Determining particle composition: Consider the path to the source
07/01/2002
Particle Counting
Ramam spectroscopy can put a name on contamination and optimize the particle-counting process
by Dr. Markus Lankers
Quick identification of contamination sources in cleanroom environments are fundamental for a clean and smooth-running production process. Conclusions regarding contamination sources are perhaps best drawn from precise information collected from the material composition of particles.
Cleanroom users can quantitatively assess particles and classify them by size using classical monitoring systems, although qualitative assessments are not usually conducted on production lines. However, knowing a particle's composition can give insight into possible faults occurring during production. With the help of an exact chemical analysis of the particle, it is possible to identify its source and thereby eliminate the contamination in the future.
There are two ways to ensure that cleanroom-produced products are free of particles: checking the air in the room and sampling the product itself for particles.
The second method is more commonly chosen, especially when parenteral drug products are being produced. In fact, checking products such as ampoules for contamination is required under the U.S. Food and Drug Administration's (FDA) current good manufacturing practices (cGMPs) to protect the consumer.
Using Raman spectroscopy, Advance Particle Systems GmbH (APSys; Berlin, Germany) has developed two methods to identify airborne particles as well as contamination in highly purified fluids. Using these methods, most compounds, that are used during clean production, can be identified.
 The scattered light reflected off the particle is captured by a detector and qualified using Raman spectroscopy. |
The two systems differ in two points: One registers and analyzes particles of 10 microns (µm) and larger, while the other examines particles as small as 0.5µm. For both systems, the particle must be applied to a sample carrier, this is achieved externally through filtration of the liquid particle, while the other simply take particles automatically from the air.
The path from "particle to source" is best described by using an example from real life. In this case, the use of the liquid particle counter is applied in the quality control area of a parenteral drug production. The same technology and the same procedures are applied when using the counter that takes particles straight from the air.
High product quality demand
In the production of parenterals and ophthalmics, the exclusion of visible insoluble contaminants from solutions is paramount-particles 50 µm and larger are visible to the naked eye.
Every bottle, ampoule or vial has to be examined by eye or by machine. Finished products are then sorted out or rejected. Rejection rates are in the range of 0.2 to 3 percent.
Particle contamination can originate during various stages of production and filling processes. Determining the origin of contamination is often time consuming. When increased particle concentrations are detected during parenteral drug quality control, the manufacturer usually attempts to determine the material composition of the particles in order to pinpoint the origin of the contamination.
No standardized technology for such analytical procedures exists to date.
Characterization possibilities
The simplest method is the light microscope, which highlights the shape and color of particles. In a short time, it is possible to find out if a particle is a black fiber or a small, undefined spherical object.
However, the methods are often carried out at a considerable distance from the production site in an external lab with results arriving several days after the production problem occurred. In addition, the current methods require the employment of specialists who can carry out the analysis and interpret the results.
Both technologies that employ Raman spectroscopy are integrated measuring systems consisting of an encapsulated and washable special steel housing. The software is operated through a touch-screen monitor and the sample can be inserted through a flap in the front of the device.
The work needed to conduct a measurement is essentially limited to the deposition of the sample on a membrane through filtration. The membrane can be directly inserted into the device without any further steps. After pressing the start button, each particle is illuminated by a laser beam. The scattered light reflected off the particle is captured by a detector and qualified using Raman spectroscopy.
The computer compares the resulting spectrum with a spectrum saved in the database and the user automatically receives the precise name of the compound. The results are automatically recorded in a hypertext document, which conforms with federal CFR 21 Part 11.
Different particle sources
Once the composition of particles is determined, it is easier to determine their origin.
Possible sources are active ingredients or other additives, water, gases or anything used to produce a product. However, foreign particles can also find their way into the product through the wear-and-tear of the production machinery.
This way, the product is contaminated by foreign particles created during the production or filling processes. For this reason, the environment must be closely monitored for airborne particles. The operators wear special protective clothing to guard against this possibility, but foreign particles can arise from various sources including the cleaning process.
However, most pollutants come by the way of containers and their closure systems.
There is a wide range of possible sources, and therein lies the challenge. However, the pharmaceutical manufacturer usually keeps a complete list of all materials involved in the process, a fact that limits the number of possible sources to a reasonable range. The long-term goal is to develop control parameters of the relevant process by statistical evaluation of the particle composition. This makes variations in the known particle pattern immediately visible and enables the user to react quickly to unknown particles.
Process-optimizing through analysis
At the pharmaceutical manufacturer that first tested the APSys liquid particle identification system, several methods for identifying particle contamination were used. It took several days after collecting the sample to obtain the results of the analysis.
Although these analytical procedures were not carried out on a regular basis, the manufacturer succeeded in optimizing the processes in question and increased yield. The team members in quality control sought to further optimize the processes by regularly carrying out chemical analyses of the particles. The next step was to then search for an analytical method that allowed quality control to carry out analysis easily and simultaneously.
Using the aforementioned list and a determination of the particle, it is possible to assign the origin of this particle to a process step. Consequently, the process can perhaps be optimized so that the particle source is eliminated in the future. Until now, however, these methods were time consuming. Now, the quality control staff is more experienced in identifying and eliminating particle sources.
But in order to improve the knowledge about particle reduction, the employees at the lab needed more data to make a trend analysis; data that could be collected without additional personnel.
This requirement prompted preliminary tests with the liquid particle identifier in the hope that the system would be able to simplify the process. The results of previous single measurements should be made complete using a standardized material composition test. The long-term goal is to develop control parameters of the relevant process by statistical evaluation of the particle composition. This makes variations in this known particle pattern immediately visible and enables the user to react quickly to unknown particles.
The first tests
The liquid particle system was used in production quality control, and a clear goal was set at the beginning of the study. The system should be able to differentiate between drug substance particles and other particles, and should be able to identify the unknown particles.
A one-hour training period qualifies an employee to operate the device and to independently identify the particles. After two hours of operation, it delivers the results.
The drug substance was added by APSys to the database before the measurement was performed, and then the liquid particle identifier branded the drug substance particles and was able to tell the difference between these and foreign particles.
Within minutes the device delivered a spectrum for a foreign particle, revealing a correlation to a spectrum with a high proportion of carbon-hydrogen. The database then delivered the corresponding result: polyethylene. That was the first indication that somewhere in the process polyethylene is used and a bit of it unintentionally comes into the product.
Future development
Standardizing particle identification is the first step towards lasting process optimization.
Using Raman spectroscopy-based technologies, manufacturers may be able to enter all constituents of a product necessary for its production into the database of an automatic analysis device.
Following this process, all materials utilized in production and filling processes can be retrieved from the databank. After the source has been recognized, it can be eliminated or reduced.
The actual particle profile is constantly compared to the historical particle profile as well as to the control parameters in order to introduce relevant measurements. With this new knowledge quality assurance will then be able to trace defects and deviations in the production before the specification limits are exceeded.
Dr. Markus Lankers is currently responsible for research and development at APSys GmbH. From 1996 to 2000, he worked in pharmaceutical development at Schering plc.