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Why improving the cleanliness analysis workflow is key for the pharma industry

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Kay Scheffler, product manager - applied microscopy at Leica Microsystems, explains how microscopy is key in identifying particle contamination and ensuring quality control in the pharma industry.

Alexander Raths Alexander Raths - stock.adobe.com

Key insights:

Many medicines are delivered as injections or parenteral infusions. They include vaccines, such as those against COVID-19, and treatments for diseases, such as cancer and muscular dystrophy. The manufacture of these and all medicines needs to be performed in controlled environments and sterile conditions to protect human health.

Cleanliness is vital as the presence of contaminants may affect the safety and efficacy of the product. Contamination can pose a risk to patients, especially as most injectable products are not thermally sterilised, which can present a risk that must be mitigated for patient safety. Injecting or infusing a drug product contaminated by particulate matter into the body, especially the bloodstream, may cause sepsis, inflammatory response, organ dysfunction, phlebitis, and pulmonary arteritis.

There are different types of contamination, one of the key types is particulate matter, which consists of extraneous, mobile undissolved particles. Particulate contamination in pharmaceutical products can come from many different sources, such as the environment, packaging materials, cleanroom personnel, and formulation ingredients.

Standards for cleanliness

There are regulations and standards that must be met to demonstrate the technical cleanliness of the pharmaceutical production process and manufacturing facility. International and regional standards and guidelines stipulate technical cleanliness recommendations. These standards and guidelines are updated regularly, and the recommendations normally become stricter over time.

It is important for pharmaceutical manufacturers to keep up with these standards. Injectable drug products must undergo several discrete processes allowing them to meet or exceed standards developed that are enforced by the Food and Drug Administration (FDA), such as the United States Pharmacopeia (USP).

Particulate matter in injections

The US standard for particulate contaminants in pharmaceutical products for injection and parenteral infusions is the USP 788. It provides criteria for how many particles are permitted depending on the size of the particles and the volume of the drug product preparation.

For large-volume preparations where the injection or parenteral infusion solution is supplied in containers with a nominal content of more 100 ml, the maximum average number of 10-μm or larger sized particles permitted is 25 per ml and 3 particles per ml of particles sized 25 μm or larger.

For small-volume preparations of 100 ml or less, the maximum averages permitted are 6000 particles sized 10 μm or larger per container and 600 particles sized 25 μm or larger per container (see Table 1). These USP limits on particulate matter have been harmonised with the European Pharmacopoeia and Japanese Pharmacopoeia.

Measuring contamination

Two procedures are specified in USP 788 for determining the particulate matter. The more common method is Light Obscuration Particle Counting. It works by shining a light through the fluid sample in such a way that the particles obscure the path of light. A light detector then picks up not only the lights that passes through the sample but also dark spots where it is obscured. These dark spots can then be measured and counted automatically, thus providing a determination of the particulate matter in the sample.

However, Light Obscuration Particle Counting cannot always be used. This can be the case if the preparation is an emulsion, colloid, or liposomal preparation, which has reduced clarity or increased viscosity. Similarly, for products that produce air or gas bubbles the particles cannot be accurately counted using light obscuration.

When the light obscuration method is not applicable, then the second procedure, Microscope Particle Counting, is recommended. This second procedure relies on filtering the fluid sample to capture the particles and an optical microscope to inspect, measure, and count them. Compared to light obscuration, this method allows the actual size and shape of the particle to be determined.

This procedure must be performed under conditions that limit extraneous particulate matter, for instance, in a laminar-flow cabinet. It may be necessary to test some preparations using first Light Obscuration Particle Counting and then Microscope Particle Counting to reach a conclusion that complies with the USP 788 requirements.

If particulate matter exceeds the USP 788 limits, then the source of the contamination needs to be identified, so that it can be addressed. With conventional optical microscopy, it can sometimes be difficult to determine the source of the contamination, however, it is still possible, unlike with the Light Obscuration method.

Advanced microscopy for chemical composition analysis

Elemental or chemical analysis of the particles can provide information regarding the contamination source. Advances in microscopy technologies and the overall workflow for cleanliness from particle extraction to analysis have made the particulate testing process less laborious and more efficient. For instance, the “Professional” cleanliness analysis system option from Leica Microsystems offers optimised software and a unique 2-in-1 solution for visual and quantitative chemical analysis (see Figure 1). This means that users cannot only detect, measure and count particles, but also analyse the particle’s chemical composition. This can provide clues regarding the source of the particulate contamination.

This is achieved by incorporating two systems into a single instrument, as the DM6 M LIBS microscope integrates Laser Induced Breakdown Spectroscopy (LIBS) to deliver an exact chemical fingerprint of the material’s structure that is seen within the microscopic image – within seconds. By integrating visual and quantitative chemical inspection into a single work step, users can avoid having to use multiple instruments and methods for microscope particle counting and root cause analysis for non-regulated environments, such as R&D and engineering labs in the pharmaceutical industry. Thus, users save 90% of the time they would have otherwise spent using scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS) respectively.

To improve the cleanliness analysis workflow in a significant way a more innovative method, such as the 2-Methods-in-1 Solution using high-resolution optical microscopy and Laser Induced Breakdown Spectroscopy (LIBS), is needed compared to the more conventional techniques already in use. By offering non-regulated pharmaceutical manufacturers the option of simultaneous visual and chemical analysis of particulate contamination, they can identify and eliminate contamination sources more efficiently compared to either Light Obscuration or Microscope Particle Counting.

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