[BLOG] Developing Risk-based Testing Strategies for Advanced Therapies

[BLOG] Developing Risk-based Testing Strategies for Advanced Therapies

How to navigate the regulatory framework to develop testing strategies that bridge the gap from research to cGMP compliance. 
By Emmanuel Casasola, Executive Director, Global Quality & Compliance, BioBridge Global
Although the advanced therapies industry is not new, no harmonised testing standards are currently available to align the industry. Some groups are actively working on building these standards and government agencies see the need to establish regulations to ensure patient safety; it is only a matter of time before standards are implemented.

Navigating the regulatory framework for biologics allows the testing strategies to be risk-based and phase-appropriate, which can help bridge the needs from research to cGMP compliance. It is exciting to support the industry with our expertise and new testing methods and this also fits well within our mission to save and enhance lives through the healing power of cells and tissue.

The testing question

Questions around required testing are asked frequently by our partners. What to test for? What is needed? How much testing is too much testing? All are very good questions and we aim to offer simple answers to the complex testing conundrum. One of the first things that need to be established is intended use: what is the therapy designed to do and how will it do it? This will facilitate the answers to some questions while also helping to identify key quality attributes.

Testing can typically be broken down into three categories: safety, purity and potency. First and foremost, the safety of the therapy is necessary. From the infectious disease testing of a donor to the final release testing of the product, all the assays need to be qualified. There are USP and EU Pharmacopeia methods that outline sterility, mycoplasma and endotoxin, which are commonly required tests, and these compendial methods are accepted by regulatory bodies. To ensure the methods are appropriate, the sample material should be qualified in a suitability study which would help identify any interfering substances that may give a questionable result. Even for a phase I clinical study, validating the suitability of safety assays is necessary to meet regulatory scrutiny.

The lack of standard purity and potency assays due to the level of innate complexity can be difficult to prove. A combination of a defined Analytical Target Profile (ATP) and the mechanism of action would establish the testing strategy required to ultimately lead to qualification of a therapy.

The USP supplement to <1224> “Lifecycle Management of Analytical Procedures: Method Development, Procedure Performance Qualification, and Procedure Performance Verification” states:
“The ATP defines the objective of the test and quality requirements, including the expected level of confidence, for the reportable result that allows the correct conclusion to be drawn regarding the attributes of the material that is being measured. It is essential to reach a high degree of confidence that an analytical procedure will consistently generate reportable results that meet the ATP requirements under all condition of use and as the material progresses through the lifecycle.”

For example, if you are looking for a specific type of cell or exosome, your assay will need to identify those within a certain level of confidence in order to support the findings of a clinical study. A further example from the USP <1224> supplement:

“Assay: The procedure must be able to quantify [analyte] in [presence of X, Y, Z] over a range of A% to B% of the nominal concentration with an accuracy and uncertainty so that the reportable result falls within + C% of the true value with at least 90% probability determined with 95% confidence”
This example states you need to have an assay that can detect a specific characteristic (analyte) within a material (therapy) within a certain level of confidence (95%) with a high degree of repeatability (90%).

Based on whether the therapy is autologous or allogeneic, the purity assay for the donor or starting material is crucial in the manufacturing of the downstream product and the overall logistics. We need to fully understand how viable the cells are, i.e. what’s the time frame from donation to manufacturing to delivery to the patient? This turnaround can be very short and with very complex logistics, as such, testing speed is crucial and a discussion around what type of testing should be implemented is vital to generate results as quickly as possible and ensure the treatment reaches the patient on time? A laboratory partner needs to be nimble enough to provide such services and with unequivocal data.
Navigating regional regulatory requirements

Understanding all the critical quality attributes (CQAs) is essential and will need to be defined in the chemistry, manufacturing and control (CMC) document that is submitted to a regulatory body as a therapy progresses through clinical development to commercialisation. The ability to justify the assays used and how that information helps in determining the efficacy of a therapy will aid in the regulatory approval of your product.

While all regulatory bodies strive for the protection of patients and ensure the safety of the products being marketed within their country’s borders, there are some small nuances between them. Those nuances tend to relate back to the host countries, such as epidemiological and cultural differences.

For this reason, the PMDA (Japan) may have donor requirements that are a little different than the FDA or the EU. The EU is comprised of many nations and depending on where the clinical trial will be conducted will also need to engage with that host country’s agency. Likewise, each region may require different documentation at various phases so it will be critical to ensure all documentation requirements are fully understood.
QualTex Laboratories is available to help

Ultimately, while QualTex Laboratories has recently launched these new services, the experience and expertise are evident by our history of supporting companies. The collaborative spirit and mission-based mentality drives our employees to help deliver new therapies to patients. They are ready to take some of the pressure and questions which may overwhelm an organisation and test samples with high quality and reliable fashion.