Best Practices in Inter-laboratory transfer of analytical methods
Working at a leading CDMO as a Director of Innovative solutions and senior scientist, I have been involved in assay development, validation, and transfer of innovative cell and gene therapy products. During the last four years, my team has developed and transferred advanced PCR/qPCR-based assays such as Mycoplasma detection, Gene expression, and DNA Copy number variation, to our QC microbiology and QC analytical teams. In other instances , my team has assisted the receiving unit in bring in different bio-assays transferred from our Assay Development (AD) department or our clients.
In recent years, I've seen incredible, innovative, and highly-sophisticated cell and gene therapy products come to our site to be developed with the highest standards of quality and manufacturing. These projects include modifying the genome of immune cells to attack cancer cells or fixing genetic mutations that cause fatal diseases. These products are on the front line of advanced, innovative, life-saving therapies and require the best practices for manufacturing and quality control. For this reason, many companies partner with an experienced CDMO like Cognate BioServices.
Most clients transfer their process to a CDMO in early clinical phases when the manufacturing and analytical procedures are still under development. Other clients move a fully-developed manufacturing process with qualified or validated assays for in-process samples and product release. In most cases, these products are between phases two and three. However, during process transfer, many clients decide to make modifications to improve the process and adjust it to its new home. These changes are tested during pilot, training, and engineering runs. Process qualification is not required at early phases; however, if the analytical assays have already been validated, these changes can require revalidation, an expansive and time-consuming process.
Transferring a validated biological assay is not trivial. The transferring unit, usually the client's lab, transfers an assay to another unit with the firm belief that it will work in other people's hands. It is not always easy for the team to 'let it go'—the developers' minds and souls are in the assay's success. They know exactly what works, which mistakes they made, and what they learned from them. The developers know best how to resolve any issues that might pop up because "Nobody knows better than mom!" To resolve this inconvenience and make sure that the assay works as intended in its new home, a policy is needed for analytical method transfer. The goal of this process is to ensure that the receiving unit, usually the quality control team, has the ability, capability, knowledge, and experience to execute the transferred assay as directed by the 'assay owner' and as closely as possible to the method of the transferring lab. The most prolonged and complicated transfers pertain to the transfer of potency assays, which were designed to present the Mechanism of Action (MOA) of the product. In most cases, these assays are much more complicated and require different conditions and live materials, like different types of "positive" and "negative" target cells, to show specific biological activity, such as is the case with cytotoxicity of CAR-T products.
For many reasons, our process and assay development teams and our main manufacturing sites are in different locations. Cognate's process and assay development team is located in Baltimore, MD, close to John Hopkins medical school, while the innovations, manufacturing, and most of our QA and QC teams are located in Memphis, TN, a short distance from the FedEx international Hub.
Because of this structure, different assays (and processes) at the development phase are being transferred from our clients to our assay development team in Baltimore, which focuses on receiving the assay, testing it, and preparing it for use in our QC lab. Once assay development is complete, the assay is transferred to our QC department for product release and stability testing, and we work intensively with the client on assay qualification and validation.
The complexity of cell and gene products, the level of technology, the performers' experience in different disciplines, and the need for a holistic plan for assay and technology transfer led our company to develop our unique master plan for Assay and Technology transfer based on USP<1224> and FDA recommendations which is aligned with ICH Q2(1) and GMP guidelines. During the tech transfer process, we focus on clients' needs and the regulatory requirements, and we consider the clinical phase of the product and ensure that the transfer process will be well-documented and in compliance with the most current guidance.
Analytical methods transfer activities, especially for validated methods, are a collaborative effort between experts from the assay development team, quality control, quality assurance, tech-transfer, and project management. Each client is intimately involved in the tech-transfer from their site and participate in our meetings as much as they deem necessary. To get the best results, the secret is in cooperation, management, training, and documentation. For each assay transfer project, we assign a multidisciplinary method transfer team which is highly familiar with the biological and method material (Flowcytometry, PCR, ELISA, bio-assays, etc.), a project lead, technical leads (from the original lab and the receiving lab), QA expert, and tech transfer specialists. Each assay transfer team includes an SME, expert in the specific area—for instance, flow-cytometry, protein quantification, or PCR/Molecular assays—and people from material management, Doc Control, and IT to support the transfer process, as needed. Together, we focus on the strategy of the specific assay transfer. As a team, we always start with assay evaluation gap analysis and risk assessment and identify potential challenges we will face.
In some cases, the assay is already fully validated for advance clinical phase's products, so we collaborate tightly with the client and the regulatory team to ensure that we keep the assay's validity during the transfer process. The duration of the assay transfer, among other factors, can affect the assay's validation. It's always important to make sure guidelines and regulations have not changed from initial validation and maintain compliance with current guidelines. It's also essential to verify that the materials and equipment used for validation and for the assay itself are still available.
To ensure that the assay stays validated through the transferring process, we first review the original validation report and verify that we can transfer the assay without invalidating it. If the materials, equipment, and lab environment are similar, the preferred method is to perform a comparative study of the data produced in both labs simultaneously using the same raw and assay materials. It's highly important to decide on the methodology, the number of samples to be tested, the acceptance criteria for accuracy and precision (for example, %CV replicates, %RE between analysts and sites), and clear criteria for passing the comparative study. It is essential to select the most suitable statistical approaches to show similarity (showing no difference between labs using a t-test or ANOVA test does not necessarily show comparison).
If the comparative study is not feasible, the next preferred approach is co-validation. In most cases, the transferring lab team can collaborate with the receiving lab team in the validation process, and the two teams can produce data together to show reproducibility in alignment with updated guidelines. For this type of validation, we highly recommend using a reference batch with documented historical data and trend analysis as part of this validation.
If comparative study and co-validation are not feasible for any reason, most commonly product or assay changes after the original validation completion, we can revalidate the method.
The process is closed with a comprehensive report describing the transfer results, a summary of data analysis, and the transfer process conclusion—either pass or fail.
A good transfer project starts with planning. We always assess the assay transfer before developing the assay to ensure that the assay is straightforward and transferrable. We have systems in place for technology and assay transfer. We also have extensive experience writing the protocols and reports required to document and close the transfer process in a short period of time.
- FDA - Analytical Procedures and Methods Validation 2015
- ICH Q2(R1) – Validation of Analytical Procedures 2005
- USP <1224> Transfer of Analytical Procedures
- EudraLex - The Rules Governing Medicinal Products in the European Union Volume 4, EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use Part 1 Chapter 6: Quality Control
About the Author
Dr. Sagi Nahum, Director of Innovative Solutions and Senior Scientist
Dr. Nahum earned his Ph.D. in Medical Science from the Faculty of Medicine, Technion Institute, Israel, where he specialized in the areas of Gene Expression, Biostatistics, and Bioinformatics. As a part of his current position at Cognate Bioservices, Dr. Nahum leads the Innovation Lab, developing and validating high throughput capable assays to support the release of clinical and commercial drug products. Dr. Nahum is also focused on the strategic development of cell processing technologies, working with equipment providers and clients on innovative solutions for cell processing including upstream and downstream solutions. Dr. Nahum has an instrumental role in Cognate BioServices’ Analytical Transfer team, helping to execute internal and external processes and method transfers. Before this position, Dr. Nahum incorporated his knowledge at Pluristem Therapeutics as a researcher and Quality control Manager, where he developed and transferred bioassays for product release and research use. Dr. Nahum is a member of the ISO Technical Committee 276 Biotechnology and an author/ collaborator on several articles in the field of genetics and assay development.