Antibody critical reagents are crucial to regulated (GxP) drug development assays. Poor quality reagents risk generating inaccurate and unreliable results, while failure in supply can delay preclinical and clinical studies. Overall, the potential consequences are losses in time, money and reputation. Read on to understand the key challenges in antibody critical reagent production and supply as the first step to de-risking your product lifecycle.
Antibody critical reagents are essential to drug development and the lifecycle of a biotherapeutic
The development of a biotherapeutic may involve four to five or more antibody critical reagents used in various bioanalytical assays (Figure 1). Bioanalytical assays depend on specific biomolecular interactions between the reagent and the target analyte. Any changes in the reagent’s characteristics, therefore, may impact assay performance.1 To ensure assays are robust, reliable and repeatable, antibody critical reagents must be comprehensively characterized and a consistent reagent profile maintained throughout their use. This requires active management of antibody critical reagents across the lifecycle of a biotherapeutic – in terms of generation and characterization, and also of supply because there is no use having the highest quality reagent if there is not a sufficient quantity and/or it doesn’t get to the right place at the right time.
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What are the key challenges in lifecycle management of antibody critical reagents?
The key challenges in the management of antibody critical reagents relate to:
- Generation of initial and subsequent lots
- Storage and distribution
Generation of antibody critical reagents
Both monoclonal and polyclonal antibodies rely on in-vivo systems, at some point, during their generation/development. Various factors influence the immune response of an animal, which in turn affects the quality of the reagent. Therefore, relying on animal immune systems is associated with considerable challenges in reproducing the original lot.
How much antibody critical reagent should you generate and what happens if you run out?
As reagents are often generated in large lots, there are difficulties associated with their management. Planning for, and guaranteeing, a continuous supply is challenging because the lifespan of an assay can range from months to years depending on the stage of drug development, which makes it difficult to predict the length of time you will use the reagents. There needs to be a balance between producing a large quantity, which is not cost effective, versus producing too little and not being able to generate consistent additional lots. If needed, one has to create a credible plan and criteria for bridging between lots.
Ensuring reproducibility between lots
When a new lot of reagent is produced, it must meet a set of established criteria for characterization and assay performance. These criteria provide information to compare initial and subsequent lots to decide whether they are suitable for use. Here, the challenges are to establish the criteria, and to use these criteria to verify assay performance with new lots.
Characterization of antibody critical reagents
The structural integrity and stability of reagents are directly related to assay performance. Therefore, it is important to ensure reagent consistency by regular characterization.
Defining assay performance criteria and ensuring consistency in their application
Reagents are characterized in terms of their sensitivity and specificity (Table 1).1,3 These characteristics determine the optimal performance of both quantitative assays (e.g., PK or biomarker assays) and quasi-quantitative assays (e.g., immunogenicity assays).3
The characterization profiles generated from multiple lots of reagents, along with assay performance over time, are essential to determine the following:3
- When an antibody qualifies for use in an assay
- The causes of assay performance problems
- When a reagent activity declines and must be replaced
Consistent characterization is difficult because of variations between laboratories and even technicians within the same laboratory.
Defining shelf-life and managing dozens of re-test dates
The reagent expiration or re-test date provides the period it will meet established characterization criteria. The expiry/re-test date, which should be based on formulation, storage conditions and available biophysical and functional data, can range from 2–10 years.1,3 Managing dozens of re-test dates is challenging.
Storage and distribution of antibody critical reagents
Degradation during storage
Storage can degrade antibody critical reagents via chemical (e.g., oxidation or deamidation) or physical (e.g., aggregation or misfolding) mechanisms, thus altering the characterization profile. Given this, the formulation must be carefully considered. For example, additives can help minimize changes in the structure or function of the protein on storage (e.g., cryoprotectants, stabilizers, preservatives, etc.).
Poorly controlled storage environment
Antibody critical reagents are typically produced in bulk and stored as concentrated samples.3 Fluctuations in storage conditions, like temperature, can alter the characterization profile of reagents. Facilities without appropriately maintained environmental storage conditions can cause antibody critical reagent degradation. As many antibody critical reagents are stored in freezers or fridges, failure in power supply or damage of facilities due to the impact of natural disasters, such as flooding or tornados, can also put lots at risk.
Managing inventory across multiple sites and vendors
Inadequate inventory management increases the risk of running out of qualified reagents, which can cause delays when resupplying the antibodies. It may also cause issues in retrieving important information about the reagent.
For companies with only one or two products, managing four to five critical antibody reagents per product does not sound too time consuming, but when scaled up per product (especially for larger pharmaceutical firms with multiple assets in various development stages), effective reagent management becomes complex and time consuming.
Getting the right reagent to the right place at the right time
Assay methods and reagents may move from one laboratory to another, either internally or externally to a CRO. Therefore, efficient distribution between laboratories is necessary for timely data collection.3 Failure at any point in the distribution chain can have wide-reaching implications, which need to be assessed, communicated and fixed.
What are the implications of antibody critical reagent failure or supply delay?
Without appropriate generation, characterization, storage and distribution of reagents, there is a substantial risk of stalling preclinical development and/or delaying clinical trials (Figure 2). Without sufficient and consistent management processes, valuable resources are wasted conducting experiments to generate and test new lots of reagents.
Looking to the future of antibody critical reagent management
The focus on antibody critical reagents is increasing. As the industry continues to increase the number and complexity of biotherapeutic drug molecules, we are witnessing a direct correlation in the demand for high-quality reagents and scrutiny, including regulatory agencies, of these same antibody reagents.
Unfortunately, current regulatory guidelines on the management of antibody critical reagents are limited. What regulatory guidelines do exist from the European Medicines Agency and the U.S. FDA6–10 lack specific recommendations on stability assessments, expiry/re-testing, characterization and monitoring of assay performance. For example, recommendations are unclear on defining in-house re-test dates of commercial reagents when given vendor-specified expiry dates. With limited regulatory guidelines, organizations define and follow their own processes for characterization, qualification and monitoring of reagents. However, regulators are beginning to understand the importance of antibody critical reagents, and a renewed focus in this area of regulation may be likely.
Advances in production and characterization of antibody critical reagents to match innovations in drug development are expected, so keeping ahead of those will be important to the future of your antibody critical reagent supply chain.
Complications with production/generation and management of antibody critical reagents represent a major risk to the efficiency, effectiveness and cost of your drug development process. You can start de-risking the process by carefully reviewing the approaches you take to generate, characterize, store and distribute antibody critical reagents to ensure you join up these different areas to optimize supply.
A comprehensive, seamless service can protect and optimize the management of your antibody critical reagents
Through our long-term partnerships with large and small pharmaceutical companies, Labcorp Drug Development is well aware of the challenges of reagent management. We believe that effective risk management can help you optimize and protect your reagent portfolio’s integrity and supply. That’s why we have leveraged our insight and expertise to build a comprehensive, end-to-end service that takes the worry and risk out of the generation and management of antibody reagents. Our service delivers consistent and reliable antibody critical reagents: efficiently generated, and well characterized, stored safely and distributed to when and where needed.
References and links
- http://www.pharmafile.com/news/511225/clinical-trials-and-their-patients-rising-costs-and-how-stem-loss. Accessed March 2021.
- www.ema.europa.eu/en/documents/scientific-guideline/guideline-immunogenicity-assessment-biotechnology-derived-therapeutic-proteins-first-version_en.pdf. Accessed March 2021.
- www.ema.europa.eu/en/documents/scientific-guideline/guideline-immunogenicity-assessment-monoclonal-antibodies-intended-vivo-clinical-use_en.pdf. Accessed March 2021.
- www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-rev1_en.pdf. Accessed March 2021.
- www.ema.europa.eu/en/documents/scientific-guideline/guideline-immunogenicity-assessment-therapeutic-proteins-revision-1_en.pdf. Accessed March 2021.
- www.fda.gov/media/119788/download . Accessed March 2021.