Optics: measuring and testing – By inspection with agitation or rotation – Of container contents
Reexamination Certificate
2000-11-05
2002-12-24
Epps, Georgia (Department: 2873)
Optics: measuring and testing
By inspection with agitation or rotation
Of container contents
C250S22300B
Reexamination Certificate
active
06498645
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to procedures and devices utilized in the visual or optical inspection of transparent containers for the presence of contaminating particulate matter and particularly to inspection of injectable pharmaceutical preparations.
BACKGROUND OF THE INVENTION
There is an ethical and legal obligation to ensure that pharmaceutical injectable solutions are free of ‘visible’ particle contaminants following manufacture and prior to their clinical use. This legal obligation can be satisfied by the use of a labor intensive and costly 100% manual inspection of injectable solutions. Less costly automated particle detection systems have been developed. However, in order to satisfy Good Manufacturing Practice, automated inspection systems must be validated prior to any pharmaceutical use. In the validation demonstration, the functioning of the automated system must be shown to be at least as effective in detecting and rejecting containers with ‘visible’ contaminating particles as the preceding manual inspection.
The performance of human ‘visible’ particle inspection has been characterized in published reports as a probabilistic process without a sharp particle size accept/reject decision threshold (i.e., a soft decisional process). In the production of an injectable product under good control, the distribution of contaminating particles is approximately hyperbolic, with the concentration of contaminating particles decreasing rapidly as particle size increases. The effect of the ‘soft’ accept/reject decision threshold is that a proportion of particle-contaminated containers that should be rejected are accepted. A false reject rate of good containers also results from the ‘soft’ accept/reject decision process. Due to the increased number of containers with particles well below both clinical and control interest, a disproportionate number of the containers that should be accepted are rejected. This disproportionate false reject rate imposes additional costs on the quality assurance program.
Validation of alternative equipment or methods is a Good Manufacturing Practice requirement. The validation of a contaminating particle inspection system is a demonstration that the automated inspection system rejects those containers identified in a manual inspection to be contaminated with “visible” particles. It must show that the rejection capability of the automated system is at least equal to or better than that achieved by the preceding human inspection method. This demonstration must be successfully completed prior to any production use of any proposed automated system.
This demonstration is based on an established statistically evaluated human ‘visibility’ performance benchmark. To make possible statistical comparisons and evaluations of particle contamination, an inspection model was defined with a statistically described rejection zone boundary. As currently accepted in the pharmaceutical field the Reject Zone includes the group of particle contaminated containers rejected in 70% of a series of manual container inspections. The group of containers with a manual rejection probability equal to or greater than 70% constitute the “must reject” visible particle contaminated group.
Holographic measurements found that the size of the contaminating particles that resulted in the 70% reject rate was 100 &mgr;m. This determination was made with the particle contaminated containers that were rejected in a 17 second, timed single container inspection performed under 225 foot-candles of illumination, the inspection time is equally divided against a black and white background. The holographic data was correlated with the statistically evaluated probability of detection data to define the minimum ‘visible’ particle size of 100 &mgr;m. Accordingly in present practice all containers with 100 &mgr;m or larger contaminating particles are considered to be ‘must rejects’.
This Reject Zone definition has become a de-facto world standard in validation demonstrations and any proposed automated inspection device must function with at least the capability of the preceding manual inspection. This equivalent functionality is demonstrated by the achievement of an equal or higher rejection rate for the containers identified in the manual inspection to have ‘must reject’ contaminating particles that are 100 &mgr;m or greater.
When current commercially available automated inspection systems were evaluated according to this standard, it was determined that none could demonstrate, in a single inspection, results as secure or as selective as that achieved by human beings. The proportion of “must-reject” containers rejected in a single automated inspection is between half and two thirds that of a skilled human inspector.
As a result, in order to validate these automated inspection systems (to match their inspection security to that of the preceding manual inspection), a two inspection sequence is currently employed. only containers accepted in both inspections are accepted for stock. Containers rejected in either of the two sequential inspections are eliminated.
It has been determined that the limiting particle rejection/detection probability for an inspection system is the proportion of the liquid contents that have been examined for particulate contamination. A complicating factor is that the position of a contaminating particle in a container at the start of each inspection is completely random. This random initial particle position results in random distribution of particle orbits and velocities within the container. The random particle velocity distribution ranges from zero-to some design maximum.
A defined velocity of particle movement is employed to distinguish between contaminating particles and stationary container markings and optical defects. Particles that do not traverse the fractional inspected volume or that move with insufficient velocity are not detected. To improve the inspection security results, the two-inspection ‘game of chance’ technique to reduce the effect of the random particle position and velocity is employed. Application of classical probability theory shows that particle detection security is enhanced but the discrimination of the accept/reject decision compared to manual inspection is impaired when this inspection technique is employed. The cost for this improvement in detection probability is a four to six fold increase in the false rejection rate of the manual inspection.
Ideally, secure detection, sizing and identification of the contaminating particulates is an essential part of the control of the production of pharmaceutical injectable products. However, secure detection of randomly occurring and randomly positioned particles in sealed transparent containers requires inspection of the full volume of the container. In addition, accurate particle sizing in the present automated inspection systems requires sharp particle images. However, with present art, the sharp image requirement cannot be achieved for the size range of containers used for pharmaceutical injectable products.
In addition, only a portion of the contents of the container volume is normally inspected for contaminating particles and accordingly the security with which ‘must reject’ containers are rejected in the partial container volume inspection cannot exceed the proportion of the container volume containing contaminating particles inspected.
U.S. Pat. No. 3,627,423, issued Dec. 14, 1971, to one of the present inventors, discloses an improvement in particle contrast, and thus detectability, that results from the use of narrow aperture lighting of the liquid volume contents of the container. This patent teaches that narrow aperture lighting of the liquid volume contents of the container that transits the glass envelope or the container in a near perpendicular condition minimizes the reduction in particle contrast that occurs when a broad area light source is employed for the inspection. The use of narrow aperture lighting of the liquid volume contents of the container to produce forward scatt
Budd Gerald W
Knapp Julius Z.
Epps Georgia
Hanig Richard
Nissenbaum Israel
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