Executive Summary

Effective process characterization for Adeno-Associated Virus (AAV) vectors requires qualified scale-down models (SDMs). These models provide a high-throughput, data-rich environment to define and validate process parameters, directly informing large-scale manufacturing and supporting robust regulatory submissions for Advanced Therapy Medicinal Products (ATMPs) in Europe. Franklin Biolabs develops representative SDMs that accurately predict full-scale performance, de-risking technology transfer and accelerating timelines for Investigational Medicinal Product Dossier (IMPD) submissions. Our approach ensures that defined quality attributes (CQAs) established in early discovery are maintained through process scale-up, from 2L to 500L+ bioreactors.

The Challenge of AAV Process Characterization

Scaling AAV production from research to clinical-grade manufacturing is not a linear exercise. Process parameters that function at bench scale often fail to produce equivalent results in larger bioreactors. Attempting process characterization and validation runs at full scale is economically prohibitive and operationally inefficient.

A scientifically sound, data-driven preclinical strategy requires a qualified scale-down model. This approach allows for the systematic evaluation of process parameters (e.g., media selection, transfection conditions, purification resin performance) in a high-throughput format. The goal is to build a comprehensive understanding of the process design space before committing to large-scale production runs.

Establishing a Representative Model

The development of a robust SDM begins with defining the target CQAs of the viral vector. These attributes are directly linked to the therapeutic’s mechanism of action and clinical performance. The SDM must be qualified to demonstrate that it can accurately predict how process inputs affect these final product attributes at scale.

This qualification is performed within our >100,000 sq ft facility, leveraging both adherent and suspension platforms. By establishing a statistically valid correlation between the SDM and the target manufacturing scale, we create a reliable tool for process optimization, characterization, and validation activities.

Linking Process Parameters to Product Efficacy

A manufacturing process must consistently yield a vector that performs as intended. For instance, the ability of an AAV9 vector to achieve phenotype rescue is dependent on maintaining the integrity of the capsid and the transgene cassette throughout production (PMID: 34454844). Similarly, for therapies requiring regulated transgene expression, the process must not compromise the vector’s ability to respond to pharmacological controls (PMID: 12727112).

Our SDM studies are designed to identify and control the parameters that influence these performance-related attributes. This work provides the process understanding needed to ensure lot-to-lot consistency and product efficacy.

“We started collaborating with UPenn Vector core in 2023 and the AAV vector which they manufactured laid a foundation for development of a gene therapy candidate which will enter soon preclinical studies. The key people from UPenn Vector Core joined Franklin Biolabs and our collaboration transitioned without interruption from UPenn Vecor Core to Franklin Biolabs Research Vector Division. Franklin Biolabs is integral to our AAV-vector based gene therapy candidate development and we hope to continue the collaboration for years to come.”
— Biotech Partner

Data for European ATMP and IMPD Submissions

For German and other EU-based biotech sponsors, a well-characterized process is fundamental to a successful IMPD submission. The data generated from SDM studies form the core of the Chemistry, Manufacturing, and Controls (CMC) section. This information demonstrates to regulators a thorough understanding of the manufacturing process and a robust control strategy.

This rigorous, data-first approach has been central to achieving a 100% successful IND rate for programs initiated since 2019, with Franklin Biolabs launching in 2024 to carry this expertise forward. By front-loading process characterization, we help sponsors enter the clinic with a scalable, well-understood manufacturing process, supporting an 18-24 month timeline to IND.