Small and mid-sized biotechnology companies play a critical role in advancing innovation. Over the last several years, these companies have contributed to an estimated 76% of the clinical stage drug pipeline and 60% of all FDA approvals, including over 100 new therapies.1 These statistics, however, belie the harsh reality that few drug products in development ever reach the market. Even if the many challenges and questions related to manufacturing are eventually resolved, the delays in getting a product to market can significantly impact a company’s valuation. A key consideration for getting compliance right the first time around is ensuring that the manufacturing operation meets widely accepted criteria for quality. To do this, small and mid-sized companies can implement quality control systems, develop robust supplier agreements, and build the analytical capability to support these efforts. Many companies have found that an effective approach is to follow industry-wide best practices, while using public reference standards to validate raw materials and ensure the suitability of analytical assays.
As small and mid-sized companies build their experience in developing a robust production process and analytical package, they often partner with contract development and manufacturing organizations (CDMOs). These organizations provide essential services, including process development and clinical drug supply, regulatory support, and commercial supply if the drug makes it to market. Outsourcing allows small and mid-sized companies to overcome their limitations while reducing costs and accelerating development timelines.
However, working with a CDMO comes with its own challenges. When the partnership is new, companies need to establish protocols, standard operating procedures, and consistent rules for working together effectively. Mistakes can occur if there’s not enough clear communication between companies and contractors.2 This can be particularly important when dealing with a smaller CDMO, which may not yet have as much experience or well-established robust processes as a bigger contractor. One way to manage this relationship is to establish a dedicated team responsible for overseeing the outsourced work. However, this team needs to understand how the CDMO operates to ensure the quality of the work.
Compendial methods and reference standards can play a significant role in facilitating this relationship. They provide validated methods and well-qualified materials that can be sent by the sponsor to the contractor, so risks inherent to new method development are avoided. Additionally, if the production process was developed using best practices and reference standards, the company can request that the partner CDMO use the same standards for process development, system suitability, assay monitoring, etc. The result is a shared understanding of quality expectations that helps foster a long-term partnership with a CDMO.
Not all standards are created equal. Developing and setting standards requires expertise and access to relevant knowledge outside the scope of most reagent suppliers. As one of the world's premier standards-setting organizations, the United States Pharmacopeia (USP) has decades of experience developing standard analytical methods for characterizing critical steps in the drug production process. USP's compendial methods provide established analytical protocols that can be used with reference standards developed in collaboration with subject matter experts to assess the quality of drugs and the materials used to manufacture small molecule drugs, excipients, and biologics.3
USP standards can also be used for developing analytical methods early in clinical development to ensure a smoother and faster transition into later clinical stages. These well-characterized standards can serve as controls against which to qualify methodologies. They also provide a benchmark to assess the success of the technology transfer program, while providing CDMOs with tools they need for performance monitoring and training their analysts. Finally, USP standards can ensure consistency across different production processes, including testing critical raw materials, identifying process-related impurities, or release testing of drug substance and product batches.
Most small and mid-sized companies will likely start with a lab-scale process to make their first drug batches for preclinical studies, and these early efforts are usually paired with analytical assays. It is much more challenging to incorporate standards after all this preliminary work has already been done. This is especially true for biologics, which require comprehensive physicochemical and biophysical characterization because post-translational modifications can result in heterogeneity that impacts the quality of the final product. If these product-related impurities are not adequately controlled early in development, they can be amplified when scaling up production. Therefore, the manufacturer should have a robust package of analytical methods to validate the desired target product profile before scaling up and outsourcing production.
Developing in-house standards to validate these assays requires time and money, two things that most small and mid-sized companies have in short supply. Instead, these companies should consider adopting relevant standards early in development. USP has developed resources that can help guide small and mid-sized companies to the standards they need. For example, mAb developers can use USP’s interactive tool to find documentary and reference standards, as well as any educational content to assess the quality and safety of their product. (https://go.usp.org/register-mab-analytical-guide)
In the fast-paced and competitive world of biotechnology, small and mid-sized companies are constantly seeking ways to enhance their operations, mitigate risks, shorten their developmental timelines, and achieve success in the market. Given the current economic landscape and the importance of expedited development times, small and mid-sized companies must consider reducing uncertainty around their operations to avoid delays that degrade a product's value.4 USP reference standards can be indispensable tools for mitigating some of these risks, providing a critical foundation for small and mid-sized companies navigating the complex drug development and manufacturing journey.