May 9, 2022 PAO-05-022-CL-03
Rapid growth in demand across the biopharmaceutical industry continues to drive ongoing efforts to outsource pharmaceutical development and manufacturing, both for more conventional engineered proteins and antibodies and for next-generation antibody-based products and cell and gene therapies. Emerging companies, which are steadily increasing in number but typically have minimal internal resources, rely heavily on service partners to provide specialized support, such as analytical method development. Major biopharma drug developers are also focusing on drug discovery and other areas of core expertise and turning to analytical service providers to supplement their core capabilities.
As a result, various market research firms estimate the value of the global pharmaceutical analytical testing market to be expanding at a compound annual growth rate in the range of 7–10%, rising from approximately $7–7.5 billion in 2021 to $10–11 billion by 2026.1,2 Part of this growth can be attributed to the demand for analytical services in support of the development of COVID-19 vaccines and therapeutics, which will decline over time. That demand will be replaced, however, with demand for support by companies developing novel RNA products; developers of cell and gene therapies, multispecifics, and antibody conjugates; and producers of engineered protein and antibody products developed against novel drug targets. They will all be looking for varying levels of assistance across all stages of drug development.
For many emerging biotech and biopharma companies, the challenge is to take a molecule that has been shown to have biologic activity and develop a process and analytical methods to support production of preclinical and ultimately clinical material. These companies rely completely on outsourcing partners to develop production processes, identify the necessary assays that must be performed to support early process development through product release, and then develop robust methods that can ultimately be qualified and validated.
The first step with respect to analytical support is to determine which assays will be needed for a particular biologic drug substance. The ideal contract service partner will have extensive expertise working with a wide range of molecules and be able to apply that knowledge to the specific molecule in question. The goal is to identify only those assays that are necessary at each stage of the project in order to minimize both time and cost.
Once the list of necessary assays is outlined, they must be developed for use in process optimization and eventually demonstrated to be sufficiently robust for qualification.
Some biopharma drug developers have established basic analytical methods for their candidate compounds. These companies want analytical outsourcing partners that can work with these existing methods and bring them up to the level necessary for qualification and validation. That generally means determining the limit of detection, reproducibility, precision, accuracy, and other core parameters. Here again, a service partner with extensive experience in method development and exposure to many types of protocols is best suited to provide this type of service and to help ensure that the resultant QC assays are robust, fit-for-purpose, and high-performance.
A key attribute of the most effective analytical CROs is the ability to communicate well with their customers, particularly on a scientific level. Regular meetings help ensure that the CRO understands the client’s needs and the technology and science behind the drug substance in question. The client’s scientists are intimately familiar with their molecule, and even if they don’t have many — or any — established methods, they have the most knowledge and understanding about their candidate molecule, have read the relevant literature extensively, and understand the goals for the project in great detail.
Consequently, communicating with the customer is essential to ensure the efficient development of successful analytical methods that are specifically designed to support the client’s goals. Discussions are often needed to confirm aspects of the process, such as the number of samples, replicates, the final readout, or the level of detail expected from a given analysis. Constant communication is needed to ensure that the project progresses appropriately and that the client is kept abreast of the progress.
Communication is also vital when problems occur, as can happen with projects involving complex drug candidates. The best CROs don’t wait for scheduled meetings to discuss these types of issues; they are willing to pick up the phone and talk to the client immediately to identify possible solutions. Working hand-in-hand is the best way to resolve issues and keep the project on track.
For example, some protocols established by clients during project scoping may in the end not fully address their needs. It is necessary to have a high level of trust and communication so that clients clearly understand the reasons why additional work may need to be completed. In such cases, our scientific team will investigate how the data is being used and help design assays or panels that fully meet the clients’ needs.
There are many assays performed to characterize drug substances and their release for clinical use, such as pH, appearance, identity, sterility, concentration, potency, and so on. While all the assays are important to evaluate and certify the drug product, we can consider the quantification and its biological activity to be the two most important assays that often need to be customized for each product. All of these assays must provide reliable data (reproducibly) with an acceptable level of precision, accuracy, and specificity. Method qualification involves identifying the acceptable ranges for these performance attributes.
The ideal contract service partner will have extensive expertise working with a wide range of molecules and be able to apply that knowledge to the specific molecule in question. The goal is to identify only those assays that are necessary at each stage of the project in order to minimize both time and cost.
Stability studies are separate from method development activities but require the use of established analytical methods. These studies are performed under various conditions designed to simulate storage and transport environments to determine whether the drug substance by itself and/or the formulated product will remain stable. The samples obtained at the end of the study are subjected to extensive evaluation using qualified methods. The results are used to determine the effectiveness of the drug and acceptable storage and transport parameters, such as time and temperature.
Assays created for research and development must then meet additional quality standards before they can be considered suitable for use in biomanufacturing, product testing, or product release. To bring the assays up to the level required for qualification and validation, they must be intensively investigated and shown to be highly robust. Each method must be shown to be effective across the full range of conditions that might be experienced with respect to drug substance concentration and its biological activity. Once the ranges for each parameter, including specificity, accuracy, precision, and reproducibility, are established, the method can be considered qualified.
When projects advance to phase II or III in the clinic, the methods used to evaluate these materials must be validated. Although a qualified and validated analytical method can be used to prove the suitability of the analytical procedure for the purpose, validation is a much more involved process in terms of robustness and depth of the assay. In addition, a validated method should meet the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) standards.
Many clients today desire qualification and validation of methods well in advance of the time a project is expected to move from development to the clinic. Ideal CRO partners will have established protocols for achieving method qualification and validation — and an extensive track record of success — to progress through these milestones.
Modifications to qualified and validated methods are avoided as much as possible, but in some cases there is no other option. One reason that has arisen more frequently since the COVID-19 pandemic is the need to switch suppliers of a critical reagent due to lack of availability of the reagent that was initially used when the method was qualified and validated.
Changes are typically avoided because of the need to establish equivalency of the “new” method to the original method. Whether the change is as simple as substituting a reagent from a different supplier or as complex as using a new analytical technology or different instrument, a comparative study is needed to clearly demonstrate that the methods provide the same results. In addition, regulatory agencies expect there to be a convincing reason why a change was made. Comparative studies take significant time and effort to complete and can thus contribute to project delays and higher costs.
Whether the change is as simple as substituting a reagent from a different supplier or as complex as using a new analytical technology or different instrument, a comparative study is needed to clearly demonstrate that the methods provide the same results.
The philosophy at Scorpion Biological Services is to provide method development support to clients as their projects move from the preclinical stage through commercial manufacturing, ultimately providing qualified and validated lot-release assays. We have the ability to develop assays needed to support a wide range of drug substances, from traditional proteins and antibodies to next-generation cell and gene therapy products.
In addition, Scorpion is a CDMO that provides services to produce clinical-scale batches of drug products such as antibodies, viral vectors, and cell therapy products. The analytical team works closely with the process development team to establish initial methods that support process development and optimization efforts, including cell-based assays, immunoassays, biomolecular assays, and bioanalytical methods. Once a process is ready to move from the lab to larger scale, the analytical team takes those methods and qualifies them to meet the regulatory requirements as guided by our Quality Assurance team. If the project continues to advance to late-stage clinical studies and commercialization, those methods are also validated.
A key differentiator for Scorpion is the breadth of expertise of the analytical team. Our leaders have extensive experience in molecular biology, protein analysis, cell-based assays, and so on, as well as flow cytometry and other advanced analytical methods.
To ensure that Scorpion continues to meet the needs of its customers, the company is constantly assessing current capabilities to identify areas for improvement and expansion. Our head of business development continuously provides insights into trends and future customer needs so that we can invest in new capabilities that will meet the needs of future clients.
Investments may include increasing the numbers of analytical instruments, bringing in new assay platforms, or adding personnel with experience in new assays. Scorpion is currently hiring additional team members with experience in protein analysis and cell-based assays, as we are largely focused on cell therapy and antibody products. However, we are open to new opportunities and have the capacity and capability to add more types of assays to meet specific customer needs.
Cancer biology is an example of a space that is rapidly evolving and leading to the development of novel immunoassays, some of which are highly specialized. We recognize the importance of this field and the need to develop capabilities in this area to support customers developing these novel drugs. We will soon be incorporating many new immuno-oncology assays (e.g., immune-mediated tumor killing, complement-dependent cytotoxicity, immune checkpoint binding, and functional assays, mixed lymphocyte reaction, T cell invasion, activation, proliferation, and exhaustion) into our offerings in order to continue to support our customers with the bioanalytical solutions they require.
Despite the fact that Scorpion is expanding very rapidly, we remain focused on our customers and staying within our general scope of work. We do track new assay technologies and, when they fit within the scope of Scorpion’s business strategies, adopt and implement them to improve the efficiency and effectiveness of our bioanalytical services.
Nick Raja is responsible for driving analytical development at Scorpion, developing custom assays to meet client needs, providing scientific insights, overseeing the execution of assays, and providing quality data in a timely manner. Nick has over 20 years of experience in the biotech, pharmaceutical, and CRO space, working on antivirals, vaccine development, assay development, clinical immunology, rare diseases, gene therapy, cancer biology, and immunology. He has broad knowledge of molecular biology, cell biology, protein biology, clinical immunology, and regulatory needs. Nick trained at Cleveland Clinic and Brown University and authored a number of peer-reviewed scientific publications. He received his Ph.D. in microbiology at Madurai Kamaraj University.