The most commonly used instrument for the detection of unwanted particles in drug manufacturing is the human eye, and manufacturers have established quality protocols and procedures governing how product is to be inspected, how long a particular inspector can be perform his/her task, and how often the inspection process is challenged. Whether relying on the naked eye or magnification under carefully controlled illumination, human inspectors are effective when the product type and packaging change often, the production throughput is low (with adequate inspection time) and the product requires manipulation to inspect.
However, market demands are continuing to push for higher throughput at increasing levels of product quality, meaning less time for operators to inspect and higher false reject or accept rates unless more staff are brought on board. The result is that industry is exploring automated alternatives to visible particulate detection.
Unfortunately, an off-the-shelf “all kinds of particulate in any kind of package” solution does not exist. Automated techniques vary depending on particulate, product and container properties. Some combinations of particle, product and container lend themselves to inexpensive technology. Other combinations require a more exotic approach, where the cost of the solution needs to be weighed more carefully against the cost of the problem.
This article will focus on automated techniques for detecting visible particles and help readers better understand the degree of complexity associated with various forms of particulate inspection.
At its most basic, particulate contamination are solid objects in your container that you do not wish to be there. These can be foreign particles that have entered from the outside environment or they could be solids that have formed out of solution.
Particulate can be stable in solution, such as container fragments or they can react with the container contents, such as iron filings in a peroxide solution. Obviously, particulate that reacts in solution is a very serious issue. However, seemingly harmless particulate could cause unexpected end user quality issues as well.
For instance, a container or delivery mechanism may have a barrier filter to prevent particulate matter from escaping the container. However, particulate could block the filter and impede flow over time. In the case where no barrier filter is present, such as with injectable products, small particulate could enter the patient with potentially fatal results.
In the regulatory world, there is a distinction between visible and non-visible particulate matter. Visible particulate is loosely defined as any particulate that can be detected with the unaided eye. Typically, visible objects are defined as objects that are 0.1 mm or larger, which are about the average diameter of a human hair although some have pegged the limits of human detection as low as 50 um.
There is precious little in terms of regulatory guidance when it comes to visible particulate matter. The most referenced guidance comes from the USP, most notably in General Chapter—Injections <1> and in <788> (although <788> generally deals with sub-visible particles).
USP <1> states that each preparation is “essentially free” from visible particles and that every container that shows evidence of visible particles shall be rejected. USP <788> also reiterates the “essentially free” requirement. As designers of processes, we are left to interpret the meaning of “essentially free” along with a vague definition of how big a visible particle actually is.
In the case of sub-visible detection, there are more specific guidance’s available for process design. Specifically, ICH Guidance for Industry Q4B—Annex 3 Test for Particulate Contamination: Subvisible Particles General Chapter (January 2009), which references USP <788> among others. Particulate sizes, counts per volume as well as automated and manual techniques are outlined. Generally, tests for sub-visible particles are destructive and require samples to be taken from a lot for qualification. Sub-visible particles fall beyond human acuity and require microscopy or similar techniques for detection.
How Difficult to Detect?
Visible particulate inspection is generally done while the product is in its container, be it in solution, lyophilized cake, powder or ointment. In an ideal world the container would be clear, uniform and free from defects, but this is generally not the case. Containers can be coloured, frosted and opaque.
Also, visual inspection of solid product is limited to the surfaces of the product that are exposed. The product would also have to be inspected from a variety of angles to ensure each surface was examined. The interior of a solid product cannot be inspected unless the inspection system uses a probe that can penetrate the solid.
The ease with which a particle can be detected depends on the following factors:
- The size of the particle: Of course, the bigger the particle, the easier it will be to detect. Particles on the order of 100 um in diameter are challenging, while particles 1 mm or larger are much simpler.
- The contrast of the particle: A black particle on a white background is easier to detect than a clear particle in a clear solution.
- The density of the particle: A particle that is much denser than its surroundings or its container will easier to detect using more exotic inspection methods.
- The transparency of the container: It stands to reason that dark, cloudy or opaque containers will offer less visibility to the particulates inside. Amber vials are a more difficult container for particulate inspection than clear containers.
- The uniformity of the container: non uniform surfaces on the container such as variations in wall thickness can cause havoc on illumination methods due to refraction of light at the surface. These surfaces include the curved areas of a glass vial or the side walls of a moulded plastic bottle.
To put the relative difficulty of detection into perspective, a 1-mm diameter black particle sitting on top of white powder in a clear vial is generally easily to detect with readily available equipment. A 1-mm partially transparent particle floating in an IV bag can be detected with repeatability, but the inspection would require specialized equipment and software algorithms.