October 15, 2021 PAO-10-21-CL-08
Samir Lakhashe (SL): Biologics need different types of assays, which can be broadly divided into four categories: safety, identity, purity, and potency. Regardless of the product type, it must undergo a set of safety assays, including microbial testing, viral safety testing, mycoplasma testing, and endotoxin testing.
The other “lot release” test category is the product's identity to ensure that the manufactured product meets acceptability criteria before administering it to the patient. Similarly, purity must also be tested against the acceptance criteria. You may use multiple different analytical methods for each of these categories, depending on the product type. The use of orthogonal methods is important so that data about the critical quality attribute is derived using more than one technique. All lot-release methods undergo phase-appropriate qualification to demonstrate and document precision, accuracy, linearity, robustness, etc. It is crucial to demonstrate that the test method is suitable for the intended use, and this data is important for the IND filing.
The ex vivo potency assay data is desired, but such assay may not be available during early clinical trials. Many of these assays are customized, even though there are unifying principles. Besides lot-release assays, which are performed in the QC lab, we also offer product characterization assays that may be performed in the GLP setting.
SL: For safety testing, there are established compendial methods, and those need to be performed in a GMP environment and must meet the regulatory requirements.
Some methods are platform-based, for example, analysis of cell surface markers by flow cytometry. Although we may be testing different cell types and attributes across other products, the technology behind those different assays remains the same. Usually, potency testing is a highly customized method. We can onboard a new method after tech transfer or develop it from scratch.
SL: One of the most critical needs is the availability of the potency assay that can predict clinical efficacy. Availability of such assay can significantly facilitate the assessment of the impact of any change in the manufacturing process, as well as stability assessment of the drug product.
SL: Each biologics product is unique and presents its own challenges. In general, cell therapy products are logistically more challenging, since they may need to be freshly administered and have a very short shelf-life. For these products, rapid assessment of safety parameters and completing lot-release assays are more challenging.
SL: We offer a complete one-stop-shop package to our clients that can save their time and effort. They can manufacture their product in our facility, perform analytical testing, and get their clinical trial samples tested under GLP and cGMP conditions. Our advantage, aside from being a trusted partner, is the availability of technical expertise and state-of-the-art equipment. It's always interesting to witness how the products we manufacture in our facility perform in the clinic.
SL: This may not be happening in real time, but we would like to see a long-term relationship with the client. Even if changes are made in the manufacturing process, we may still be performing the same or similar analytical methods that have been already established. This can save a lot of resources.
If clients see a clinical benefit in the phase I trial and decide to manufacture the same product for the next phase, having the same manufacturing partner can save a lot of resources and ensure that the remanufactured product has the same profile.
SL: I think it boils down to the two R's: reaching the maximum number of patients who are eligible to receive that therapy and reimbursement, because how many people can afford those treatments out of pocket?
These therapies may not be the traditional blockbuster but need to be sustainable. The goal for the industry should be to create therapies that are more affordable and accessible. I think those are the two most important aspects, apart from science and other technical developments.
SL: Automation is incredibly helpful, because it minimizes the risk of human error and optimizes the process. I see this continuing and being widely beneficial across the industry. The analytical testing platforms (e.g., flow cytometry) offer software to build automated data acquisition and analysis templates so that each sample and time point is analyzed the same way. The new software also provides the audit trail to meet the regulatory requirements.
SL: It depends on the scale. If you are doing commercial manufacturing and generating the same product on a large scale, it makes sense to bring more automation into your workflow.
SL: The types of data we're dealing with are very diverse. We're challenged by the need to retain all raw data, not just analyzed data and published reports. We're currently evaluating different options, including electronic notebooks and LIMS to identify the optimal solution for our and the client's requirements.
SL: Changing the method is especially challenging when you're in a later stage of product development or are manufacturing a commercial product and then you want to change. However, in many situations, we may need to adopt a new method to overcome a supply chain bottleneck or achieve desired shorter turnaround time, robustness, or some other logistic advantage. The new method must be either similar or better than the older method in its precision, accuracy, and sensitivity. We need to test reference material using both methods and generate bridging data to convince ourselves and the regulators that the new method is acceptable.
SL: I will give you examples of two methodologies. One is digital PCR. Traditionally, people have used quantitative PCR (qPCR) — for this, you need a reference standard, which allows relative quantitation. However, using digital PCR, you eliminate the need for a reference standard. It's an absolute quantitation of target molecules using cleverly designed assay and statistical principles. This is one of the methods gaining wider acceptance — I prefer the digital PCR rather than the qPCR, because I have seen the limitations. Digital PCR is handy for determining the number of inserts in the cell genome after transduction with viral vectors.
The second area is spectral flow cytometry. Traditional flow cytometers detect only a small section of the emission spectrum. In spectral flow cytometry, you analyze the entire emission spectrum, allowing many more and even closely related fluorescent dyes. You can differentiate your signal from noise much better than you can with traditional flow cytometry, which is an advantage when looking at dim markers.
Both of these areas are rapidly growing and will likely be adopted by many laboratories soon. Scorpion lab has already installed a 5-laser, 64-detector spectral flow cytometer that can simultaneously analyze up to 40 parameters.
SL: Our motto is, "Experience the smoothest path to the clinic." I will add to this, "The smoothest path to the clinic and beyond." This is because we offer state-of-the-art services that support the entire spectrum of biologics (from early clinical trials to commercial manufacturing).
Our team consists of highly trained and experienced scientists. We want to work more collaboratively and transparently with our clients, allowing them to benefit from our agility, efficiency, and expertise. We are committed to facilitating "bench-to-bedside" translation of new therapies and helping our clients in every possible way.
Samir has over 20 years of experience in biologics, focusing on the development of various analytical methods. His experience includes defining analytical target profiles, identifying critical quality attributes, and management of analytical process life cycle. He has expertise with viral vaccines, monoclonal antibodies, mesenchymal stromal cells, engineered tumor-infiltrating lymphocytes, CAR-T cells, and has worked across the disciplines of immunology, cell biology, virology, molecular virology, and protein chemistry-based analysis. His specialty is analytical method development, phase-appropriate qualification or validation, QC transfer, and method implementation in the GXP environment.