Product-related impurities are molecular variants formed during manufacturing and storage, that have properties different from those of the desired product with respect to activity, efficacy and safety. These molecular variants could be aggregates, truncated species, precursors and degradation products.
Monitoring these product-related impurities is a regulatory requirement. As per ICH Q6B guidelines, a comprehensive analytical panel should be incorporated to understand their impact on the safety and efficacy of the biopharmaceutical.
N- and O-glycosylation analysis
Determination of deamidation
Determination of oxidation
Determination of glycation
Determining the presence of aggregates (Oligomers)
Evaluation of N- and C-terminal amino acid modifications
C-terminal lysine truncation analysis
Monitoring of proteolytic cleavages, etc.
We provide services for the analysis, purification and characterization of product-related impurities as per ICH Q6B guidelines. We perform analytical as well as semi-preparative scale purification and characterization of these impurities using a diverse range of analytical methods. We also provide comprehensive structure-function relationship studies to understand the impact of post-translational modifications on the mechanism of action (potency of the molecule).
Process-related impurities are unwanted substances present in a biopharmaceutical. These substances could arise from the production process itself (e.g. nutrient media). Examples of process impurities are shown below:
Very often the process-related impurities impact the safety and efficacy of the biopharmaceuticals. It is also a regulatory requirement. Hence, a strong understanding of process-related impurities in early drug development facilitates a good understanding of the process and helps in establishing acceptance criteria for ongoing testing requirements such as batch release testing. These process impurities are typically present in trace levels in sample matrices making their quantification very challenging.
Establishing % coverage of HCP antibody by western blotting
Quantitation and characterization of cell culture associated impurities such as IPTG, antibiotic, serum process enhancing agents including Glutathione and DTT by LC-MS, capillary electrophoresis
Identification and analysis of process leachables such as Protein A by HPLC, ELISA etc.
Using an extensive analytical panel (including chromatography, spectroscopy, mass spectrometry, 2-D gel electrophoresis etc.) in accordance with ICH Q6B Guidelines, our experts can analyze, purify and characterize various residual host cell proteins, host cell DNA and other manufacturing derived impurities. We also provide high quality data from these analytics to support process validation, batch to batch comparability, GMP lot release activities to ascertain that products meet specification requirements for process residuals.
Aside from product-related impurities and process-related impurities, ICH Q3A, ICH Q3B, ICH Q3C and ICH Q3D provide guidance for registration applications on the content and qualification of inorganic impurities that may present in the biopharmaceuticals. During the product manufacturing process, very often, chemically synthesized compounds and various reagents/inorganic salts are used. These chemically synthesized products may contain some inorganic as well as solvent impurities which might cause product safety issues.
Growth selection agents
Surfactants
Purification column binding agents
Viral inactivation agents
Excipients and their contaminants
Extractables
Leachables
The inorganic impurities could be immunogenic to patients and hence they need to be monitored.
We offer defined methods using our expertise to monitor and report these inorganic and solvent impurities, which helps during risk assessment and identifying Critical Quality Attributes (CQAs).
Solvents are inorganic or organic liquids used as vehicles in bio-process production to support cell growth and/ or during protein purification steps. As a trace amount of these solvents in the final dose form can cause aggregation of therapeutic proteins, which can affect efficacy significantly, highly sensitive and specific analytical methods are required to detect them. The ICH Q3C guidelines must be followed for the control of residual solvents in the manufacturing process of new drug substances.
We offer services to develop specific methods for determination of solvents impurities according to the ICH Q3C guidelines.
