Ercoli. “One roadblock is the need to understand a variety of processing methods that differ for each biologic modality.”
Roadblocks to expediting biologics, according to Steven L. Walfish of Statistical Outsourcing Services, include 12 months of real-time stability, analytical method validation, and licensing of manufacturing facilities. Biologics rushed to market also require more risk-based quality control in the development stage, says Walfish. “Companies must determine which quality control tests are vital to ensuring quality versus running all tests because the regulatory landscape expects it.”
Expediting most biologics may not be as viable as the COVID-19 vaccines, according to Ercoli. “Given the critical nature of the COVID-19 pandemic, for which there were no existing viable treatments, scaled up production and regulatory approval of mRNA vaccines occurred in only six to nine months. This was a special case in which expedited approval meant focusing the entire world’s resources and attention on it. Getting other drugs manufactured, tested, and through regulatory agencies will continue to take years, not months, unfortunately. We may be able to shave a few months off that timeline for a rare disease treatment that gets fast-track designation,” he says.
Manufacturers must ensure, however, to not sacrifice quality control when speeding up production, says Ercoli. “Process development and manufacturing of biologics is complex, including development of cell lines, fermentation, and downstream purification of proteins or mRNA.” Robust processes may decrease the time to market, but regulatory guidance must be followed, according to Ercoli. “Taking what we learnt from the COVID vaccine approval process, we need to ensure quality control is adequate at each stage of development, manufacturing, and post-approval. Then, we can take what we learnt from the COVID vaccine approval process and apply it to other biologics in the future.”
Quality by design and historical knowledge should be used during development, according to Walfish. “Tasks that are usually performed later in the product life cycle can be moved up to earlier stages,” he states.
Consistency of manufacturing is necessary for commercial readiness of a biologic, explains Vincent Villegas, senior director, Government Affairs and Strategic Initiatives at Jubilant HollisterStier. Qualification of equipment, facilities, and utilities must be guaranteed as well as the reproducibility of the process. “There must also be a continuous process verification that includes a control strategy, ongoing assurance the process is in control, and that there is statistical analysis and proactive improvement to the process,” stresses Villegas.
Adequate chemistry, manufacturing, and controls (CMC) information is a challenge, according to Melissa El Khouri, head of Quality, BioCina, “in particular for comparability assessments and stability programs, to support the approval of the biologic.” El Khouri recommends using a phase-appropriate and risk-based approach. “[One should] consider the type of product (microbial, plasmid, mRNA), the characteristics of the molecule, the clinical phase of the program, and the quality control data available to support changes and impact on the critical quality attributes of the manufacturing process,” she says. Artificial intelligence and machine learning may also be used to understand process variability quickly and determine how it impacts product quality, “in line with support and approvals required from the applicable regulatory bodies,” according to El Khouri.
Walfish stresses that manufacturing of expedited biologics includes making more risk-based decisions so that time is not wasted on methods that do not add information to the process. “Most organizations have orthogonal methods to confirm results of methods,” he says.
Contract development and manufacturing organizations (CDMOs) and contract manufacturing organizations (CMOs) play an integral role in expediting therapies to market, including the ability to offer facilities and expertise. Contract organizations, and the sponsors who utilize them, should use sound scientific approaches to ensure safe products, according to Villegas. “The CMO should develop a continually improving process in conjunction with pharmaceutical quality systems that meet or exceed GMP [good manufacturing practice] requirements. CMOs should not underestimate the complexities during scale-up and tech transfers and should utilize all tools available to them to ensure a smooth process. It is a collaborative effort with multiple divisions within the organization for a successful technology transfer and final manufactured product,” he says.
“A CDMO that has handled hundreds of different processing methods and biologics has the ability to anticipate potential issues, smoothing the path to validation and regulatory approval of a new molecule,” says Ercoli. And he stresses that CDMOs must understand if a sponsor needs full CMC development or if processes need to be replicated and scaled up to productions. “The foundation of what a CDMO does is technology transfer of a customer’s existing process, followed by scale-up. It’s the ability to bring in a new product, evaluate the robustness of the process, scale up production, and transfer it to commercial manufacturing. The key to ensuring quality is to do it right the first time. We never want to be in the position of sending something back to development and saying, ‘This doesn’t work, we need to start again from scratch.’”
Villegas agrees that tech transfer is essential “to achieve product realization during vital situations when CMOs are more than likely utilized to mass produce these products. This knowledge forms the basis for the manufacturing process, control strategy, process validation approach, and ongoing continual improvement so that the product is safe, effective, and consistently manufactured for patients.”
El Khouri offers three ways CDMOs can assist sponsors to expedite a biologic to market: efficiency of operations and phase-appropriate approaches to timelines; effective communication between sponsor and CDMO; and providing regulatory expertise. “A CDMO should offer end-to-end services, new technologies, and strong quality expertise; foster a collaborative approach to partnerships with their sponsors; and encourage early conversations with regulators and sponsors,” says El Khouri.
“In terms of quality, there are no shortcuts whether the process is expedited or not,” says Ercoli. “A good quality system is the most robust business process. One tempting shortcut is to try to generate quality data faster by cutting back on the number of test batches or on stability testing. Usually, that just means having to do it all again because the statistical significance of the data isn’t sufficient to ensure the drug is safe and effective.”
While the regulations for expedited drugs are the same as drugs that go through the traditional approval process, according to Ercoli, regulations for biologics differ from those for solid dosage drugs. “Chemical synthesis of solid dose drugs is a less variable process than the production of biologics. As biologics are derived from living organisms, they have inherent variability, are more prone to degradation, and require a greater degree of product characterization to ensure quality control. Sourcing high-quality raw materials, analyzing critical quality attributes of the drug substance, and stability testing are some of the areas where the regulations differ,” he summarizes.
Susan Haigney is managing editor of BioPharm International®.
Vol. 36, No. 12
When referring to this article, please cite it as Haigney, S. Reducing Time Not Quality for Biologics Approvals. BioPharm International 2023 36 (12).