Particle size characterization is a foundational CQA for nanomedicines like mRNA-LNPs, as size and PDI dictate in vivo biodistribution, cellular uptake, and stability. Minor size changes from stressors cause aggregation and efficacy loss. Creative Biolabs' Custom Particle Size Characterization Service uses advanced platforms and QbD reporting to ensure regulatory compliance and delivery system stability, covering from synthesis to administration. It integrates into biopharmaceutical pipelines, turning size data into a tool for therapeutic success.
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We provide a comprehensive suite of analytical services tailored to the unique requirements of complex nanoparticle systems.
We report the Z-Average (hydrodynamic diameter), typically determined by Dynamic Light Scattering (DLS), which is the most common metric for regulatory submissions. Additionally, we provide Number-weighted and Volume-weighted means (via Nanoparticle Tracking Analysis, NTA) to detect smaller subpopulations not visible by DLS.
This measurement assesses the homogeneity of the sample. We provide full distribution histograms and statistical analysis. Narrow, monomodal distributions are essential for predictable in vivo performance. We specialize in detecting aggregation (large particle sizes) or premature dissociation (small component sizes) that indicate formulation failure.
The PDI is a dimensionless measure of the width of the size distribution. A low PDI indicates a highly uniform batch, which is essential for ensuring consistent dosing and reducing unexpected toxicity or immunogenicity risks in clinical trials. A rising PDI is often the first indicator of instability.
While particle shape is inferred by DLS, we provide complementary analysis through techniques like Asymmetrical Flow Field-Flow Fractionation (AFFFF) coupled with light scattering to separate and characterize non-spherical particles, providing better insight into the LNP's true structural integrity, particularly post-stress testing.
We determine the precise concentration of the nanoparticles (particles/mL) using Nanoparticle Tracking Analysis (NTA). This count provides crucial data for accurately calculating dosing and is vital for understanding batch yield and loss during processing steps like filtration or freeze-drying.
Creative Biolabs utilizes a suite of orthogonal detection methods to ensure data accuracy and cross-validation:
| AFFFF | Used for the separation and characterization of complex samples, with better resolution than DLS for multimodal particle populations. |
| DLS | Measures scattered light intensity fluctuations to quickly obtain average particle size, size distribution, and PDI. Suitable for routine analysis of nanoscale particles in suspensions (easy to operate), but highly sensitive to particle concentration and agglomeration. |
| NTA | Tracks individual particles’ Brownian motion in real time to calculate size via the Stokes-Einstein equation; also assesses particle concentration. Highly sensitive to low-concentration samples and can distinguish subpopulations in complex systems. |
| Transmission Electron Microscopy (TEM) | Uses electron beam imaging to directly observe particle morphology, size, and dispersion (nanoscale resolution). Requires sample processing (fixation, staining), which may alter particles’ original state. |
| Cryogenic Transmission Electron Microscopy (Cryo-TEM) | Rapidly freezes samples into a glassy state to observe 3D structure and size under near-physiological conditions. Avoids morphological distortion from conventional TEM processing, ideal for fragile LNPs. |
| Laser Diffraction (LD) | Relies on laser scattering angle vs. particle size for analysis; applicable to a wide size range (micrometers to nanometers). Often used for large particles or polydisperse systems, but has low resolution for small nanoscale particles. |
| Field-Flow Fractionation (FFF) Coupled Technology | Separates particles by size using a fluid field; combines with DLS or UV detection to accurately analyze LNP size distribution and purity in complex mixtures. Particularly suitable for highly dispersive samples. |
Our comprehensive approach ensures every critical quality attribute (CQA) related to particle size is rigorously measured and documented, suitable for direct submission in regulatory filings.
Client provides 2–3 key details: a) LNP formulation/lipid molar ratios, b) target drug load (e.g., mRNA concentration), c) critical storage conditions. In-depth review of the regulatory context and administration route to clarify service scope.
Samples prepared per client’s final drug format (e.g., buffered solution, lyophilized cake). Controlled stress tests (freeze-thaw cycles, high-shear stress, accelerated storage at 4°C/25°C/-80°C) based on identified pain points.
Stressed/control samples tested via cross-validated techniques (DLS, NTA, FFF) to generate size profile, PDI, and concentration data. Data benchmarked against the client’s target CQAs.
For systems like LNPs, particle size data predicts/confirms functional stability. E.g., -80°C aggregation data correlated with protein expression loss to verify therapeutic relevance.
Client receives: a) CFR Part 11-compliant Final Analytical Report, b) raw data/method parameters, c) expert interpretation and regulatory summary with optimal storage/handling recommendations.
The client receives a) a Comprehensive Final Analytical Report (compliant with CFR Part 11), b) raw data files and method parameters, and c) an expert data interpretation and regulatory summary that recommends optimal storage and handling protocols.
The typical timeframe for this service ranges from 3 to 6 weeks, depending on the complexity of the stress testing protocols and the scope of the required functional correlation assays.
Elevate your therapeutic program's confidence with Creative Biolabs' precise and predictive Particle Size Characterization Service. We move beyond basic QC checks to deliver the data fidelity required for complex nanomedicines, offering fully customized modules to match your unique vector and phase of development.
Orthogonal Multi-Modal Analysis
Conduct cross-validated particle sizing using gold-standard techniques such as DLS, NTA, and FFF. This ensures full coverage of the particle population and eliminates false size readings.
Predictive Stress Testing
Provide customized protocols to accurately simulate real-world thermal degradation (e.g., -80°C storage and thaw cycles) and mechanical degradation (e.g., shear stress from filtration or aspiration). It proactively identifies critical failure points (such as cold-induced aggregation) before they affect clinical batches.
Functional Correlation Module
Establish a critical link between physical changes of particles (size/PDI shifts) and functional outcomes (decreased encapsulation efficiency or protein expression), transforming your characterization data into a powerful tool for predicting in vivo efficacy.
Regulatory-Grade Data Packages
All data and reports are structured in line with Quality-by-Design (QbD) principles, enabling seamless integration into the Chemistry, Manufacturing, and Controls (CMC) sections to accelerate the regulatory approval process.
Customized Analytical Design
Offer flexible and personalized service designs, allowing you to select specific techniques and stress protocols. This ensures the analytical package is perfectly tailored to the unique properties of your LNP, viral vector, or protein therapeutic.
This study selected different lipids, including C12-200 (ionizable), DDA (cation), and DOTAP (cation), etc. The particle size and its related polydispersion index were determined by NTA, as well as the surface charge of LNP, determined by zeta potential analysis measured by the Zetasizer instrument.
Fig.1 Characterization of saRNA lipid Nanoparticle preparations.1
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DLS provides excellent data on the overall batch average, but it is heavily biased toward larger aggregates. A slightly increased PDI might signal a big problem, but a stable PDI can still mask functional loss (e.g., lipid oxidation at 25°C). We strongly recommend correlating physical data with functional assays (like encapsulation efficiency or protein expression) to truly confirm therapeutic viability.
We specifically model the "Cold Paradox" problem demonstrated in key literature, where LNPs aggregate when stored at -80°C without cryoprotectants. Our stress testing protocols include controlled freeze-thaw cycles and -80°C storage checks, allowing you to validate your final formulation and identify the necessity and optimal concentration of stabilizing agents like sucrose.
Shear stress. Processing steps like sterile filtration and syringe aspiration can damage the delicate LNP structure, leading to aggregation and loss of potency. We model these specific physical stressors in the lab, providing size and PDI data immediately post-stress, ensuring your final drug product administration is safe and effective.
Absolutely. While we specialize in LNP technology, our multi-modal platforms (DLS, NTA, AFFFF) are fully validated for a wide range of biological products, including AAV and lentiviral vectors, liposomes, exosomes, and complex protein aggregates. The core principles of CQA control apply universally to all nanomedicines.
Creative Biolabs' Custom Particle Size Characterization Service provides the unparalleled analytical precision required to navigate the complexities of modern nanomedicine. By moving beyond basic metrics to provide data correlated with functional efficacy and structural integrity under stress, we ensure your formulation is stable, predictable, and ready for clinical success.
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