8.2 Drug substance and drug product stability

Formulation similarity

(b) a polyol, (c) a polysorbate at a concentration of 0.1 to 10 mg/mL, and (d) a buffer system comprising histidine and having a pH of 4.5 to 7.0, wherein the antibody comprises the light chain variable region and the heavy chain variable region of D2E7.

The example provided above should serve as a warning to biosimilar product developers of the challenges they will face in establishing formulation similarity. The native structure of a protein molecule is the result of balancing effects such as covalent linkages, hydrophobic interactions, electrostatic interactions, hydrogen bonding, and van der Waals forces. Protein stability is controlled by innumerable intrinsic and extrinsic factors, but the major ones are primary sequence, 3D structure, subunit associations, and PTMs. Extrinsic contributing factors include pH, osmolarity, protein concentration, formulation excipients, and exposure of a product to physical stress from temperature, light, and/or agitation. Leachables from container-closure systems and contamination from the environment (e.g., metals and proteases) also exacerbate product degradation. All these features make protein degradation a very complex physiochemical phenomenon, so formulation optimization is a core aspect of biotechnology product development.

A biosimilar developer has access to the exact formulation used by the originator because of the nature of the product being an injectable. In almost all instances, unless otherwise dictated by IP, safety improvement and constraints related to the availability of inert components of the correct specification, the formulation of a biosimilar should be the same as that of the originator product. However, in developing a QTPP, the biosimilar developer must analyze multiple lots of the originator product since the labeling of inactive components gives no indication of the acceptance ranges; for example, it is not uncommon for a product to contain a surfactant with a range of ±50% to 80%. The formulation of biopharmaceuticals is a vast field of study with two peculiarities compared to small-molecule drugs. First, most protein drugs are administered by parenteral routes, and, as a result, most of the science of protein drug formulation deals with the art of injectable formulations. Second, there are several common structural features of all proteins, such as functional groups like methionine, cysteine, histidine, tryptophan, and tyrosine, all of which are subject to oxidation, requiring some common approaches to establishing stable products. On the other hand, conformational changes and aggregation are properties peculiar to large molecules that require the inclusion of formulation components that can be highly specific. The quality of inactive components can have a far greater impact on the formulation than those found in pharmaceuticals, 291

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Table 8.1 Impact of Various Formulation and Environmental Factors on the Degradation of Proteins

Factor Impact

pH Hydrolysis, deamidation Buffer species Deamidation Other excipients Maillard reaction Light Photodecomposition Oxygen Oxidation Metal ions Hydrolysis, oxidation Temperature Most routes

and it requires detailed studies, particularly those components that can enhance oxidation of proteins. Also significant for proteins is the physical degradation that can lead to significant safety issues. Varieties of formulation factors that can induce instability are shown in Table 8.1. These factors are well studied and anticipated from the knowledge of the chemistry of all types of molecules. However, the impact on safety and efficacy is peculiar to biopharmaceuticals. Compared to small-molecule drugs, biopharmaceuticals are typically more sensitive to slight changes in solution chemistry. They remain compositionally and conformationally stable only within a relatively narrow range of pH and osmolarity, and many require additionally supportive formulation components to stay in solution, particularly over time. Even lyophilized protein products are subject to significant degradation,

Table 8.2 Typical Stability Problems Observed in Protein Pharmaceuticals

Problems Potential Causes Possible Solutions

Noncovalent aggregation Solubility, structural changes, heat, shear, surface, denaturants, impurities pH, ionic additives, amino acids, surfactants, protein concentration, raw material purity

Covalent aggregation Disulfide scrambling, other unknown mechanisms pH, inhibit noncovalent aggregation

Deamidation pH <5.0 or pH >6.0 pH optimization

Cyclic imide pH around 5 pH optimization

Cleavages Protease impurity, other unknown mechanisms pH, product purity, inhibitors

Oxidation Active oxygen species, free radicals, metals, light, impurity

Surface denaturation, adsorption Low-protein concentration, specific affinity, protein hydrophobicity Excipient purity, free-radical scavenger, active oxygen scavengers, methionine Surfactants, protein concentration, pH