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What justification can you provide to ensure that this sampling plan will disqualify any lot that could result in defective
finished product?
One additional key to sampling plans for incoming packaging
components is to consider the potential for remediating or correcting lot concerns identified during inspection. In other words,
oftentimes, a lot that fails incoming inspection is desperately
needed for production. Can you design a procedure that allows
for inspection/rework of the nonconforming lot, then release the
lot? The answer is, Yes, under certain circumstances. If the
defect that resulted in failure of the lot can be inspected, and easily detected and removed, it may be possible to result in a
release disposition after inspection. This process must be specified in SOPs, and documentation must exist to demonstrate that
the lot was acceptable after rework/inspection.
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Note: Some raw materials, such as bagged ingredients, will contain more than 500 units. When lots of materials are greater than
500 units, an alternate sampling plan should be considered.
In each case above, the sampling plan must specify that all portions of the batch, beginning, middle, and end, must be sampled.
Even in the worst-case scenario above, the batch can be well represented in the final sample.
It must also be pointed out that some materials and product
requirements specify that more rigorous sampling regimens be followed. For example, if a material is microbiologically sensitive and/or
potentially non-homogeneous, it may be prudent to sample every
container regardless of lot size. Knowledge of the material and the
process must be included in the risk assessment associated with
selecting a sampling plan.
For other materials, samples taken are eventually composited
into a single container and mixed. Several issues exist for this
approach:
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Labeling Materials
Sampling plans and inspection approaches for labeling materials must typically consider several factors:
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How are printed labels cut? How many replicates of each label
are printed for each shot?
For label manufacturers that print multiple shots of each label,
the sampling and inspection plan for incoming labels must ensure
that all representatives of the shot be inspected. A shot would
be a multi-lane printing system that prints multiple versions of the
same label (i.e., four different print mats, for example) that are
then cut and combined. In these cases, it is important that the
sampling plan include an inspection of consecutive labels that
represent all members of the shot.
For example, a label printing press prints four labels across on
a sheet of label paper. The four labels are eventually cut into four
separate rolls. In this case, the incoming sampling plan must
include at least minimal samples from each roll. In other cases,
the print shot might include four across and six down for each
printing event. In this case, the sampling plan must include representative samples from each roll, plus at least six consecutive
labels from each roll inspected. This plan will ensure that at least
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How does the printer handle splices in label rolls? What controls exist?
Several recalls occur each year when label manufacturers
improperly splice the end of one label roll to the beginning of the
next. These splices must be properly handled and controlled to
avoid splice errors. Label manufacturers must ensure proper
cGMP practice, such as line clearance and double-checks, to
avoid these concerns. Incoming sampling plans should include an
inspection of these splices, or at least some minimal number of
them. Ideally, label manufacturers will avoid entirely, or at least
minimize, the number of these splices required.
Is it possible for labeling to change after approval? What computer systems are used, and what controls exist to ensure that the
label approved will be the label printed and delivered?
The label manufacturers processes and procedures for controlling changes to master labels is critical. Unless the label manufacturer has superior controls for ensuring that the approved label
is the printed label, the incoming sampling plan and inspection
must include a thorough review of each printed label lot against
the master label.
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Does your firm use many different labels of similar size and
shape, or a relatively small number?
One key question you should ask about your own operations is,
How great is the actual risk for using an incorrect label? If your
number of labeling materials is low, or if each label is clearly of a different size, shape, or color, the risk for failure might be relatively low.
In these cases, less incoming inspection may be warranted. The
reverse would, of course, also be true.
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Do you use an optical comparator or similar intelligent instrumentation to verify all incoming labeling prior to release?
The use of intelligent instrumentation to inspect incoming
labeling may provide significant confidence that incorrect labeling
could not be used. Care must be exercised, however, to not use
technology as an excuse to minimize incoming inspection without
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beling has been one of the top ten causes for pharmaceutical
product recalls in each of the last ten years. Despite the fact that
cGMP requirements for labeling and label control have remained
essentially unchanged since issuance in 1978, firms still struggle
with the basic concepts of development, inspection, use, control,
release, and segregation of labeling.
Sterile Products
Several special sampling concerns exist for sterile products.
These products require additional controls for the production environment, product protection, and product handling to ensure that
sterility is assured. With these products, product and environmental protection has been engineered into the process. For example,
protection from environmental contamination is controlled by the
use of filtration to remove essentially all particulates, control of airflow and direction, sterilization of equipment, containers, potential
product contact surfaces, and rigorous controls to prevent people contamination. Sampling plans for these products typically are
used to assess the proper function of these systems. The following aspects of the process are usually sampled and monitored:
Air
Equipment sterilization
Personnel
Materials
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data are available that define the length of downtime of mixing systems without affecting the mixture (or emulsion, etc.), the batch
may be in jeopardy. Thus, it may be useful during validation to
intentionally cease mixing at key points in the process, sample at
various time points, and test the product to determine the length of
time the mixing
step can be
Despite all controls, procedures, and
down without
high-quality attitude, the most important negatively
factor relating to reducing incoming
impacting the
product.
inspection of labeling is results.
Composite Samples
Can cream, emulsion, and suspension samples be composited
and tested? In most cases, composite samples can be used to
assess the overall quality of the product. Individual samples can be
collected, then combined to produce an overall sample reflecting
the quality of the batch. However, you must use caution with these
products to ensure that the mixing of individual samples does not
introduce additional variability in the process that can mask product issues. You should validate the sample compositing process.
This can occur by analyzing the individual samples, then comparing results (or average results from all individuals) to the composite
sample result. A failure to yield statistically comparable results can
indict the compositing process.
In short, if you produce emulsions, creams, or suspensions, you
already know that these products pose special concerns. The sampling plan designed to either validate the processes for these products, or to assess ongoing production, must consider these special
concerns and greater effort to pre-determine the purpose of
each set of samples is warranted.
Powder Blends
Perhaps the area of sampling that has caused the most controversy is how sampling is applied to powder blends. In other words,
what sampling plan is required to demonstrate, in a consistent,
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formity by sampling at the discharge stage, or from final inprocess blend storage units (i.e., drums, totes, etc.). In all cases,
firms uniformly utilize unit-dose sampling sizes to fulfill Barr
Decision and FDA current expectations.
Because of the numerous issues mentioned above with thief
sampling of oral drug blends, dealing with blend sample failures is
an ongoing concern. In other words, the uncertainty of blend sampling technology and approaches often lead to blend analysis failures. So, we face the age-old question, How do I know these failing results are real? What additional testing is needed to overturn
these failing results? Some firms universally interpret blend sample failures as true failures, and reject any study exhibiting failing
results. Other firms attempt to discredit failing results through an
investigation that can involve OOS investigations, resampling,
retesting, utilization of scientific rationale, or a combination of
these. The risk of this approach to overturning failing blend results
can be a delayed regulatory approval or FDA inspection issues.
As a result of these issues and industry concerns, the Product
Quality Research Institute (PQRI) Blend Uniformity Working Group
developed an approach to demonstrating blend uniformity by combining blend testing and compendial dosage unit testing. This
approach (stratified sampling) postulates that the analysis of
dosage units (i.e., finished tablets) can supplement or provide statistical evidence that a failing blend result was due to poor sampling or handling technique. This approach has not been officially
accepted by FDA, though several members of FDA served on the
PQRI expert committee that developed the recommendation. Despite this lack of official acceptance, several firms have utilized stratified sampling to justify acceptance of failing blend data.
For a full copy of the stratified sampling approach and rationale
supporting it, reference the PQRI web site (listed in the final section of this document).
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Web Sites
Several Internet web sites provide helpful information that can aid
the pharmaceutical practitioner develop an appropriate sampling plan:
www.aafes.com/qa/docs/supqap-statistical_
sampling_plans_home_page.htm
This site is the Army and Air Force Exchange Service (AAFES)
site. In this site, you will find the details presented briefly in the section on Incoming Packaging Components. On this site, you can
locate the AAFES approach using continuing inspection criteria
based on the MIL-STD 105E or ASQ/ANSI Z1.4 sampling plans.
This site is easy to follow, easy to read, and a good site for the statistical novice to locate and learn more about these plans.
www.samplingplans.com
This site is administered by H&H Servicco and provides an
excellent tutorial on basic statistics of sampling plans (Operating
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www.ispe.org
The Society for Life Science Professionals (formerly Institute for
Pharmaceutical Engineers) provides excellent technical and
industry information regarding aspects of cGMP compliance.
www.gmp1st.com
The GMP Institute provides a wealth of helpful cGMP compliance information.
www.asq.org
The American Society for Quality is one of the largest and oldest organizations dedicated to providing information for professionals involved in quality.
This discussion could never identify all of the excellent organizations providing information on cGMP compliance and, specifically,
sampling and sampling plans. If the above web sites cannot provide
the information required, query other web site search engines to find
the specific information desired.
Textbook Reference
Several classic textbooks provide extensive information on the
development and use of sampling plans for quality assurance purposes. However, the ultimate resource is Jurans Quality Control
Handbook (A. Blanton Godfrey and Joseph M. Juran (coeditors-inchief), 5th Edition, McGraw-Hill, 1999). is the universal reference book
for information about quality control sampling plans. All quality practitioners should have, and refer often to, this excellent resource.
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Reference
1. A. Blanton Godfrey and Joseph M. Juran (coeditors in-chief). Jurans
Quality Control Handbook. 5th Edition. McGraw-Hill. (1999).
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