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Analysis, Purification and Characterization of Impurities
In addition to the assessment of purity of biomolecules containing a desired product, and their variants, the manufacturer should also evaluate the presence of impurities in their products. Impurities may be either process or product-related, of known or unknown structure, partially characterized, or unidentified. These impurities should be quantified, characterized and their impact on the biological activities of the products should be evaluated according to ICH Q6B guidelines.

There are four different categories of impurities:
Product-Related Impurities
Product-Related Impurities
Process-Related Impurities
Process-Related Impurities
Inorganic Impurities
Inorganic Impurities
Solvent Impurities
Solvent Impurities
Product-Related Impurities
Process-Related Impurities
Inorganic Impurities
Solvent Impurities
What are product-related impurities?

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.

Why do these need to be monitored?

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.


How are these impurities monitored?
  • 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.

What we provide?

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).

What are process-related impurities?

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:


Process-related_impurities.png

Why do these need to be monitored?

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.

How are these impurities tracked?
  • 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.


What we provide?

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.

What are these impurities?

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.

These inorganic impurities may derive from the following sources:
  • Growth selection agents

  • Surfactants

  • Purification column binding agents

  • Viral inactivation agents

  • Excipients and their contaminants

  • Extractables

  • Leachables


Why do inorganic impurities need to be monitored?

The inorganic impurities could be immunogenic to patients and hence they need to be monitored.


What we provide?

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).

What are these impurities?

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.

What we provide?

We offer services to develop specific methods for determination of solvents impurities according to the ICH Q3C guidelines.

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bd_global@crystalpharmatech.com +1-609-604-8303
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Suite 500-B, 3000 Eastpark Blvd, Cranbury, New Jersey 08512, USA
Canada
6800 Kitimat Rd, Unit 1, Mississauga, Ontario, Canada L5N 5M1
China
Suite B4-101, Biobay, 218 Xinghu Street, Suzhou Industrial Park, Suzhou, China, 215123
Suite 500-B, 3000 Eastpark Blvd, Cranbury, New Jersey 08512, USA
bd_global@crystalpharmatech.com +1-609-604-8303