Current Perspectives on Stability of Protein Drug Products during Formulation, Fill and Finish Operations

Abstract

Commercialization of protein-based therapeutics is a challenging task in part due to the difficulties in maintaining protein solutions safe and efficacious throughout the drug product development process, storage, transportation and patient administration. Bulk drug substance goes through a series of formulation, fill and finish operations to provide the final dosage form in the desired formulation and container or delivery device. Different process parameters during each of these operations can affect the purity, activity and efficacy of the final product. Common protein degradation pathways and the various physical and chemical factors that can induce such reactions have been extensively studied for years. This review presents an overview of the various formulation-fill-finish operations with a focus on processing steps and conditions that can impact product quality. Various manufacturing operations including bulk freeze-thaw, formulation, filtration, filling, lyophilization, inspection, labeling, packaging, storage, transport and delivery have been reviewed. The article highlights our present day understanding of protein instability issues during biopharmaceutical manufacturing and provides guidance on process considerations that can help alleviate these concerns.

Effect of pH and Light on Aggregation and Conformation of an IgG1 mAb

“…These stresses include freeze-thaw, shaking, shear stress, as well as liquid-surface and liquid-air interfaces. 9,11 There are two pathways that proteins can degrade; chemical and physical. [11][12][13][14] Chemical degradation of proteins can proceed via a number of reactions.…”

“…9,11 There are two pathways that proteins can degrade; chemical and physical. [11][12][13][14] Chemical degradation of proteins can proceed via a number of reactions. Hydrolysis involves either the cleavage of peptide bonds or deamidation of asparagines and glutamine residues.…”

Increased aggregation propensity of IgG2 subclass over IgG1: Role of conformational changes and covalent character in isolated aggregates

“…4 Such instability can impact the ability to consistently manufacture the high purity drug product. 7 Further, aggregation poses a potential safety concern, because protein aggregates may have the capacity to cause immunogenicity. 8 Therefore, it is essential to understand and control the process of antibody aggregation.…”

“…10 Antibody aggregation is influenced by formulation conditions, such as pH, buffer, and excipient. 4,7 Techniques have been detailed to quantitatively measure antibody aggregation. 9 Size-exclusion chromatography (SE-HPLC) has been the workhorse of the pharmaceutical industry to assess and quantitate the presence of HMW species.…”

Inducing protein aggregation by extensional flow

“…The force applied onto a protein as a consequence of hydrodynamic flow has also been observed to trigger protein aggregation and has fundamental (3), medical (4), and industrial relevance, especially in the manufacture of biopharmaceuticals (5)(6)(7)(8). Although a wealth of studies have been performed (7,(9)(10)(11)(12)(13), no consensus has emerged on the ability of hydrodynamic flow to induce protein aggregation (7,14,15). This is due to the wide variety of proteins used (ranging from lysozyme, BSA, and alcohol dehydrogenase to IgGs), differences in the type of flow field generated (e.g., shear, extensional, or mixtures of these), and to the presence or absence of an interface (16).…”