Objective

Particulates in parenteral drug development and production have always been a serious issue. In biopharmaceuticals, including protein therapeutics, the issue is compounded by reported impacts of aggregates and particles on the product’s efficacy, safety and immunogenicity. FDA regulations strongly recommend in-depth characterization of the identity and quantity of particles in protein therapeutics. Particle concerns are increasingly common in FDA submissions, and in some cases, particle matters have resulted in drug recalls.

Quantifying particles larger than 10µm and 25µm has been a USP <788> requirement for drug product release since 1975. In protein therapeutics, the addition of “inherent” particles in the form of protein aggregates, alongside the “intrinsic” particles (such as silicone droplets) and “extrinsic” (foreign) particles usually found in parenterals makes particulate characterization more difficult than with small molecule formulations. For this reason, the USP <1787> informational Chapter states that: “Because multiple potential sources of particles exist, it is important to identify the particles and determine whether they are extrinsic, intrinsic, or inherent.”

While conventional microscopy can be used, the time required for sample preparation and the lack of statistical significance caused by small sample sizes are limiting factors. As a result, other automated particle sizing methods such as light obscuration, electrozone sensing and laser diffraction have also been used. The problem with these techniques is that they assume all particles are spherical in shape, recording only an Equivalent Spherical Diameter (ESD) for each particle. As a result, they can not infer information on a particle’s identity. In addition, light obscuration, one of the most common techniques used to meet USP requirements, has challenges detecting and properly sizing particles with a low refractive index (such as protein aggregates). As a result of this insensitivity, a batch might pass USP <788> even though it may contain unacceptable levels of protein aggregates which the light obscuration system could not detect.

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