The ICH Q6B guidelines state that for all biopharmaceutical products an assessment needs to be made to determine the presence or absence of any process related impurities and contaminants. These are derived from the manufacturing process and are classified into three major categories:
- Cell substrate-derived impurities (e.g. derived from the host organism and nucleic acid, such as host cell DNA).
- Cell culture-derived impurities (e.g. inducers, antibiotics, serum).
- Downstream-derived impurities (e.g. enzymes, chemical and biochemical processing reagents, inorganic salts, solvents etc.).
A downstream process should be designed to remove or minimize process residuals and methods should be developed to allow quantitation of process-related impurities of interest via the analysis of process intermediates, Drug Substance and Drug Product.
BioPharmaSpec provides methods for the analysis of a significant range of impurities. These methods have been developed to allow identification and quantitation to low ppm/ppb limits. Our service includes:
- Method development and optimization (where required).
- Testing of process intermediate, Drug Substance and Drug Product samples.
- Qualification of each method for the process-related impurities of interest in the product/formulation(s) of interest.
|Process-related impurity||Examples||Method||Usual quantitation limit|
|Inducer||Sugars (Arabinose, Isopropyl-β-D-thiogalactopyranoside (IPTG))||GC-MS||100ppb|
|Cell culture antibiotic||Streptomycin
|Antioxidants (Ascorbic acid)||GC-MS||100ppb|
|Solubilizer||Amino acids||Derivatization LC fluorescence||1ppm|
|Surfactants (Tween, Polysorbate, Triton)||LC-MS/MS||10ppb|
|Denaturants (Guanidine, Urea)||Derivatization LC fluorescence||1ppm|
|Buffering capacity||Amino acids||Derivatization LC fluorescence||1ppm|
|Tonicity modifier||Amino acids||Derivatization LC fluorescence||1ppm|
|Reducing agents||Glutathione, DTT etc||LC-MS/MS||10ppb|
|Antifoam agents and processing additives||PEG and PPG||LC-MS/MS||10ppb|
|Free PEG in a PEGylated protein product||PEG||LC-MS/MS||10ppb|
BioPharmaSpec has significant experience with these methodologies and is able to develop pre-analysis purifications to reduce interference as and when required. Our scientists can also develop bespoke methods for new/unusual process additives. Please contact us if you would like to know more.