Visible Particulate Matter in parenteral drugs causes great damage on quality and the reputations of pharmaceutical companies. Sub-visible particulate matter is as an adjuvant in the immunogenicity response to protein-based therapeutics. Therefore, the control of the number, size, and especially the chemistry of particles over the entire size range - from several hundreds of µm down to sub-micrometer– improves the control strategy for these unwanted particles.
Visible particulate matter control starts with the visual inspection process and is successfully covered by a sequenced approach. Investigation stages begin with the visual characterization in the closed container by trained investigators. In the second step, the visible inspection reject can be documented by a video microscope image.
Then the Raman particle identification instrument Single Particle Explorer, SPE raman.ID LIBS.ID can be used to generate spectroscopic identification of the particles.Particulate Matter can be identified by means of Raman and/or LIBS in the closed container, this is limited to larger visible particulate matter. With the wet cell setup the sample is measured between a glass window and a stainless steel bottom. Image directed spectroscopy can be applied with Raman to particulate matter down to a size of approximately 1 µm directly in a protein based formulation. By means of vacuum filtration on the filtr.AID particles can be isolated from the formulation, counted and sized and also identified by means of Raman and LIBS particle identification.
So the variation of the sampling technique ensures a spectroscopic identification through the entire investigation process.
To preserve the integrity of a sample in situ, Raman and LIBS can be performed. The application of both independent methods to particles in the closed container e.g. between the ribs of a pre-filled syringe piston is a great advantage since cross contamination is impossible. This gives great information on product and container closure integrity and also preserves the contamination from destruction by removal of the piston. In addition, gaining spectroscopic intelligence on these particles is possible. The only obstacles are the potential interference of the signal with the formulation and the packaging superimposing the spectra of the particle. Also the process of finding the particle is time consuming and requires some extra training.
To solve the problems, we have a novel design of a wet cell optimized for Raman spectroscopy in protein based formulations. Sampling with the wet cell preserves not only the shapes of semi-solid and even liquid particles, it also bridges from Flow Imaging (shadow counting) to scientific proof. Examples of the measurement of inherent particles,
mainly protein aggregates in a highly concentrated antibody formulation demonstrate the low spectroscopic background of this wet-dispersion.AID design. With the integrated spectroscopy, we can identify silicone droplets (intrinsic particles) that give great Raman signals down to 1 µm diameter and fatty acids resulting from the hydrolysis of polysorbate.
Any user will also be able to analyze larger visible particles > 80 µm easily with this setup.
Filtration is great for solid foreign particulate matter, which is mainly considered to be intrinsic (glass, rubber) or truly extrinsic particulate matter such as cellulose. Sampling volume is virtually infinite; one customer was able to filter 8 liters of water for injection (WFI) on one filter. With the filtr.AID particle isolation kit, all micro particles are – after vacuum filtration - neatly dispersed on a 4 mm spot. All particles on the spot are enumerated and sized, and typically the largest 200 particles are identified by means of Raman, and LIBS when applicable.
LIBS is especially powerful for discriminating different glass types or revealing inorganic filling materials in rubber mixtures. Particles once isolated on the filter can also be cross-examined by SEM/EDS and/or FTIR.The goal is to collect as much physical evidence (color, shape, surface structure) as well as chemical evidence, from vibrational (structure) and emission (elements) spectroscopies, as possible on the previously unknown contaminants. Physical evidence and spectroscopic identification are necessary steps for elimination of particulate contamination for improved quality.
All the above mentioned steps are routine in our laboratory investigations and are also implemented by many of our customers. This different stages of investigation can be combined into standard protocol. The continuous application of this approach leads an excellent root cause analysis and prepares companies for the next FDA
inspection. The strategy is common sense and leads to a superior control over particulate matter contamination. We provide workshops in our laboratories near Princeton, NJ and in Berlin, Germany as well as on-site training for the users of our instruments, thus leading to higher quality and better yield.