Small-molecule drug substances: Regulation-compliant, reliable particle sizing using the Mastersizer 3000+

Instrument adaptability and reliability, together with regulatory compliance and ease of method transfer between instruments, are all key factors to consider when choosing a laser diffraction instrument for particle sizing in the pharmaceutical industry. Enter the new Mastersizer 3000+, which, built on the solid foundation of previous Mastersizer models, now offers even more appealing features for streamlined measurement of particle size distributions of APIs (active pharmaceutical ingredients).

Particle sizing using laser diffraction

Laser diffraction instruments within the Mastersizer range have long been well-regarded by the pharmaceutical industry for their accuracy, reproducibility, versatility and ease of use for the particle sizing of APIs (active pharmaceutical ingredients).

Today, Mastersizer is used to analyze wet and dry API particle dispersions at various points in the workflow (Figure 1), including preclinical development, clinical development and scale-up, and manufacturing.

Figure 1: The API workflow and the challenges that can be resolved with the help of particle sizing data acquired on the Mastersizer 3000+.

The Mastersizer 3000+ now builds on this success and our decades of technical knowledge and experience, with three new software features to enhance your particle-sizing capabilities still further:

• Size Sure for improved confidence in routine measurements and method development
• Data Quality Guidance for helping you to make independent decisions on real-world samples
• SOP Architect for standardized, streamlined method development for wet samples.

How do the new and existing features come together? Read on for an overview of why we think the Mastersizer remains top of the field for generation of reliable particle size distributions (PSDs) for APIs.

Figure 2: Mastersizer 3000+ with a range of accessories. 

Challenge 1: Adapting to different sample types

The variety of samples encountered in pharmaceutical research, development and manufacture demands that particle-sizing methods must be adaptable to a wide range of particle sizes, in the form of dry powders and wet suspensions. 

Fortunately, Mastersizer 3000+ is ready for any challenge, with its dynamic range of 0.01–3500 µm and a suite of accessories for sample presentation (Figure 3). Our Hydro accessories for wet dispersions give excellent results for all the dispersants commonly used in API studies (whether volatile or less stable), while our Aero accessories for dry dispersions ensure that everything from cohesive powders to fragile materials are presented consistently, rapidly and reproducibly. 

Importantly, these accessories allow you to get repeatable results even when measuring small amounts of sample – meaning you’ll be able to get data you can trust, even when your API is in short supply. And of course, switching between any of the accessories is quick, easy and convenient.

Figure 3: Six grades of lactose measured as either wet or dry dispersion, showing the versatility of the Mastersizer.

Challenge 2: Maximizing instrument uptime

When important processes hinge upon getting a particle size measurement, you need to be able to trust your laser diffraction instrument to be ready to deliver spot-on measurements, time after time.

So it’s reassuring to know that Mastersizer leads the field of laser diffraction instruments regarding reliability and measurement-to-measurement repeatability (Figure 4) – as attested by the many years of service in the hands of hundreds of satisfied customers in pharma.

In addition, like other Malvern Panalytical instruments, the operation of Mastersizer 3000+ is supported by our Smart Manager. One feature of this is that the instrument can connect to the Malvern Panalytical cloud, so that on the rare occasion that something does go wrong, our Tech Support Center can support you remotely, and schedule specific maintenance as needed. 

Figure 4a: PSDs showing the excellent repeatability of the Mastersizer for the measurement of an ibuprofen suspension in water. 

Figure 4b: PSDs showing the excellent repeatability of the Mastersizer for the measurement of coarse-grade lactose in a relatively volatile solvent (isooctane).

Challenge 3: Ensuring regulatory compliance

Increasing regulatory attention is currently being focused on the data integrity of analytical systems used in the pharma industry – and not just at later stages in the pharmaceutical pipeline.

To address this, Mastersizer 3000+ integrates with OmniTrust. This is our software platform for ensuring data integrity in accordance with 21 CFR Part 11, giving you confidence that no surprises will be discovered during an audit. OmniTrust also integrates with other instruments from Malvern Panalytical, including Zetasizer and our XRD platforms, simplifying the control of access and permissions and viewing activity logs. 

With regard to validation of analytical procedures, in November 2023 ICH Q2 revision 2 was approved and published, and many people in the pharma industry are already using it to inform submissions to the regulatory authorities. One aspect recommended by ICH Q2 R2 is the use of an orthogonal method to validate the laser diffraction results. Mastersizer 3000+ has a ready-made answer to this, in the form of the Hydro Insight accessory for dynamic imaging of particle size (and shape). Alternatively, a dry method can be used to validate a wet method, and vice versa.

We’ve always helped Mastersizer customers to work through the complexities of validation issues, and you can find out more about the latest developments regarding the validation of laser-diffraction particle-sizing methods in this webinar.

Challenge 4: Transferring methods between instruments and labs

The manufacture of materials often changes sites as the volumes scale up or down, or simply move for commercial reasons. As the manufacturing process transfers between sites, so must the technology and methods for operation.

Mastersizer 3000+ meets the highest standards in that regard, with its instrument-to-instrument reproducibility typically being better than 1% for polydisperse standards, which exceeds ISO 13320:2020 and USP recommendations. 

Malvern Panalytical has developed a Quality Audit Standard (QAS) which is a polydisperse standard to meet all of the requirements of ISO 13320 for a certified reference material. Glass beads are an appropriate reference material for laser diffraction as they are spherical particles with well-known optical properties. When this material was tested on 50 different Mastersizer 3000+ systems with a Hydro MV dispersion accessory, the %RSD for the Dv50 was calculated to be 0.4% (Figure 5). 

Figure 5: Reproducibility scatter plot of 50 QAS measurements on the Mastersizer 3000+ 

And when those needing to carry out measurements have different levels of expertise, the Mastersizer 3000+ is there to support them with its ease of use and easy-to-learn user interface.

This user-helpfulness is boosted further by the intelligent feedback offered through our Data Quality Guidance software module. Data Quality Guidance uses machine-learning algorithms to identify when there might be a measurement issue, and suggests a course of action to resolve it (Figure 6). In this way, with the best advice from Malvern Panalytical’s experts on-tap, you’ll be able to spot problems as soon as they occur, and take swift and targeted action to avoid wasting time.

Figure 6: A typical measurement window, showing the Data Quality Guidance panel on the right-hand side, accessed through the Data Quality tab [1]. Potential issues [2], causes [3] and actions [4] are flagged and grouped according to whether they relate to the background, the sample, or the dataset variability analysis. A tab at the bottom of the window [5] links directly to the help pages on the Malvern Panalytical website.

A further feature of Mastersizer 3000+ is SOP Architect, which helps you with the complexities of method development for wet samples, by offering situation-specific feedback on measurements founded on best practices in the field (Figure 7). Methods generated using SOP Architect use Malvern Panalytical’s ‘.sop’ file type, meaning that they run on SOP Player, and can be edited using SOP Editor, forming part of a complete ecosystem for SOPs that is easily transferred between labs, wherever they’re based.

Figure 7: A typical example of SOP Architect being used, showing real-time results obtained during a stir-speed titration.

Last but not least, methods developed on the Mastersizer 3000 can be transferred to the Mastersizer 3000+, streamlining the process of integrating new instruments into your workflow.

Challenge 5: Troubleshooting unexpected results 

In an ideal world, dispersions of particles for size analysis by laser diffraction would be completely clean, and the analytical process would run without a hitch to generate particle size distributions (PSDs) that accurately reflect the true sample.

But analyses in real life are rarely that simple. If bubbles or unwanted contaminants are present, they have the potential to affect your sample PSD. You can be left wondering if your sample truly contains coarse particles or not, as well as facing the need to invest time and sample into troubleshooting and investigations. 

But this is where Size Sure can help. The Size Sure measurement mode, using Malvern Panalytical’s Adaptive Diffraction, provides additional confidence in routine measurements whilst also streamlining method development. 

Size Sure classifies your data into two states, reported separately:

• Steady-state data describes the particles that are observed most of the time
• Transient-state data describes any events – from particles or otherwise – that are only observed occasionally, typically less than 10% of the time.

Take this example of an ibuprofen sample. Without the Size Sure measurement mode applied, we observe an additional peak at larger particle sizes (Figure 8a). When Size Sure measurement mode is applied, we now observe that this additional peak is only present in the transient state (Figure 8b) i.e. this peak is caused by particles which are not entirely representative of the sample. But what are they? Well, in this case, the previously tested sample was a 300 – 400 µm glass bead sample. Some residual material must have been left over in analyses and leads to the appearance of the additional peak (Figure 8c). 

Figure 8a: PSD for an ibuprofen sample from a standard laser diffraction measurement. The PSD shows a main mode from 1 to 100 µm, as well as an additional peak at > 100µm

Figure 8b: A steady state PSD (solid line) and transient state PSD (dotted line) from a Size Sure measurement. The additional peak at > 100µm is only present in the transient state. 

Figure 8c: Overlay of PSD for 300 – 400 µm glass beads and transient state PSD for ibuprofen sample, which has been zoomed in on the peak at >100 µm. The 300 – 400 µm glass bead PSD coincides with this additional peak at > 100 µm. 

Conclusion

Across several key stages of pharmaceutical development and production, particle sizing plays a key role, and the Mastersizer range has for many years been the instrument of choice for industry professionals.

The Mastersizer 3000+ is the best tool to support you with addressing the key challenges associated with API particle sizing and the regulatory and quality frameworks that relate to it.