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ParticleScope™ - System Background
Patented Non-Destructive Particle Detection and
Measurement System used for Parential (SVI) Products.
The ParticleScope™
instrument is unique in its approach for the isolation of suspect contamination
particles in the solution. The instrument was developed to aid in studies
of human and machine inspection capabilities.
According to cGMP practice, the validation demonstration
of any alternative method or mechanism used on a USP approved product must show
functionality at least as effective as the preceding method or mechanism. In the
case of visible contaminating particles, a demonstration of at least equivalent
performance to the single container clinical inspection for visible particles is
required. The Knapp-Abramson methodology has achieved de facto status as the
standard methodology for this purpose since its 1980 PDA Journal publication.
The present USP Attribute Sampling Inspection methodology, a descendent of MIL
SPEC 105D, is in current use as an injectable product batch release assay. This
attribute sampling inspection bases results of its analysis on a sample of 2 to
2,000 containers randomly extracted from a production batch. The sample size and
the non-conforming number of containers in the test group for acceptance of the
production batch are dictated by the AQL required and the size of the production
batch. To satisfy the prerequisites for accurate analyses from the Attribute
Sampling Tables, the data on which the analysis is based must be, to quote from
the introduction to ANSI/ASQC Z1.4-1993, "must be simply repeatable". Another
requirement is that the data considered should be normally distributed. It must
be stressed that Sampled Inspection conclusions are incompatible with PAT
continuous batch quality improvement perspectives. This incompatibility traces
to the crudeness of the Attribute Sampling Decision and it's planned to
restriction to data with "simply repeatable errors" describable by a normal
distribution.
This incompatibility traces to four factors: 1) Visible
Particle data is probabilistic and is therefore not "simply repeatable". 2) The
random nature of visible particle data cannot be described with a normal
distribution curve. 3) The crudeness of the Sampling Inspection rejection set
point (it is set at twice the Accept Quality Level, the AQL). 4) The asymptotic
approach to zero acceptance of the Operating Characteristic, the OC that can
result in the acceptance of a multiply flawed batch as typified in the Detroit
"lemon car".
From Knapp's seminal publication in the PDA Journal in 1980, the prime parameter
for the analysis of visible particle contamination in injectable products has
been demonstrated to be the probability of detection for the contaminating
particle. Visible particle detection data has been shown to be both randomly
sourced and randomly located in the containers of a batch. Consequently, the use
of the Attribute Sampling Tables with incompatible probabilistic raw visible
particle inspection data has been shown to result in the rejection of good
batches and the acceptance of batches with sub- standard quality.
An alternative batch evaluation methodology based on the reject rate of a
validated 100% inspection which uses the size of the contaminating particle is
proposed and has been demonstrated. The probabilistic nature of the data results
in improved accuracy of the determination when made with the entire data of a
batch compared to the smaller number of data points available in the sampled
data procedure.
Conversion of the manual raw visible inspection data into equivalent particle
size measurements is accomplished with a calibration curve. The calibration
curve uses a standard test set of containers seeded with a range of single,
durable, micro sized spheres whose dimensions are traceable to NIST Dimensional
Standards to define the relationship of (particle size) to (particle
detectability) in accurately specified test conditions.
The accurately specified test conditions include: the
quantity and quality of the light at the inspection point and the contrast of
the background. The selected test conditions provide for a ˝% overlap between
the visible and sub-visible particle regions. The inspection rate and the
fatigue of the inspector performing the inspection are also critical test
conditions. Particle movement during the inspection period is essential to
distinguish the low ratio of contaminating particles from the bulk of the
extraneous visible information.
From the previously cited Knapp publication in the PDA Journal in 1980, the
prime parameter for visible particle inspection data has been demonstrated to be
the probability of detection for the contaminating particle. The direct use of
raw visible inspection data has been shown to result in the rejection of good
batches and the acceptance of sub-standard quality batches. Conversion of the
raw, probabilistic inspection data into equivalent particle size measurements is
accomplished with a calibration curve. The calibration curve uses a standard
test set of containers with a set of durable range of micro sized spheres, whose
dimensions are traceable to NIST Dimensional Standards, to define the
relationship of (particle size) to (particle detectability) in accurately
specified test conditions. The accurately specified test conditions include:
light quality and intensity at the inspection point, the contrast of the
background, particle movement during inspection to distinguish the low ratio of
particle signals from the bulk of the extraneous visible data, inspection rate
and the fatigue of the inspector performing the inspection.
Each batch is tested to determine the quantity of non-conforming containers in
the test group against the batch acceptance limit determined from production
records.. An alert level is set at 120% of the standard acceptance limit and an
action level is set at 150% of the targeted reject rate.
Note: the alert and action levels are respectively 5 times and twice as
sensitive as the hoped for results from the sampling inspection.
The conversion of raw visible inspection data to particle
size can be accomplished by repeated re-inspection of each container to achieve
0.05 significance level rejection probability as described in Knapp's
publication. The mean rejection probability determination is converted to
particle size with a calibration curve. An alternative, more economically
desirable method is to use a calibrated low power stereo microscope to directly
measure the particle size to determine the accept/reject status of the
container. From present data, the edge of the Reject Zone is set at
contaminating particles sizes equal to or larger than 95µm (average rejection
probability = 0.7071).
The use of a calibration curve based on NIST traceable particle size measurement
converts Knapp's methodology from a local validation method whose results were
difficult to communicate to a securely transportable quality determination
derived from NIST dimensional standards.
Following the quality control mishaps in Japan in 1995 in which insect bodies,
hair and lint were found in accepted containers of injectable products, the USP
then reaffirmed its reliance on the single container inspection for
contaminating particles at the injection site.
Therefore any other manual, semi-automated, or automated particle inspection
procedure must be shown to be at least equivalent to the manual benchmark
performance before it can be used on any USP listed product.
It has been demonstrated that a well defined inspection
environment is required to obtain consistent results from manual human
inspection procedures. The environment must provide uniform illumination within
a large enough volume of inspection chamber to allow for position deviations
while being inspected. The amount of lighting (intensity at the subject) is
critical to achieve repeatable results. It has been found that 550 foot-candles
at the point of inspection will allow the detection of a 95 µm diameter object
to be detected 70.7% of the time by trained inspectors with 20/20 vision at a
distance of approximately 400 mm. Small changes in the lighting conditions can
have a large influence in the apparent size of the contaminating particle.
Optimized Manual Inspection Environments
The art of visual inspection requires a consistent
environment for the acquisition and analysis of all the information in the sharp
image and its blur surround. Phoenix Imaging has developed a well defined
inspection environment to support the requirements of human inspection
procedures. The environment provides very uniform illumination within a 1 cubic
foot volume of inspection chamber. Special inspection chambers such as the
Phoenix Imaging MIB-50 & MIB-100 have been constructed to yield a standardized
inspection environment with a large useful inspection volume. The large
inspection volume of the MIB-100 provides a 550 foot-candle illumination source
anywhere within the volume, minimizing the effects of variations in container
placement from sample to sample. The MIB series of inspection environments
implement a patented dual-source illumination approach to produce consistent
results.
The design of the MIB-50 & MIB-100 products strive to
minimize inspector fatigue. The MIB-100 allows the inspector to adjust arm rest
height, in-feed and acceptable product tray height, tray angle, and tray tilt
without the use of any tools. Each inspector can adjust the unit for maximum
ergonomic use and comfort. The MIB-100 provides a PLC based timer for inspection
pace and inspection count. The MIB-50 is a bench top inspection system designed
to fit in to laboratories where space is a concern. The MIB-50 provides about
7.5 Liters of inspection volume with the illumination within ±10% of center
value.
If any factor is compromised, the reliability of the
instrument will be questionable and possibly jeopardize the ability to validate
the inspection process. None more so than the standard sample set used for the
training and qualification of inspectors.
An essential lack in visible particle measurements has been that of an accurate
transferable standard. This lack is now being supplied by Phoenix Imaging as a
standard stable micro-particle set whose measurements are referred to the
national dimensional standards maintained by the NIST. This standard set when
inspected for 5 seconds per container against the recommended Kodak 18% Gray
background results in a procedure with twice the output of white/black
background inspection at higher accuracy. The higher accuracy is due to the
fifty percent reduction of movements required by the inspector for the container
inspection.
The strobe-free light quality and 550 foot-candle intensity provided by the MIB
is essential for the accuracy of the particle size detectability data required
for an accurate transferable standard.
The Phoenix Imaging RLPS™ Standard Particle Calibration Set provides a unique
set of single seeded NIST traceable particles in stabilized water. The set
includes glass, stainless steel and polystyrene spheres that range in diameter
from 40µm to 1,000µm, fibers of nylon and cellulose that range in length of 0.5
mm to 2 mm, aluminum and glass shards of measured length. The sample set also
includes "Clean" or uncontaminated containers. The entire set is comprised of 50
containers each coded with a unique serial number to identify the contents. The
range of detectability for this set is from poorly detected (<10%) to a size
that is securely detected in every inspection.
The standard particle set is used in conjunction with the MIB Standard Lighting
Environment to train human inspectors the art of manual inspection and to
determine the inspection reliability limit of the individual inspectors. The
beginning of a national standard calibration curve has been published at the
2004 PDA Annual Meeting. All data generated in the same defined environment will
added by Phoenix Imaging to improve the precision of the national standard
curve.
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