Q&A: USP is Building Quality and Confidence in Cell and Gene Therapies

As cell and gene therapies (CGTs) continue to reshape the treatment landscape for complex and genetic diseases, the challenges behind bringing these innovative medicines to market remain substantial. In this Q&A, Anthony Blaszczyk, PhD, United States Pharmacopeia (USP) Principal Scientist, Global Biologics, discusses the intricate manufacturing demands of CGTs, from the use of living cells and viral vectors to the need for highly precise analytical methods. He also discusses how organizations like USP support developers through standards, reference materials, and best practices that promote quality, consistency, and regulatory confidence.

Pharmacy Times: What are the unique manufacturing complexities of CGTs?

Anthony Blaszczyk, PhD: CGTs are large-molecule biologic medicines that are used to treat several chronic and genetic conditions, and, in some cases, can provide life-long cures. However, their large and complex structures present real manufacturing challenges. Compared to traditional small-molecule drugs, which are typically chemically synthesized with well-known and easily managed starting materials, CGTs require a large number of more structurally intricate components, relying on highly complex raw and starting materials such as living cells, viral vectors, and plasmid DNA.

These complex materials must undergo more stringent quality control processes, as even slight variations in certain quality attributes can impact the quality of the target drug substance or drug product.

For example, a plasmid DNA starting material with a minor sequencing error can greatly affect the identity, potency, safety, and stability of the CGT product. As a result, properly developed and validated analytical methods are required to accurately assess critical quality attributes for many starting materials.

Beyond the structural complexities of the raw and starting materials, manufacturers may also encounter hurdles pertaining to industry-leading practices. While best practices continue to evolve for more established CGT products, such as adeno-associated virus (AAV) therapies, manufacturing processes for newer CGT therapies are often unique. These challenges can make scaling-up production difficult and require significant resources to establish robust manufacturing processes and ensure consistent production and product quality.

Pharmacy Times: How do organizations such as USP contribute to the manufacturing ecosystem for CGTs? What types of support or resources can independent standards-setting bodies provide to help the industry?

Blaszczyk: As an independent, expert-led standard-setting organization, USP works closely with drug developers, manufacturers, and regulators globally to help address some of the most complex aspects of CGT manufacturing. USP is focused on developing standards to help improve the efficiency of drug development by providing tools and solutions to help manufacturers assess and characterize quality attributes throughout the production process. This is accomplished by working with stakeholders to identify industry challenges and potential solutions, including physical materials, validated methods, or best practice documents.

[Currently, we are] prioritizing the development of both physical standards and validated compendial methods [that are] specific to CGTs. The initial package of physical standards and reference materials is focused on AAV gene therapies and includes standards for raw materials (endonuclease and plasmid DNA), process impurities (residual plasmid DNA and residual host cell DNA), and viral vector characterization (empty/full analysis, capsid titer, and genome titer).

Although AAV therapies target a wide range of genetic diseases, USP standards and methods support platform analytical methods that can be applied across the entire class of AAV therapies. Throughout the development lifecycle, USP collaborates with manufacturers and regulatory agencies to ensure that each standard is appropriate for its intended use and remains relevant to address key manufacturing challenges, allowing manufacturers to operate with greater confidence throughout the drug development and approval process.

In recent years, USP has also developed several General Chapters that outline best practices for CGTs. Two particularly relevant chapters are USP <1040> Quality Considerations of Plasmid DNA as a Starting Material for Cell and Gene Therapies and USP <1067> Best Practices in Manufacturing of Recombinant AAV Vectors. These chapters offer critical guidance to support quality, consistency, and regulatory confidence across the CGT manufacturing ecosystem.

Pharmacy Times: What role does analytical data play in the development of CGTs?

Blaszczyk: As with other medicines on the market, it is vital to verify CGT product quality, and reliable analytical data plays a central role in manufacturers’ confidence in their product; however, improper use of or insufficiently qualified analytical methods can lead to inaccurate and unreliable analytical results. To ensure analytical procedures are accurate and robust, these methods must be thoroughly qualified and validated. Additionally, these methods require appropriate system suitability criteria to ensure assay performance and reliable results. USP physical standards are highly characterized materials that can support the development, validation, and verification of analytical methods. USP Standards are built on deep scientific understanding and provide a high degree of analytical rigor that helps ensure accurate, precise, and consistent results.

The complexity of CGT products makes analytical characterization difficult, and this challenge is amplified by the lack of harmonized methods in the field. USP Standards help ensure confidence across analytical tests by monitoring assay performance and helping bridge results across different analytical methods. Inadequate characterization of raw materials, such as plasmid DNA, has caused delays in approvals. [For example,] this was seen in 2018 when an out-of-specification plasmid DNA lot resulted in a clinical hold on a Duchenne muscular dystrophy phase 1/2a trial.

Strong analytical data are also a cornerstone of regulatory submissions. Regulatory submissions must show that analytical methods are validated and produce consistently accurate results. Many regulatory bodies are familiar with USP Standards, which can help alleviate some of the manufacturer’s burden throughout the filing process.

Pharmacy Times: What are the current industry gaps that you see as the greatest challenges today for developers of CGTs? How are USP Standards and solutions able to address these gaps?

Blaszczyk: Some of the industry gaps that create the most pressing challenges for CGT developers today are the high cost of manufacturing, a lack of harmonized analytical methods and production processes, the rapid emergence of new therapies, and the quality of raw and starting materials—all of which can limit patient access to these life-changing medicines.

USP Standards help provide manufacturers with a consistent benchmark for analytical testing throughout the product lifecycle, setting a common bar of quality for evolving and complex medications like CGTs. USP has invested in the development of standards that support manufacturers from production through fill finish to help accelerate approvals and improve market access.

Pharmacy Times: What is your perspective on the role of quality standards in supporting developers in expediting product reviews regarding the US FDA’s regulatory flexibility in chemistry, manufacturing, and control (CMC) for CGTs?

Blaszczyk: The FDA’s recent efforts to introduce greater regulatory flexibility for CMC requirements in CGT development reflect the rapid evolution of this field. It is also reflective of the recognized urgency in accelerating patient access to CGT products, as delays in approval can have serious and sometimes life-threatening consequences. [Although] stakeholders continue to assess how this flexibility will translate into practice, compendial methods can support developers in building strong analytical frameworks within these new pathways.

USP’s compendial methods are a prime example of standards that can help accelerate development and regulatory approval. By using these validated methods, developers leverage approaches the FDA is already familiar with, which can lead to a smoother and more efficient review process. One of the key advantages of using USP compendial methods is not having to develop and validate each method itself, making development easier for manufacturers. Many of these methods are also accompanied by USP physical Reference Standards that provide assurance of good method performance. By providing stable, consistent benchmarks, standards can help manufacturers demonstrate that product quality attributes remain controlled—even in an environment where CMC expectations continue to evolve.

USP aims to align its standards with established scientific and regulatory expectations. To facilitate collaboration, FDA staff participate in USP's standard-setting activities as government liaisons

Pharmacy Times: How can standards and reference materials contribute to long-term safety and potency monitoring for approved CGTs?

Blaszczyk: Long-term safety and potency monitoring are essential for CGTs, many of which have complex mechanisms of action. Standards and reference materials provide the analytical consistency needed to monitor critical quality attributes over a product’s lifecycle.

USP develops compendial methods and Reference Standards that directly support key safety tests, including those for bioburden, endotoxin, and mycoplasma, which remain essential at every stage of a product’s life. Using well-defined standards helps to ensure that measurements are accurate, robust, and comparable across different manufacturing sites and timepoints.

In addition, stability testing is fundamental for long-term monitoring, and USP’s General Chapters on stability, such as <1049.1> Design of Stability Studies for Biotechnology Product Development and Lifecycle Management, provide guidance on best practices for establishing and maintaining product quality. USP <1049.1> is currently being revised to ensure the chapter is aligned with the most up-to-date industry best practices. By anchoring analytical methods to reliable reference materials, manufacturers can better track potency, detect degradation, and sustain consistent quality throughout the post-approval period.

Pharmacy Times: Are there any USP products in the pipeline that will help support manufacturers with their raw and starting materials and/or process and product characterization?

Blaszczyk: USP is actively expanding its portfolio to address the unique needs of CGT manufacturers, including critical raw and starting materials, as well as expanding to cell therapies. USP is also working to provide manufacturers with solutions to analytical challenges. Current CGT projects in the our pipeline include:

• Plasmid reference materials for topology assessment, supporting the characterization of an essential upstream component in gene therapy manufacturing;
• an IL-2 Reference Standard and compendial method to support characterization of cytokines integral to cell therapy workflows;
• a lentiviral vector reference material, addressing a key starting material used in CAR‑T manufacturing and providing a benchmark for assessing vector physicochemical properties;
• USP General Chapter <1267> Best Practices for the Production and Characterization of Lentivirus Vector for Cell and Gene Therapy is being drafted and [is slater for publication] in USP-[Pharmacopeial Forum] later in 2026;
• USP General Chapter <89.3> Endonuclease (Serratia marcescens), a compendial method for determining the activity of endonuclease, is in preparation for publication in USP-NF later this year. This chapter is also accompanied by a USP Reference Standard;
• And updates to existing CGT general chapters to ensure they reflect current best practices. This task is being led by USP Expert Committee members.

These initiatives reflect USP’s broader commitment to help developers strengthen quality control strategies, improve characterization, and support product quality across the CGT ecosystem.