Increased customer demand and authority expectations leads to new analytical technologies
The growth in complex biologics is on the rise, increasing the need for innovative delivery mechanisms such as prefilled drug-delivery systems. Due to a variety of reasons, sub-visible particles can form in injectable drugs, especially biologics during the manufacturing process or transportation. These contaminants can lower the effectiveness of the drug. As such, regulatory authorities are demanding processes be developed, validated, and set up in such a way as to minimize all forms of contamination, particularly sub-visible particles. In order to be successful, companies must have significant knowledge of the processes as well as scientific expertise in characterizing and identifying these sub-visible particles and allowing for reliable manufacturing procedures that are ready for approval and the subsequent filing.
The formation of sub-visible particles
There are different types of particles and a variety of reasons why they are generated. Sub-visible particles are those in the nanometer to micrometer range (1- 100 µm). Regardless of their size, particle origination falls into different categories.
Extrinsic particles are those which are foreign, additive particles, not part of the drug product formulation or primary packaging material and are unexpected. For example, cellulose fibers from cleaning processes and packaging system materials such as rubber. They can also result due to friction with metal or Teflon. Because these particles arise externally, hence the term ‘extrinsic’, they may not be sterile and could be considered contaminants for the filled unit.
Intrinsic particles are those which are generated directly from the formulation of the drug product or its manufacturing. For example, protein aggregates may be the result of inherent properties of the drug product, interactions of the drug product formulation components, their contact with primary packing materials or processing aids. Intrinsic particles may also emanate from the drug substance itself. On the other hand, inherent particles are generated from the formulation, for example, when a drug substance or an excipient forms a haze or aggregates which can be the result of greater shearing forces, among other causes. Inherent particles cannot actually affect the sterility, however, they could lower the effectiveness of the drug product.
Reinforced particle-related regulations
With the increase in biologics over the past years regulatory authorities like the Food and Drug Administration (FDA) have tightened their requirements for the identification and characterization of visible particles. On the other hand, they enhanced their expectations on the characterization of the process and formulation-related sub-visible particle formation during the development phase.
The sections of the corresponding pharmacopeias covering these particles are regularly reviewed and expanded where needed. Additionally, corresponding regulations for sub-visible particles have also been introduced by the European Medicines Agency (EMA). The guidelines require that companies not only discover sub-visible particles but also focus on their characterization and root cause analysis of particle type and source in commercial batches. The ultimate goal for manufacturers is to adjust their manufacturing processes so that units contaminated with sub-visible particles are understood and avoided as much as possible.
Advancing the science of sub-visible particle analysis
Different analytical technologies have greatly progressed the science of sub-visible particle analysis and support extensive characterization and identification. By drawing on state-of-the-art technologies and the latest methods of analysis and experienced specialists, pharma and biotech companies are now able to carry out fast and efficient root cause analysis. Until now, the standard procedure for quantification of sub-visible particles in the micrometer range has been light obscuration. Because this method has limitations, today’s innovative analytical labs use a variety of novel techniques for particle detection, sizing, characterization and identification. These new methods include Micro-Flow Imaging (MFI) which combines the possibilities of digital microscopy with modern microfluidics generating high-resolution images of sub-visible particles. The precise nanoparticle determination methods used today are Dynamic Light Scattering to determine particle size, particle mobility and Zetapotential. A Morphologi 3G-ID which is a digital microscope with Raman spectroscopy for chemical identification and classification of sub-visible and visible particles, and, ETAC ProView which provides a digital visual inspection at a laboratory scale. These techniques are combined and used in addition to the standard procedures to gain a deeper knowledge of sub-visible particle formation during the development phase.
With the number and types of biological drugs growing at a continuous pace, stricter guidelines from authorities, especially those pertaining to sub-visible particles might increase. Thus, manufacturers will need to adjust their analytical techniques as well as production processes to quickly identify and reduce the causes of their generation. In the long term, manufacturers of parenteral drugs will benefit from detailed data about the processes involved in their commercial manufacturing. They will also be able to comply with the stricter regulatory guidelines and customer demands while maintaining high-quality standards.
About the Author
Dr. Melanie Zerulla-Wernitz is the Head of the Analytical Science Laboratory and therefore responsible for a diverse team of excellent scientists combining various natural and applied sciences. She holds a PhD in natural science from the University of Konstanz, Germany. After many years in preclinical development Dr. Zerulla-Wernitz joined Vetter Pharma in 2004. Her career started in the quality control department but lead her after a little while into the upcoming Development Service. With a one year excursion to Vetter’s Development Service in Chicago, she is continuously leading the Analytical Science Laboratory and constantly working on the enlargement of its service and analytical portfolio.