Recently, both the EMA and FDA have sharpened their expectations around particle size distribution (PSD) and solid-state form (e.g. polymorphism, amorphous content) – especially in formulations where the Active Pharmaceutical Ingredient (API) remains undissolved.
But what’s behind this increased focus, and when is it relevant?
When is PSD and solid form characterization required?
The particle size and solid form of an active substance become critical when the drug is not dissolved in the final formulation – meaning it stays in particulate form during manufacture, storage, and use.
Common examples include:
- Suspensions (e.g. nasal sprays, oral/ophthalmic/injectable suspensions)
- Topical creams and ointments
- Dry powder inhalers (DPIs)
- Implants and depot formulations
In these cases, PSD and solid-state properties directly impact:
- Dissolution rate and bioavailability
- Dose uniformity
- Product stability
- Therapeutic performance
What are the updated regulatory expectations?
1. EMA Guidance on Nasal/Inhalation Products (2023–2024 updates)
For suspension-based formulations, EMA now explicitly states:
“For products containing an active substance not dissolved during manufacture, storage, or use, the particle size is crucial. It must be characterized and justified, and linked to in vivo performance.”
Laser diffraction is widely accepted for PSD; in some cases, ingredient-specific techniques like MDRS (Morphologically-Directed Raman Spectroscopy) are needed to separate API from excipients.
2. FDA Guidance on Solid Polymorphism and Complex Generics
The FDA emphasizes that different polymorphic or amorphous forms can:
- Affect solubility and bioavailability
- Lead to variability in clinical performance
- Require method validation and robust solid-state characterization
They also recognize MDRS as a valuable tool for API-specific PSD in nasal and suspension products, particularly in bioequivalence studies for generics.
Why is this shift happening?
As more complex formulations and locally acting products enter the market, regulatory bodies need assurance that every critical quality attribute (CQA) is controlled. Particle size and solid-state form are among the most impactful CQAs in non-dissolved APIs — but were often under-characterized in the past.
This shift reflects a broader trend toward:
- Quality by Design (QbD)
- Stricter expectations for generic drug approvals
- Reduced reliance on clinical trials through stronger in vitro evidence
What does it mean for you?
If you’re developing:
- A suspension or semi-solid product
- A generic of a locally acting drug (e.g. nasal spray, inhaler)
- A formulation with micronized API
- A product where solubility or stability is critical
…you likely need detailed PSD and solid-state data, supported by qualified analytical methods and GMP documentation.
How can Particle Analytical help?
We offer:
- Validated PSD analysis using laser diffraction, MDRS, microscopy, and air-jet sieving
- Solid-state characterization (XRPD, DSC, Raman, FTIR)
- Support for method transfer, development, and validation under GMP
- Experience with bioequivalence studies and regulatory submissions
- Comprehensive material profiling to ensure CQAs are characterized
