Quantifying Sub-visible Particles in Parenteral Drugs

Parenteral drugs are generally administered to patients by means of injections and must be essentially free of visible particles. In order to ensure this, the USP <788> Particulate Matter in Injections test is utilized to measure the size and count of sub-visible particles in parenteral drugs (Figure 1). This test calls for counting particles on a filter by microscopy as well as a light obscuration particle counter.

Parenteral drugs

Figure 1. Parenteral drugs

Requirements for Complying with USP<788> Testing

The system requirements for a light obscuration instrument utilized to comply with USP<788> include a light obscuration sensor with appropriate sample feeding device, a sensor and a sampler.

The sensor must be calibrated for size at a number of points, tested for resolution, and validated for count efficiency. The concentration range should be greater than the concentration of the particles to be counted. The dynamic range must contain the smallest size particle to be quantified.

The accuracy of the sample volume must be within 5% of the appropriate sample volume for the test. For reporting, particle concentration must be greater than 10 and 25µm.

AccuSizer 780 SIS Syringe Injection Sampler

AccuSizer 780 SIS Syringe Injection Sampler

Figure 2. AccuSizer 780 SIS Syringe Injection Sampler

The AccuSizer 780 SIS Syringe Injection Sampler (Figure 2) from Particle Sizing Systems is particularly designed for customers who perform USP<788> particle testing. This instrument meets and exceeds all requirements in USP <788>.

LE400 is a high resolution particle sizing sensor utilized for USP <788> testing. Featuring a patented optical design, the sensor can measure from 0.5 to 400µm at concentrations up to 9000 particles/mL. Each sensor is calibrated with 10 particle size standards across the whole range and is verified for count efficiency at 15µm.

The sensor is integrated into the AccuSizer high resolution counter which includes more than 512 size channels, unlike traditional contamination monitoring systems which have only 6 or 8 size classification channels.

The resolution is usually 5%, which is better than the 10% required in USP<788> particle testing. Figures 3 and 4 show the results using few and many size channels, respectively.

Results using few size channels

Figure 3. Results using few size channels

Result using many size channels

Figure 4. Result using many size channels

The new FX series sensors increase the concentration limit up to 400 times than that of traditional light obscuration sensors and extend the lower size limit to 0.15 microns.

Fully Automated Single-particle Sizer

The AccuSizer 780 SIS sampler is the first fully automated single-particle sizer and is designed to provide highly precise volumetric sample aliquots for applications ranging from protein aggregation studies to USP <788> testing at reduced sample volume (< 1mL). The sampler serves both as a high resolution particle sizing instrument and a particle counter, and provides high resolution particle size distributions sans any assumptions with regard to the shape of the distribution.

The instrument reports raw data which includes particle counts versus size. By means of simple statistics, the software changes these data points into a range of other useful weighted distributions such as area, volume, volume/surface, number, etc. and provides precise statistical data that can be traced to the raw data.

The combination of high resolution particle size and contamination monitoring in a single instrument enables users to find the cause of the contamination by rendering a high resolution size picture of contaminants. In case the contaminants are in a single size range, it can be assumed that they were caused by some kind of failure in the process and not from a natural phenomenon which usually produces particles having a wider size distribution.

Quantifying Sub-visible Particles

In many applications, the presence of even a few large agglomerates can make a major impact on the success and failure of a product. In certain pharmaceutical products, the presence of a few large particles can significantly modify the content uniformity of a dose. In emulsions, the appearance of a larger peak may indicate that the sample is becoming unstable.

The AccuSizer 780 SIS sampler can count and size low levels of aggregate particles that are several standard deviations away from the main peak of the distribution. Customers have utilized this information to make new and more stable formulations.

Since the AccuSizer can detect the smallest variations in size distribution, it has assisted customers in developing better products and has prevented potentially harmful releases.

AccuSizer with CFR 21 Part 11 Compliant Software

Available with CFR 21 Part 11 compliant software, the AccuSizer 780 SIS sampler is extremely flexible and is designed to work with USP <788> particle testing. The instrument includes an endless number of user-defined recipes for experimental parameters with simple tables. These tables define the types of samples and the size pass fail criteria. Users can either employ the standard USP <788> or use their own internal tests for investigating their samples. This flexibility is very useful when working on internal standards that meet or surpass the USP criteria.

The AccuSizer 780 SIS sampler comes with two customer interface modes: the standard contamination monitoring mode and the high resolution particle sizing mode with up to 32 user-defined channels and up to 512 logarithmically spaced channels, respectively. In the high resolution mode, all the sample analyses are saved and channels are integrated into the user-defined channels. With just a single click of a mouse, customers can shift between the two modes and can also change the user-defined channels and calculate the results again without having to rerun the samples.

In addition, the built in Pass/Fail criteria tables in the software enable users to define up to 32 Pass/Fail parameters depending on size and particle counts greater than that of size. The table given below is based on the USP <788> criteria of 10 and 25 microns for small volume injectables.

Table 1. USP<788> pass/fail criteria

  > 10 microns > 25 microns
Small volume Injections 6000 600 per container
Large Volume Injections 25 3 per ml

Conclusion

The AccuSizer 780 SIS Syringe Injection Sampler from Particle Sizing Systems is specifically suited to applications in the pharmaceutical industry such as USP <788> small and large volume injectables. It is designed to meet and exceed all requirements of USP <788> particle testing.

This information has been sourced, reviewed and adapted from materials provided by Particle Sizing Systems, An Entegris Company

For more information on this source, please visit Particle Sizing Systems, An Entegris Company

 

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