Overview of drug formulation development steps
Drug formulation development is the process of combining an active pharmaceutical ingredient (API; also known as a drug substance) with non-active components (called excipients). The resulting mixture (called the drug product) enables the delivery of the drug to a patient in a safe and efficacious manner, via the desired route of administration.
In practice, teams don’t “just make a formulation and test it”. Instead, they run a structured, risk-reducing workflow that balances:
- API physicochemical constraints (solubility, stability, compatibility)
- Regulatory feasibility (using well-precedented excipients when possible)
- Manufacturability (scale-up, filtration, packaging) and
- IP strategy (white space, blocking, design-around).
Drug Formulation Development Steps Overview
The following steps are commonly used to develop a functional, scalable, and approval-ready formulation. In practice, the process is iterative—teams often loop between screening, testing, and refinement until the formulation is both clinically practical and manufacturing-realistic.
Step 1: Pre-formulation Assessment
Preformulation assessment evaluates the physicochemical characteristics of the drug substance to identify the constraints that will drive dosage form selection, excipient strategy, and early manufacturing and regulatory risk reduction. Typical work includes:
- Prior work (“history”): Review of prior formulation attempts to identify what worked, what failed, and the shortcomings driving reformulation.
- Solubility: Solubility in water, buffers, solvents, and co-solvents; pH-solubility behavior; and any concentration limits relevant to the target dose.
- Stability: Chemical and physical stability (including in solution) under relevant conditions that could limit formulation approaches (e.g., hydrolysis, oxidation, aggregation, or precipitation).
- Excipient compatibility: Identify API–excipient interactions and excipient stability concerns that could limit or eliminate specific excipients. When relevant, also consider compatibility with key container-closure materials.
Step 2: Intellectual Property Review & Strategy
An intellectual property (IP) review evaluates issued, pending, and planned patents related to the drug substance and/or drug product to inform formulation design decisions and reduce freedom-to-operate risk. Typical work includes:
- White space analysis: Competitive review of the patent and scientific literature landscape to identify unclaimed areas and opportunities for differentiation and innovation.
- Blocking IP strategy: Develop a formulation approach that strengthens a defensible IP position by maximizing protectable features around the drug substance and drug product.
- Design-around analysis: Identify practical formulation options that avoid competitor claims while still achieving the target product profile.
Aligning IP strategy early helps steer formulation development toward approaches that are both technically viable and commercially defensible—reducing the risk of late-stage pivots.
Step 3: Target Formulation Profile
Based on the physicochemical properties of the drug substance and its intended clinical use, the next step is to define a Target Formulation Profile (TFP). The TFP documents the ideal vs acceptable product attributes up front so formulation screening has a clear finish line, and tradeoffs are made intentionally (not late in development). An example TFP is shown below:
| Attribute | Ideal | Acceptable |
|---|---|---|
| API concentration | 10 mg/mL | 5-9 mg/mL |
| Dosage Form | Liquid or emulsion | Lyophilized powder |
| Viscosity | < 2 cP | 2–3 cP |
| pH | 7.0 | 5.5-6.5 |
| Osmolarity | Isotonic (280–300 mOsm/kg) | Slightly hypotonic (240–270 mOsm/kg) |
| Reconstitution stability (for lyophilized products) | > 24 hrs | 3-23 hrs |
| Excipients | At or below IID levels | Above IID levels |
| Route of Administration | Subcutaneous (preferred) | Intravenous (IV) (fallback) |
| Stable Storage Conditions | Controlled room temperature (20–25°C) | Stored frozen (–20°C) |
| Sterile Strategy | Sterile Filtration | Aseptic processing |
| IP | New drug product IP | Limited IP expansion (terminal disclaimer strategy) |
*IID = FDA Inactive Ingredient Database; “at or below IID levels” refers to excipient levels with precedent in approved products for the intended route.
A well-defined TFP keeps screening efficient and aligned—so you don’t “discover” your true requirements during scale-up or clinical supply.
Step 4: Protype Generation
Successful drug formulation development often comes down to excipient selection—to achieve target attributes and reduce risk by using excipients with regulatory precedent when feasible.
When possible, teams start with excipients (and use levels) that have precedent in FDA-approved products for the intended route (often checked using the FDA Inactive Ingredient Database (IID)). When that approach can’t meet the TFP (e.g., due to solubility, stability, viscosity, or delivery constraints), novel excipient and enabling formulation technologies may be evaluated. In other words, we start with established excipients and escalate to novel technologies only when required by the API constraints and the TFP.
Prototype generation typically follows these steps:
- Excipient screening: Screen formulations using established excipient technologies first, then expand to novel approaches as needed to meet TFP criteria.
- Formulation compounding: Prepare and compare prototypes using appropriate compounding methods—from conventional mixing to more complex processes (including, when relevant, nanoparticle-forming techniques) for promising excipient strategies.
- Formulation technique screening: Evaluate how components are combined (order of addition, mixing energy, temperature, pH adjustment, and hold times). In many cases, the formulation technique can be as important as the components—high-energy methods (e.g., high-shear mixing, homogenization/microfluidization, sonication) can improve dispersion and consistency.
- Formulation refinement: Refine lead prototypes to the final dosage form. This may include lyophilization (water removal), tangential flow filtration (TFF) for solvent exchange or impurity removal, and other process steps needed to achieve the final drug product presentation.
Lead prototypes are selected based on performance against the TFP and manufacturability considerations such as filterability, robustness, and container-closure compatibility.
Step 5: Testing & Scale-up Readiness
Lead prototypes are evaluated against the Target Formulation Profile (TFP) and screened for downstream risks that commonly derail development during scale-up and GMP manufacturing. Typical work includes:
- Analytical method compatibility: Confirm the formulation matrix does not interfere with potency/assay readouts (e.g., activity assays) and supports reliable impurity/stability testing.
- In vitro performance (as applicable): Evaluate key functional attributes relevant to the dosage form (e.g., release behavior, dissolution, viscosity/injectability, osmolality/pH drift, or container/closure interactions).
- In vivo evaluation: Dose the formulation—ideally via the intended route from the TFP—to assess PK, exposure, efficacy, local tolerability, and safety signals.
- Stability studies: Monitor chemical and physical stability over time under intended and accelerated storage conditions (e.g., assay/purity, degradation products, particulates, pH, viscosity, and appearance).
- Scale-up and GMP readiness: Stress-test preparation parameters (mixing, order of addition, shear, temperature, and hold times) and define a robust process suitable for tech transfer and clinical GMP manufacturing.
- Sterile filtration and aseptic processing: If terminal sterilization is not feasible, develop small-scale filtration models early to inform filter selection, adsorption risk, flux/pressure limits, and scalable filtration parameters for GMP production.
Together, these studies confirm the formulation is not only effective, but also stable, manufacturable, and ready for clinical supply.
FAQ: Drug formulation development
What is preformulation in drug development?
Preformulation is the set of studies that characterize an API’s physicochemical behavior (e.g., solubility, stability, and excipient compatibility) so you can choose a viable dosage form and de-risk development early.
What is the FDA Inactive Ingredient Database (IID), and how is it used?
The FDA’s Inactive Ingredient Database (IID) provides information on inactive ingredients present in FDA-approved drug products, and it can be used as an aid when developing drug products. In general, if an excipient is already present in approved products for a given route of administration, it may reduce the amount of “new excipient” burden compared with truly novel excipients.
What is a target formulation profile (TFP), and why does it matter?
A TFP is the formulation team’s “definition of success.” It lists ideal vs acceptable product attributes (e.g., concentration, dosage form, viscosity, storage conditions, excipient constraints, and route) so screening work has a clear finish line.
How do you choose excipients during prototype generation?
Start with the TFP, then screen excipients to solve the dominant constraints (commonly solubility, stability, tonicity/pH, viscosity, or delivery feasibility). When possible, prioritize excipients with precedent for the intended route (often checked using the IID), then move to more specialized/novel technologies if the API simply can’t meet targets with standard approaches.
When do you need a lyophilized product instead of a liquid?
Lyophilization is often considered when a liquid formulation can’t meet shelf-life targets due to hydrolysis/oxidation, precipitation, or other instability pathways, or when concentration targets are difficult to hold in solution. It can also be used to support long-term storage or enable challenging APIs—at the cost of more complex development (cycle development, reconstitution, container/closure considerations).
Why does sterile filtration become a problem late in development?
Because filtration is a system problem: API/excipient interactions, viscosity, particulates, adsorption to filters, filter area, and process parameters can all change during scale-up. If the drug product can’t be terminally sterilized, sterile filtration is commonly used—so developing small-scale filtration models early helps avoid painful surprises during tech transfer or GMP manufacturing.
How long does formulation development usually take?
It depends on dosage form complexity and how constrained the API is. A straightforward aqueous solution might move quickly, while a poorly soluble/unstable API, an emulsion/suspension, or a lyophilized product typically requires more screening loops, stability time, and manufacturability work before it’s scale-up-ready. (The key variable is usually how many prototype → test → refine cycles are needed.)
Conclusion
In an ideal world, drug formulation development would move through these steps once and proceed directly to clinical manufacturing. In reality, the process is iterative.
A formulation may perform well in vivo but prove difficult to manufacture at scale, challenging to sterile-filter, unstable under the required storage conditions, or not meaningfully differentiated from an IP perspective—requiring one or more steps to be revisited. The goal isn’t a perfectly linear path; it’s a disciplined one.
Address each step deliberately, document decisions against the TFP, and iterate early—because skipping steps can save time in the short term but create fatal flaws later in development.
