Choosing the right excipients is key in formulation development. For CDMOs working on early-stage development, clinically approved medicines are reliable reference standards, offering valuable insights into excipient choices that are both effective and compliant. 

In today’s fast-evolving biopharma landscape, Contract Development and Manufacturing Organizations (CDMOs) have become indispensable strategic partners, helping pharmaceutical companies accelerate time-to-market and reduce costs. By offering a blend of formulation expertise, scalability, and regulatory know-how, CDMOs provide support from pre-clinical development and formulation optimization to large-scale production.  

Using clinical-grade reference products sourced from approved biologics in early formulation can be a game-changer for CDMOs – especially when it comes to understanding excipients.  

To take a closer look, let’s explore excipients and how using clinical-grade reference products can give CDMOs a true edge in formulation development. 

Why do excipients matter in biologics? 

Biologic drugs are produced in cell lines, which makes them inherently unstable and susceptible to degradation by several physical and chemical factors.  

To overcome this major challenge, excipients (additives) are added to the active pharmaceutical ingredient (API) to maintain stability and biological activity during its processing, storage, and drug delivery. 

The selection of excipients depends on multiple factors, including the type of API, route of administration, dosage form, intended final form (e.g. liquid or lyophilized drug), regulatory requirements, as well as the purity, availability, and cost of the excipients.  

Depending on the formulation goals, excipients may be selected to: 

• Enhance solubility of the API 

• Augment process and shelf-life stability of the API 

• Regulate pH and tonicity 

• Retain the preferred stable conformation of the protein, including exposure of the functional epitopes, 

• Prevent aggregation or degradation of API 

• Act as bulking agents, antioxidants or preservatives 

Given the inherent instability of biologics, identifying the right excipients for a formulation is often complex. That means balancing stability with manufacturability, patient usability, and robustness across scale-up and delivery formats.  

As a result, while early formulation screening can be done in months, stability testing and regulatory considerations can add 1-3 years to the process of formulation optimization. 

Which classes of excipients are used in biologic formulations? 

Biologic formulations use various classes of excipients, each serving a specific role in ensuring product quality and performance.  The most commonly used excipient classes are:  

Buffers 

Buffers such as acetate, succinate, citrate, histidine, phosphate and tris help maintain a stable pH during formulation and downstream processing of biologics. The choice of buffer strength depends on many factors, such as target pH, solubility, API type, and product form (liquid or lyophilized). 

Sugars and Polyols 

Sugars (e.g., sucrose, trehalose, maltose) and polyols (e.g., mannitol, sorbitol, glycerol) are widely used in in both solid and liquid formulations as stabilizers, tonicity agents, and bulking agents. They enhance protein stability by raising melting temperatures, increasing water surface tension, exerting excluded-volume effects, and promoting preferential hydration.  

Additionally, sugars and polyols also work together as bulking agents to maintain the integrity of the solid form in lyophilized products.  

Here’s how:  

• Sugars: A sugar-to-protein ratio of at least 1:1 is typical in formulations. In subcutaneous injections, sugars also regulate osmolality (~300 mOsm/kg) to minimize injection-site pain. In lyophilized products, high-purity disaccharides such as sucrose and trehalose act as cryo- and lyoprotectants, protecting APIs from freezing and drying stresses. Glass transition temperature (Tg) is a key parameter influencing stability. Reducing sugars, however, are avoided in mAb formulations due to Maillard reaction–mediated protein degradation. 

• Polyols: The stabilizing effect of polyols in aqueous protein solutions is well documented and is strongly influenced by pH and concentration. Larger polyols generally exhibit greater stabilization, reducing protein unfolding and aggregation. 

Amino acids 

Amino acids such as glycine, histidine, and arginine are commonly used as stabilizers and osmolytes in biologic formulations. Unlike sugars, they are not pH dependent. Positively charged amino acids can interact with immunoglobulins to enhance solubility and reduce protein unfolding and aggregation. 

Let’s look at the most commonly used amino acids in more detail: 

• Glycine serves as a buffering and bulking agent in lyophilized products, protecting proteins during freeze-drying and sometimes preferred over sucrose to avoid renal effects.  

• Histidine, while less effective at improving solubility, can reduce protein viscosity by modulating hydrophobic interactions.  

• Arginine is increasingly used in mAb formulations to enhance solubility and suppress aggregation without compromising stability. 

Surfactants 

Surface-active agents help inhibit adsorption, denaturation and/or aggregation of proteins at interfaces (both air-water and solid-water) and affect stability through differential binding to native or denatured states of the protein.  

Surfactants such as Polysorbate 20, Polysorbate 80, and Pluronic F68 have shown to decrease both soluble and insoluble aggregates. 

Salts 

Salts – primarily sodium chloride- are used as tonicity agents in injections to maintain osmotic pressure and to increase ionic strength, which reduces electrostatic interactions between protein molecules.  

This addition can help maintain pH and improve protein solubility (“salting in”), but salt concentrations must be optimized for each API due to potential effects on conformational stability. 

Antioxidants and Preservatives 

Antioxidants (e.g., histamine, methionine, ascorbic acid, glutathione, vitamin E, polyethylenimine) and chelators (e.g., edetate disodium, DTPA, citric acid, hexaphosphate, thioglycolic acid, zinc) help prevent oxidation and maintain biologic stability.  

Approved antimicrobial preservatives, such as benzyl alcohol, metacresol, phenol, and 2-phenoxyethanol, are crucial in multidose formulations to limit contamination. However, some preservatives, including metacresol, phenol, and zinc, may cause allergic reactions and must be carefully considered during formulation and administration route selection. 

How clinical-grade reference drugs help de-risk formulation strategies 

As we’ve seen, excipient selection is a critical step in early formulation development, directly impacting drug stability, manufacturability, and patient safety.  

The challenge lies in choosing excipients that not only ensure stability and performance but also align with regulatory expectations. Making the wrong choice at this stage can lead to reformulation and delays in the later stages of development.  

For CDMOs, clinical-grade reference products offer a powerful way to mitigate these risks. By analysing formulations that have already been validated in the clinic and approved for commercial use, CDMOs gain direct insight into excipient classes, concentrations, and combinations that are proven to work.  

This evidence-based approach helps de-risk formulation strategies, supports more confident decision-making, and provides a clear starting point for innovation. 

Using clinical-grade reference products allows formulation scientists to: 

• Analyse buffer systems and excipients used in both liquid and lyophilized biologic formulations 

• Compare excipient composition across: 

• • High- and low-concentration monoclonal antibodies (mAbs), bispecifics, Antibody-drug conjugates (ADCs), fusion-proteins and other classes of drugs 

• • Antibody-drug conjugates (ADCs) with varying linkers, payload classes, and drug-to-antibody ratios (DARs) 

• • Isotypes and target antigens 

• Evaluate the type and concentration of stabilizers such as sugars, polyols, and amino acids across different biologic classes (e.g., mAbs, ADCs, fusion proteins) 

• Assess excipient selection and concentration based on route of administration (e.g., intravenous, subcutaneous, intravitreal) 

In addition to compositional insights, clinical-grade reference products offer broader strategic benefits. They enable comparative stability studies, support Quality by Design (QbD), and accelerate the transition from pre-formulation to candidate formulation. This helps CDMOs reduce development timelines, minimize risks, and optimize costs. 

In contrast, research-grade reference products are formulated with basic buffers such as PBS. They don’t contain excipients or provide any insights on approved buffers or concentrations.  

In this way, scientists who use research-grade reference products miss out on information that could be critical to the success of the formulation.  

Looking ahead: Excipient choices that shape outcomes 

For CDMOs, formulation decisions can directly influence the trajectory of a biologic’s success. Understanding how excipients function in approved reference medicines provides a practical foundation for building stable, safe, and regulatory-ready formulations. Clinical-grade reference products make this insight accessible in a way that supports faster and more confident development. 

How to find the right molecules for you? 

Evidentic supplies clinical-grade molecules in original formulation and concentration as research consumables.  

Our team helps you select approved reference medicines that match specific program needs – whether it’s buffers or excipients for high-DAR ADCs or high-concentration IgGs for subcutaneous delivery. With the right references, CDMOs can make excipient decisions that reduce risk and keep innovation moving forward. 

References 

1. Ionova Y, Wilson L. Biologic excipients: Importance of clinical awareness of inactive ingredients. PLoS One. 2020;15(6):e0235076. Published 2020 Jun 25. doi:10.1371/journal.pone.0235076 

1. Medi MB, Chintala R. Excipient selection in biologics and vaccines formulation development. European. Pharmaceutical Review [Internet]. 2014 Apr 11(1). Available from: https://www.europeanpharmaceuticalreview.com/article/24136/excipient-selection-biologics-vaccines-formulationdevelopment/ 

1. Wlodarczyk SR, Custódio D, Pessoa A Jr, Monteiro G. Influence and effect of osmolytes in biopharmaceutical formulations. Eur J Pharm Biopharm. 2018;131:92-98. doi:10.1016/j.ejpb.2018.07.019 

1. Zhang Y, Williams Iii RO, Tucker HO. Formulation strategies in immunotherapeutic pharmaceutical products. World J Clin Oncol. 2020;11(5):275-282. doi:10.5306/wjco.v11.i5.275