Subvisible particulate matter is under increasing amounts of scrutiny in the field of parenteral and ophthalmic drug products.
USP <1788> and <1788.3> explicitly recommend the use of flow imaging and Dynamic Image Analysis (DIA) as an orthogonal method alongside conventional Light Obscuration (LO) and membrane microscopy.
This article explains what USP <1788> means, why it matters, and how the Vision Analytical Raptor 1788 can support pharmaceutical QC labs’ efforts to meet these expectations without replacing existing LO systems.
The Importance of USP <1788>
Subvisible particles (typically particles between 2 µm and 100 µm) are regarded as a critical quality attribute in parenteral and ophthalmic products. The assessment of these particles can help to highlight:
- Contamination from foreign particulates
- Formulation stability, particularly in the case of biologics and proteins
- Integrity of containers or closures
- Particles inherent to manufacturing processes
Traditional compendial methods such as USP <787>, USP <788>, and USP <789> focus on the use of LO and membrane microscopy to determine numerical limits. These methods alone are unable to fully characterize many particle types, however, particularly silicone oil droplets, protein aggregates, fibers, and other irregular particles.
USP <1788> guides improved testing practices in this area, encouraging the use of orthogonal methods like DIA. It is important to note that USP <1788> is informational rather than mandatory, but it is widely considered to be modern best practice.
The Relation Between USP <1788> and USP <787>, <788>, and <789>
Normative USP chapters should be considered as “what to do,” while USP <1788> should be considered as “how to do it well.” For example:
- USP <787> covers the analysis of therapeutic protein injections.
- USP <788> covers the analysis of particulate matter in injections.
- USP <789> covers the analysis of particulate matter in ophthalmic solutions.
- USP <1788> describes the correct application of LO, microscopy, and imaging methods, including the value of orthogonal methods like flow imaging and DIA, the strengths and limitations of each technology, appropriate sample handling and mixing, calibrations, system suitability, and method control.
The Contents of USP <1788>
USP <1788> covers three primary sets of analytical tools:
- Light Obscuration (LO)
- Membrane microscopy (MPC)
- Flow imaging / Dynamic Image Analysis (DIA) (covered in USP <1788.3>)
Several important themes are highlighted. For example, the use of multiple orthogonal techniques is advised. LO is considered essential, but imaging provides information on particle identity rather than simply quantity.
Method-dependent differences are highlighted as being normal, and it is expected that different technologies will ‘see’ particles differently.
The importance of sample handling is also considered, because results can be dramatically altered by factors such as mixing approach, sample viscosity, container type, and environmental controls.
USP <1788.3>: Flow Imaging / DIA in the 1 µm to 100 µm Range
USP <1788.3> provides useful technical guidance for imaging-based methods, such as the Raptor 1788.
Flow imaging and DIA generally cover subvisible particles with sizes between 2 µm and 100 µm, and larger particles beyond 100 µm (depending on the instrument). These techniques also boast the ability to discriminate between particle types and morphologies.
Imaging adds shape descriptors such as aspect ratio, circularity, and elongation. The more shape descriptors are available, the more accurately software can differentiate between specific particle populations.
Imaging also offers insight into opacity, brightness, and texture features through the provision of thumbnail images of each particle. Classification of particle types is also possible. These capabilities are crucial for biologics, for example, where protein aggregates may be inherent but foreign contaminants are not.
The Limitations of Light Obscuration (LO) Alone
LO continues to be the primary compendial method, but this approach alone is unable to:
- Identify particle type
- Distinguish solid particulates from silicone oil droplets
- Effectively detect low-refractive-index particles, such as soft or transparent particles
- Offer visual proof as part of investigations
- Accurately determine morphology
USP <1788> therefore recommends that LO be complemented by orthogonal methods like DIA.
The Raptor 1788: DIA Optimized for USP <1788>
The Raptor 1788 from Vision Analytical is a purpose-built DIA module able to improve existing LO workflows by offering powerful dynamic image analysis for subvisible particles.
The Raptor 1788 leverages its high-resolution optical components to capture detailed images of each individual particle, providing multiple size metrics and shape descriptors of particles down to 1 micron.
It also provides insight into texture and brightness features while capturing image thumbnails for each detected particle.
These capabilities enable useful particular classification, including glass fragments, fibers, protein aggregates, silicone oil droplets, rubber or elastomer particles, and manufacturing or packaging contaminants.
Retrofitting Potential
The Raptor 1788 can be used as a stand-alone instrument or can be integrated into an existing LO system with minimal workflow changes and similar sample volumes. This means there is no need to replace validated methods, and LO can continue to be used as the primary compendial method.
Built for USP <1788> and <1788.3>
The Raptor 1788 has been designed to analyze particles around the 1 µm to 100 µm range, supporting trending, risk assessments, and investigations while providing the recommended morphological detail outlined in the USP and meeting the expectations for advanced biologics.
Key Use Cases
The Raptor 1788 is suitable for use in a wide and varied range of applications and settings, including:
- Therapeutic proteins and biologics, supporting USP <1787>-recommended risk assessments, including the differentiation of protein aggregates from contaminants and trend aggregation under stress or storage.
- Cell and gene therapy and other high-value, low-volume products, including a reduction of sample volume requirements while still being able to extract maximum data per microliter and comprehensively analyze morphology-rich particle profiles.
- Pre-filled syringes and silicone oil, including the identification and quantification of silicone droplets, the distinguishing of droplets from harmful particulates, and the study of formulation–container interactions. Samples can be run directly from a pre-filled syringe to eliminate external contamination sources.
Implementing USP <1788> with the Raptor 1788
Successfully implementing the Raptor 1788 in line with USP <1788> requires a practical rollout strategy.
Step 1: Mapping Current Testing
This begins by identifying where LO alone is insufficient, for example, working with biologics, new containers, or complex investigations.
Step 2: Defining Where Imaging Adds Value
It may be prudent to use the Raptor 1788 for comparability studies, investigations, stability studies beyond the capabilities of LO, and the characterization of protein particles versus silicone.
Step 3: Developing a DIA Method Aligned with USP Guidance
This method should include steps such as mixing procedures, method verification, system suitability checks, and appropriate data review criteria.
Step 4: Integrating the Raptor 1788 Into an LO Workflow
LO can continue to be the primary compendial test, but DIA can be used to add orthogonal confidence.
Step 5: Using Images for Root-Cause Analysis
Particle libraries should be built and deviations reduced.
Conclusion
USP <1788> represents a significant shift from simply counting particles to understanding what particles are.
The Raptor 1788 adds Dynamic Image Analysis without replacing existing LO setups. This allows analysis to be performed in line with USP <1788> recommendations, allowing users to enhance investigations, improve root-cause analysis, and future-proof their QC for advanced therapies.
Acknowledgments
Produced from materials originally authored by Vision Analytical Incorporated.
This information has been sourced, reviewed, and adapted from materials provided by Vision Analytical Inc.
For more information on this source, please visit Vision Analytical Inc.