Biopharmaceutical drug products are monitored for critical quality attributes during regulatory filings and throughout the development of manufacturing processes. Critical quality attributes (CQA) are defined by FDA as “a property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired drug quality/safety.” Impurities are potential CQA, and impurities that are identified as CQAs should be within an appropriate limit, range, or distribution to ensure the desired product quality.
Biological Product Impurities Defined
Impurities can be of known structure, partially characterized, or unidentified. ICH Q6B defines biological product impurities as:
Product-related impurities (e.g. precursors or certain degradation products) are molecular or post-translational variants that arise during manufacturing and/or storage that don’t have properties comparable to those of the desired product with respect to activity, efficacy, or safety.
As described in ICH Q6B guidance, process-related impurities in biologics are derived from the manufacturing process, which can include:
- Cell substrates (e.g. host cell proteins or host cell DNA)
- Cell culture (e.g. inducers, antibiotics, or media components)
- Downstream processing constituents (e.g. bioprocessing enzymes, chemical and biochemical processing reagents, inorganic salts, solvents, carriers, ligands, and leachables)
Process-related impurities may pose direct risk to product stability, safety or efficacy, including immunogenicity or clinical safety risk. It is important to note that impurities that don’t pose a direct risk to patients may still impact the safety or efficacy of a biologic product in some manner.
Assessing, Controlling & Monitoring Impurities in Biologics
Understanding the impurities present in a biologic is a critical first step in constructing control strategies to reduce or remove them from the final product. Development, small-scale, and validation studies need to accurately represent production processes and capture worst-case scenarios for clearing impurities. Additionally, effective and robust test methods are needed to monitor impurity control.
An experienced analytical lab who acts as a true, consultative partner can be an invaluable resource. In addition to providing input and guidance regarding assay validation criteria for methods, they can help you to determine and plan which assays will you need and when. Avomeen has the technical capabilities to support the analytical testing required to assess and control impurities in biological products throughout the development process, and our consultative, expert scientists are true partners throughout the entire drug development lifecycle, working hand-in-hand with clients.
Success and the Benefits of Platform Assays and Methods
Rapid availability of methodologies to evaluate the quality of biologics are essential due to regulatory expectations and aggressive development timelines. Furthermore, standard assays to quantify product and process impurities are becoming more and more standardized in certain industries, such as gene and cell therapies. Expedited timelines and reduced cost are just some of the benefits platform assays and methods offer. By utilizing existing robust platform methods that have been developed for a broad range of matrices, there’s a likelihood that an entire pipeline of biologic products can be analyzed using these developed methods with minimal modifications and with product-specific validations, if required.
Are Platform Methods the Right Approach for Your Biologic?
Platform methods can be a powerful tool throughout the biologic product lifecycle, but especially to expedite the process of getting a method ready for use in the release of drug product for human clinical trials. Once the impurities that need to be assessed have been identified, a review of existing methods and platforms will be completed to determine whether the use of a platform method is an appropriate approach.
If a method or platform exists for the impurity of interest, matrix suitability will be performed to establish the assay conditions specific to the drug substance at any given stage of the bioprocess. The amount of time it takes of perform a matrix suitability test is much shorter compared to the amount of time it would take to develop a brand new method for the CQA if a platform method was not available. If required, based on the phase-appropriateness of the program, matrix verification or validation would be performed to establish a cGMP-compliant method that is specific to the sample type and product at hand. Sample analysis can be performed either following matrix suitability (non-GMP) or following validation (cGMP-compliant), depending on the stage of the product lifecycle. As detailed in the graphic, the time commitment is shortened significantly when platform methods are utilized as a starting point.
Are you interested in exploring platform methods? Avomeen has a host of established methods for many of the most common process-related impurities (Kanamycin, Streptomycin, IPTG, Glutathione, etc.). Get in touch with an expert to learn more.
Our expert blogger is Khanh Ngo Courtney, Ph.D., Director of Biologics at Avomeen. Khanh provides clients with unparalleled expertise and tactical knowledge of protein biochemistry and molecular biology. Her experience extends from R&D to analytical method development, validation, implementation, method transfer, and optimization of test methods for the cGMP setting per USP and ICH guidelines. This understanding of the entire process helps guide successful and productive collaborations across different laboratories, sites, and functions. Khanh is also adept at protein expression and purification from E. coli and mammalian cells, in vitro potency assays, protein/DNA/peptide binding studies, ELISAs and other immunological methods, analytical chromatography, forced degradation studies, product quality investigations, and manufacturing investigations. Her technical background provides the foundation for effective authorship of analytical sections in BLAs and MAAs, as well as responses to requests and questions from the FDA, EMA, and PMDA.