Why early-stage formulation development is critical for biologics success

Developing a promising biologic candidate is only the first step on the long path to delivering a safe, effective, and commercially viable therapy. One of the most common pitfalls for biotech companies is overlooking formulation development until later in the process. By then, challenges with stability, manufacturability, or delivery can create delays, increase costs, or even derail the programme.

Formulation is increasingly recognised as a critical success factor in biologics development, yet it has too often been underestimated in the past. Challenges such as antibody aggregation, cell cryopreservation, or vaccine stability can cause setbacks at any stage, even when pharmacological effects appear promising. Recent analyses of FDA Complete Response Letters show that quality and manufacturing (CMC) deficiencies are among the most frequent reasons for non-approval, cited in around 74% of letters issued between 2020 and 2024. Peer-reviewed reviews also highlight that developability and formulation liabilities, such as protein instability, aggregation, and high viscosity, represent major attrition risks in biologics. In advanced therapies, manufacturing and formulation are consistently identified as leading barriers to successful development.

At 3Biotech, we believe formulation development should be integrated early in the biologics development journey. Embedding this work into early CMC (Chemistry, Manufacturing and Controls) strategy gives biotech companies a significant advantage: stronger molecules, reduced risk, and a smoother route to clinical and regulatory success.

What is biologics formulation development in early-stage drug development?

Formulation development is the process of determining the optimal conditions under which a biologic drug product can remain stable, effective, and deliverable to patients. For biologics such as monoclonal antibodies, recombinant proteins, cell and gene therapies, or nucleic acid-based products, formulation encompasses:

• Selecting excipients (buffers, stabilisers, surfactants) that protect the molecule and maintain bioactivity.

• Optimising solubility, viscosity and concentration to ensure dosing feasibility and consistent delivery.

• Preventing degradation and aggregation pathways that can compromise safety and efficacy.

• Determining the dosage form and route of administration — intravenous infusion, subcutaneous injection, or intranasal spray.

• Considering logistics and supply chain such as storage temperature, freeze–thaw cycles, or cold-chain transport.

In the small-molecule world, formulation development is often considered a downstream activity. But for biologics, where the molecular structure is large, delicate, and highly sensitive to its environment, formulation needs to be addressed much earlier.

For example, monoclonal antibodies often face aggregation issues at high concentrations, which can limit the feasibility of subcutaneous dosing. mRNA therapies require stabilising lipid nanoparticle formulations to protect fragile RNA strands from rapid degradation. Cell therapies must ensure cell viability and function during storage and transport, demanding novel cryopreservation strategies. These examples show that formulation is not a “one-size-fits-all” activity. Each modality brings unique challenges that need to be considered early in development.

Why early-stage formulation development matters for biotech companies

Ensuring biologic stability and manufacturability

Biologics are structurally complex and inherently unstable. They can denature, degrade, or aggregate under stresses such as temperature shifts, agitation, light exposure, or pH changes. These instabilities not only reduce efficacy but also introduce safety concerns such as immunogenicity.

Early formulation studies help characterise these risks, identify stabilising excipients, and optimise conditions that extend shelf life. For example, incorporating polysorbates may reduce aggregation, or selecting an appropriate buffer system may prevent pH-induced denaturation.

This work also provides insight into manufacturability. A biologic that is highly stable in a controlled lab environment may not withstand the stresses of large-scale production, filtration, filling, and shipping. By addressing manufacturability questions early, biotech companies reduce the risk of late-stage surprises that can disrupt clinical and commercial supply.

Reducing development costs and timelines

Reformulating a biologic candidate once clinical studies have begun is a costly and time-consuming process. It may require repeating stability studies, re-running toxicology tests, or even restarting early-phase clinical trials.

By contrast, early formulation development integrates stability and delivery considerations into the candidate selection process. This prevents companies from advancing molecules that look promising in vitro but are impractical to manufacture or deliver to patients.

From an investor perspective, demonstrating a clear formulation strategy also signals that a biotech is reducing risks and managing its development programme with foresight. This is particularly important in today’s funding climate, where investors are more selective and risk-averse.

Optimising drug delivery and patient compliance

The route and form of drug delivery are critical to both clinical outcomes and patient acceptance. Formulation decisions shape these parameters:

• Subcutaneous vs. intravenous administration: While intravenous infusion may be feasible, subcutaneous delivery is often preferred for patient convenience. Achieving this requires high-concentration, low-viscosity formulations that remain stable.

• Lyophilised vs. liquid formulations: Lyophilised products may provide better long-term stability but add complexity for patients and healthcare providers, who must reconstitute the drug prior to use. Liquid formulations are simpler but can be more prone to degradation.

• Novel delivery technologies: For RNA-based therapies, lipid nanoparticle formulation is central to successful delivery. Similarly, nasal sprays or inhalation routes may be explored for certain biologics.

Making these decisions early helps companies design studies and clinical protocols that reflect the intended final product, rather than relying on stop-gap formulations that may later need to change.

Supporting regulatory strategy and Quality-by-Design (QbD)

Regulatory authorities, including the EMA and FDA, expect developers to demonstrate control and understanding of their products as early as possible. A formulation-first mindset supports compliance with ICH Q8–Q11 Quality-by-Design (QbD) guidelines, which emphasise embedding quality into development rather than retrofitting it later.

By identifying Critical Quality Attributes (CQAs) early and linking them to formulation decisions, biotech companies can create a strong scientific rationale for their product design. This not only smooths the regulatory pathway but also increases confidence during due diligence by potential partners or acquirers.

The industry is also responding by investing more heavily in early-phase formulation. The global biologics CDMO market, which includes early formulation and process development services, is projected to almost double in value, from $9.93 billion in 2020 to $18.90 billion by 2026. This growth reflects confidence that early investment reduces attrition and shortens development cycles. Involving formulation experts from the outset, assessing candidate molecule developability, and collaborating with specialist CDMOs are all strategies now commonly employed to reduce risk.

Key challenges in biologics formulation and how to overcome them

Despite its importance, early-stage formulation development comes with significant challenges.

1. Limited material availability

   Early-stage biologics programmes may only generate milligrams of drug substance, making it difficult to perform comprehensive screening studies.

    Solution: Employ miniaturised and high-throughput formulation screening methods that maximise data output from very small amounts of material. Analytical methods such as nanoDSC (differential scanning calorimetry) or microfluidic-based stability assays can help.

2. Analytical uncertainty

   At this stage, the full set of CQAs may not be defined. Selecting the right indicators of stability can therefore be challenging.

    Solution: Use orthogonal analytical approaches — combining thermal stability, aggregation propensity, and chemical degradation studies — to build a holistic picture of molecular behaviour. Advanced modelling tools can also predict long-term stability from accelerated conditions.

3. Resource and expertise gaps Many biotech start-ups lack the internal infrastructure or formulation expertise required for advanced studies. Attempting to manage formulation without the right knowledge can lead to misleading results and costly setbacks.

    Solution: Partner with experienced consultants and contract development organisations (CDOs) that can provide the necessary expertise, platforms, and regulatory perspective. Collaborating with external experts allows biotech teams to focus on their scientific innovation while ensuring CMC risks are addressed.

4. Modality-specific complexity

   Different biologic modalities present unique formulation challenges. For example:

   1. Antibodies may require high-concentration formulations to support subcutaneous dosing.

   2. mRNA and DNA therapeutics depend on the stability of lipid nanoparticles or other delivery systems.

   3. Cell therapies require cryopreservation strategies that preserve cell viability and function during transport.
      

Solution: Tailor formulation development to the modality from the outset. Early integration ensures that formulation challenges unique to the therapeutic class are not overlooked until it is too late.

The strategic advantage of early formulation for emerging biotechs

For early-stage biotech companies, embedding formulation into CMC strategy provides clear strategic advantages:

• Investor confidence: A biologic candidate with a well-defined formulation strategy is more attractive to investors, who see reduced technical and regulatory risks.

• Stronger CDMO/CDO partnerships: CDMOs prefer to work with companies that have clarity on formulation requirements. This accelerates tech transfer, process scale-up, and clinical supply readiness.

• Credibility in regulatory interactions: Companies that demonstrate a scientific, data-driven approach to formulation gain credibility with regulators, partners, and potential acquirers.

• Competitive differentiation: In crowded therapeutic spaces such as oncology or immunology, superior formulation (e.g., patient-friendly dosing or room-temperature stability) can be a key differentiator.

In fact, formulation-related failures remain a significant driver of attrition across biologics development. Depending on the phase, they can represent several tens of percent of overall failures, with case studies showing that neglecting formulation can account for up to half of late-stage project failures. Conversely, mastering formulation early can prevent around 10% of critical failures, accelerate development timelines by a year or more, and substantially improve overall success rates. For biotech companies, integrating formulation across the full development lifecycle is not optional; it is a prerequisite for clinical and commercial success.

Embedding formulation into early biologics development with 3Biotech

Ultimately, formulation development is the foundation of a viable biologic. If a drug cannot be formulated for stability, manufacturability, and patient delivery, it cannot reach the market, regardless of its therapeutic promise.

At 3Biotech, we help biotech companies integrate formulation development into their early-stage CMC strategy. Our expertise ensures that promising biologic candidates are supported by the right stability, delivery, and regulatory framework from day one.

If you are developing a new biologic, now is the time to build formulation into your programme. Contact 3Biotech to learn how we can support your pathway to success.

Contact us