Process-related impurities or residual impurities are formed at any time during upstream or downstream processes. They are compounds that are present at very low concentrations in complex biomanufactured products and can vary from large proteins to small chemicals. Luc-Alain at SGS Health Sciences reviews the most common types of residual impurities and identifies appropriate monitoring methods for a successful adaptive control strategy.

Extract:

‘Residual Impurities in Biopharmaceutical Products’

Process-related impurities or residual impurities are formed at any time during upstream or downstream processes. They are compounds that are present at very low concentrations in complex biomanufactured products and can vary from large proteins to small chemicals. Therefore, the proper detection and evaluation of residuals requires extensive knowledge of biotherapeutics manufacturing as well as solid expertise in current analytical methodology. This article reviews the most common types of residual impurities and identifies appropriate monitoring methods for a successful adaptive control strategy.

Introduction

Biopharmaceuticals represent a wide range of therapeutic drugs manufactured in living cells or organisms. The characterisation of these products is particularly difficult because biopharmaceuticals are composed of several different structures, more commonly referred to as variants. Variants of the biopharmaceutical product presenting different safety and/or efficacy profiles are defined as product-related impurities or residual impurities. On the other hand, process-related impurities or residual impurities are not structurally related to the intended biopharmaceutical downstream process. This makes their detection and evaluation particularly difficult, requiring extensive knowledge of the biopharmaceutical drug manufacturing process.

Different impurity types can form at various stages during the manufacturing process. It should be noted that adventitious viruses, endotoxins, and mycoplasma are considered as contaminants, not impurities, and therefore will not be discussed in the articles.

Types of impurities:

• The first impurity type to be considered are upstream impurities, which are split into two categories, cell-substrate derived and cell culture-derived impurities. Examples of cell-substrate derived impurities are host cell proteins (HCPs), DNA residues or virus-like particles. Examples of cell culture-derived impurities include antibiotics, inducers, antifoam or media components, and virus inactivating agents.
• The second type are downstream impurities, are common components such as purification reagents (chromatographic solvents, buffers), column and tubing leachates, or metals.
• The third important type of residuals are raw or ancillary material related impurities. Compendial monographs often provide useful standardised tests and specifications for assessing the purity, presence and concentration of raw and ancillary materials.

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