Identification of visible product particles, like protein aggregates, can form the foundation of an effective, in-process contamination control program
BY DR. OLIVER K. VALET
Parenterals are subject to high requirements in regards to purity. These solutions are regulated by United States Pharmacopoeia (USP) and have to be free of any visible particles (less than 50 µm). The limit values for non-visible particles are to be followed, while intense efforts in production and quality assurance are required to ensure that they are.
Depending on the process, 0.2 to 3.0 percent of waste due to particles is accrued. If the cost of waste exceeds a significant amount, the source of the impurification certainly needs to be sought. The simple identification of the particles facilitates the detection and elimination of the source; and, in turn, the cost of this waste and the empirical attempts to solve the problem are reduced.
Simple contamination information
A system has been developed for the automatic chemical analysis of particles on the basis of RAMAN spectroscopy.1 The measuring device identifies all particles of organic and inorganic nature larger than 2 µm.
The key design piece that makes this possible is the metalized polymer membrane (below) through which the product is passed. The size of the nuclear pore is based on the solution's viscosity and size of the particles to be examined. The contrast between particles and membrane is optimized for particle recognition through automatic image analysis.
The membrane, once coated with particles, can be analyzed using a Liquid Particle Explorer, which was developed for the identification of particles according to the standards of measuring devices in a cGMP-controlled surrounding.2
Similar to the method of membrane evaluation described in the USP, microscopic images (below) of the entire membrane surface covered with particles are automatically recorded and evaluated.1
The position, length and width of the particles is determined exactly, to the micrometer. The device carries out RAMAN spectroscopic examinations on the particles, and resulting spectra are automatically identified on the basis of the pharmaceutical and customer-specific database.
The database was created with RAMAN spectra of material samples. The system can, therefore, also clearly recognize mixtures of materials, such as rubber stoppers or dyed polymers, due to their characteristic spectra. An automatically created report provides the size, identification and spectrum quality as well as the result for each individual particle.
Particle sources at the production level
The search for the source of the impurification begins when a process exceeds the specification of the acceptance quality level. Currently, most end users responsible for production rely on their experiences. They have known their process for years and can, therefore, eliminate the contaminating source with a few trials and errors. For example, filter candles are replaced or stoppers are checked in regards to their particle load. This method may suffice; however, it often takes days, and some errors can't be contained and may disappear after some time.
Only a full analysis can provide information on the effect of the measures. External laboratories are rarely consulted due to the long time period between test and result, and because of the small statistical relevancy of a particle's single spectroscopic examination.
Identification of foreign particles from parenteral solutions supplies direct information regarding the impurification source.3, 4 Different sources during the production process are all considered—personnel, clothing, containers and caps. The established database contains 500 RAMAN spectra of substances, and end users may add new material samples to the database within minutes.
Examinations completed with the Liquid Particle Explorer enable a statistically relevant and comparable conclusion about the particles' chemical composition in a relatively short time. The main impurification sources can be detected on the basis of the particle spectrum of a product sample.
 Resulting table of parenteral solutions, main source PVDF, and historical particle spectrum. |
Figures 1 and 2 show the results of the measurements of a product of two different batches. The main contamination source of batch A is polyvinylidenfluoride (PVDF). In a secondary database, PVDF was identified as part of the membrane of a candle filter. A significant increase of the yield was achieved through the removal of the candle filter (a typical sample is shown in Figure 2).
Continous identification = clean intellingence
Continuous monitoring of particle composition is preventative quality assurance which, in turn, increases product safety.
To guarantee permanent protection, additional samples and rejects of this product and current batches were continuously examined. In the beginning, less noticeable impurification sources were detected and minimized.
Subsequently, some particles remained in the non-visible area and were assigned to this process. The specification of the product was extended through the historical as well as through the product- and process-specific particle ID distribution.
Deviations from the historical particle profile can, therefore, be quickly detected. Total particle load count can be constant using a particle counter, but the composition of the particles may vary significantly. The identification of a new particle type makes latent impurification sources visible before the damage is done.
The FDA also recommends characterization of foreign particles for the rapidly growing number of inhalers. Analysis of the particle composition can prove that no contaminating particles are present in these products.
Another application field is the analysis of particular drug delivery systems. For quality assurance purposes, analysis of the particles' material composition is exact to less than a micrometer and provides exact information about the particles and the production processes.
