Introduction to cGMP
Sampling: The Basics
This article is an
attempt to provide
both a general
overview of
sampling as it
applies to
pharmaceutical
manufacturing,
AND a series
of specific
applications
of sampling
approaches for
various products
and activities
encountered in
industry.
“S
ampling” is a key current
Good Manufacturing
Practice (cGMP) activity
that impacts nearly every activity of
manufacturing pharmaceutical products. Sampling is used during the
assessment of:
• Raw materials, labeling, and
components prior to release
• Validation of equipment, processes, systems, and products
• Products during production
• Finished products prior to release
• Products during stability studies,
and
• Data before, during, and after production
The appropriate knowledge and
application of cGMP requirements for
sampling is critical to the development
of a scientifically sound quality system.
This article is an attempt to provide both a general overview of samby pling as it applies to pharmaceutical
Eldon Henson manufacturing, and a series of specifDirector, Quality Assurance ic applications of sampling approachKV Pharmaceutical es for various products and activities
encountered in industry.
2
A Pocket Guide to cGMP Sampling
Eldon Henson
In this article, a general discussion of cGMP requirements for
sampling will be followed by targeted discussions for incoming
materials and dosage forms. Where applicable, specific examples
and experiences of the author are provided to address typical situations that can arise.
The purpose of this article is not to provide a statistical tutorial
on the mathematical principles of sampling plans, or to recommend definitive sampling plans to use in every circumstance. Instead, the general principles and approaches that should be considered for cGMP applications of sampling are presented and
discussed. It is the author’s hope that this report will stimulate alternative approaches, introduce new considerations, and answer
basic questions that create hurdles and issues in pharmaceutical
manufacturing.
Though the final section of this article provides a listing of several important and useful resources on sampling that may answer
specific questions and concerns, the ultimate reference on
acceptance sampling is Juran’s Quality Control Handbook. This
exhaustive resource should be viewed as a “must-have” for every
Quality Assurance (QA) professional. Juran’s Quality Control
Handbook 1 includes sections on sampling risks, implementation of
acceptance sampling programs, attributes versus variables, reliability sampling, bulk sampling, and the definitive statistical basis
for all aspects of sampling programs. No sampling plan should be
developed without some regard for the approaches and considerations discussed by Juran, et at.1
cGMP Requirements for Sampling
Before we look at the specific cGMP requirements for sampling,
let’s look at what a sample is and means from a general perspective. According to the American Heritage Dictionary, a sample (or
sampling) as it might relate to cGMPs is defined as:
“… a portion, piece, or segment that is representative of a
whole; a specimen; a set of elements drawn from and analyzed to estimate the characteristics of a population…”
A Pocket Guide to cGMP Sampling
3
Eldon Henson
In short, a sample is a portion that accurately represents the
population from which the characteristics of the population can be
determined.
The cGMPs mention samples, sampling plans, or sampling
methods repeatedly. When reviewed overall, there are four themes
that occur throughout these references:
❶ Sampling plans and methods must be written and defined
❷ Samples must be representative of the population
❸ Samples or sampling plans must be based on appropriate
statistical criteria, and
❹ Samples must be properly identified and handled
Let’s examine each of these overall requirements in more detail.
❶ Sampling Plans and Methods Must be Written and Defined
As with all cGMP requirements, sampling plans and methods must be predetermined and written. The most common approaches to written methods for sampling are:
• Develop a single Standard Operating Procedure (SOP)
that details the plan to use with predetermined inspection
levels, sampling sizes, and acceptance limits – then, any
individual requirement for sampling will simply refer to the
sample plan SOP.
• Develop a specific SOP detailing the sampling plan for
use with each individual type of material – for example,
an SOP will be written individually for incoming packaging components, raw materials, labeling, etc.
Each approach has advantages, but the key consideration is that
you must pre-determine the specific sampling plan to be used for
any type of material to be tested.
❷ Samples Must be Representative of the Population
Typically, we assume that any sample we obtain will accurately
represent the entire population. However, this is not always the
case. Some materials are not homogeneous due to:
4
A Pocket Guide to cGMP Sampling
Eldon Henson
• Segregation that occurs during blending, transport, or
handling
• Variability occurring during the manufacturing process,
especially if the process is prolonged (such as during
campaigns to manufacture packaging components)
• Part-to-part variability, due to differences in manufacturing
components (such as bottles formed on equipment with
multiple heads)
• Changes in operators during manufacturing
• A variety of other factors that impact production consistency
Let’s face it… though process validation is a key element in the
pharmaceutical manufacturing process, it is not always considered by vendors producing raw materials, packaging components,
excipients, or labeling. Thus, the importance of an appropriate
sampling plan is heightened for materials supplied by others.
❸ Samples or Sampling Plans Must be Based on Appropriate
Statistical Criteria
The use of an appropriate statistically-based sampling plan is
important to ensure our sample is truly representative of the population. In other words, a solid sampling plan based on statistical criteria can provide additional confidence that the sample, or specimen,
on which we base accept/reject decisions, will provide the “true”
answer regarding the quality of the material.
The term “statistics” often creates the impression that the sampling plan must be complex, and use extensive statistical tables,
formula, and calculations. Though in some cases, it is appropriate
to utilize and perform more complex data manipulations (for example, with Design Of Experiments [DOE] studies), sampling plans
for routine uses can and should be simple and easy to use.
Likewise, some feel that the use of a “universally accepted sampling plan,” such as Square Root of N plus one, fulfills the burden
of a statistically-based sampling plan. There is actually no statistical
basis for this particular sampling plan. Additionally, the use of MILSTD 105E or American Society for Quality/American National
A Pocket Guide to cGMP Sampling
5
Eldon Henson
Standards Institute (ASQ/ANSI) Z1.4 sampling plans does not
ensure that the plan is statistically-based. Some sampling plans
derived from these widely used programs would actually allow
acceptance of some lots with critical defects. Each sampling plan
must be developed to consider the specific attributes being measured, and the risks associated with accepting a defective lot.
❹ Samples Must be Properly Identified and Handled
Finally, cGMPs mention, in several locations, the need to properly identify and handle samples. Despite the relative simplicity of
this requirement, most firms routinely fail product or material lots,
or undergo Out-of-Specification (OOS) investigations due to either
improper sample identification or poor handling of samples prior
to testing. Any testing program and sampling plan must include
appropriate requirements for labeling and handling.
Now that we have discussed general cGMP requirements for
samples or sampling, we will look in more detail at some
approaches for sampling plans for specific materials and product
dosage forms. In the following pages, approaches for sampling
plans will be discussed for:
• Incoming Packaging Components
• Incoming Raw Materials
• Labeling Materials
• Non-sterile Liquid Products
• Sterile Products
• Creams, Suspensions, and Emulsions
• Powder Blends
• Tablets, Capsules, and Other Solid Dosage Forms
First, let’s look at a few basic concepts related to sampling and
sampling plans.
Basics of Sampling and Sampling Plans
Several concepts of sampling and sampling plans should be
discussed briefly before we launch into a discussion on specific
6
A Pocket Guide to cGMP Sampling
Eldon Henson
pharmaceutical product types:
■ What is a Sampling Plan?
A sampling plan is a written approach to collecting and testing
samples to ascertain material conformance to quality requirements. Included in the plan will be:
• Sample size – The number of samples taken (or quantity)
must be specified in the written plan. This will eliminate sampler discretion, and better ensure an appropriate and adequate sample.
• Method of sampling – The exact manner in which samples
are to be taken, and the sample location must be included.
• Tests or assessments – The testing, inspection, or assessment required will be specified in the plan. Because the sampling (and testing) plan is pre-determined and written, the
tests conducted will be directed toward determination of conformance to requirements.
• Criteria for acceptance/rejection – Specific criteria for determining whether the material is acceptable or fails requirements must be specified. Again, unless this is pre-determined, the tendency to compromise for borderline situations
will arise.
■ Must Sampling be Random or Specified?
In general, samples taken for pharmaceutical purposes are chosen randomly. Random sampling means that the samples are chosen
without regard for appearance, ease of sampling, location, etc.
Random samples must be truly random with the method for selection specified. However, there are situations (such as for determination of blend uniformity – see section below) in which the exact
location of sampling is specified. In each case, the plan for selecting
samples must be specified in the sampling plan.
■ What is Sampling Bias?
When an error occurs in the sampling process or post-sampling handling that yields testing or inspection results that do not
represent the population, an effect called sampling bias has
A Pocket Guide to cGMP Sampling
7
Eldon Henson
occurred. This bias can lead to acceptance of non-conforming lots
or rejection of conforming lots. Thus, caution must be exercised
when designing a sampling plan to ensure that bias is not introduced. The use of sampling devices, such as a sample thief, often
introduces biases that cannot be predicted or easily eliminated.
Thus, care must be used to either eliminate the bias or identify its
impact.
■ What is Meant by Batch Homogeneity and Batch Uniformity?
Batch homogeneity means that each increment or portion of a
batch is visually or analytically the same as all others. Batch uniformity means that the trend of results, not necessarily all individual results, is similar through all portions of the batch. Though
these terms are not the same, they are similar and used nearly
interchangeably.
Concepts of Sampling Risk
Any discussion of sampling and sampling plans must also consider the elements of risk associated with any inspection involving
less than 100% of the population. Two types of risks are inherent
in any acceptance sampling plan. These risks are illustrated in
Figure 1.
A Type I risk is called a “Producer’s Risk,” because the impact
would be primarily financial to the manufacturer – that is, a lot that
8
A Pocket Guide to cGMP Sampling
Eldon Henson
actually would have met acceptance criteria if 100% of the units
would have been evaluated. In actual practice, this “risk” is minimized because most pharmaceutical manufacturers utilize a retesting process to fully investigate results that are initially OOS.
However, this process of investigating OOS results is time consuming and adds expense.
A Type II risk is called a “Consumer’s Risk” because the impact
would be that the ultimate consumer would actually receive a
defective or nonconforming product. This risk is certainly of
greater concern, both because of the potential for harm, but also
because an acceptable test result is rarely questioned – in other
words, there is no “back-up” opportunity for recognition of a consumer’s risk that exists for a producer’s risk (i.e., retesting).
Neither type of risk can be totally eliminated. Thus, the sampling plan for pharmaceutical products must include a risk assessment of the potential for making an incorrect disposition decision
and the likely outcome if incorrect decisions are made. For evaluating product attributes (items classified as either good versus
defective, such as tablet appearance), this risk is usually determined by a management decision or corporate philosophy, and is
expressed as Acceptable Quality Level (AQL). AQL is the maximum average percent defective that is acceptable for the product
being evaluated.
So, let’s see how this risk assessment might be expressed as
an AQL by looking at two examples dealing with labels:
❶ Correct label print text – because the “risk” associated with
accepting as-good labels that are defective is significant
(both to the consumer, and because this would be a direct
cGMP violation), the AQL for this type of defect would be
very low. The lowest AQL typically defined in sampling plans
is 0.01, meaning that a larger sample would be required to
detect even a low level of defects. No defects would be tolerated in the sample population. Thus, the consumer’s risk is
significantly minimized.
❷ Correct label print color – because the “risk” associated with
accepting as-good labels with off-color is insignificant (no
consumer or cGMP concerns), the AQL for this defect would
A Pocket Guide to cGMP Sampling
9
Eldon Henson
be higher. In this case, the firm may choose an AQL of 6.5,
which would require a smaller sample needed to assess the
population, and more tolerance for random defects.
For product variable characteristics (parameters that are measured, such as analytical test results on products), this risk assessment is usually alleviated by the overall process design, process
validation, and analytical method validation combined to provide
an acceptable level of confidence in product released. For example, if a process is incapable of consistently yielding product with
drug active results 90-110% (the product specification range), the
consumer’s risk increases. Or, if the analytical method has a
method variability of + or -3%, can you have confidence releasing
a batch with a final drug active result of 91%? Thus, this risk is at
least partially alleviated, in this case, by establishing a release
specification outside the “danger zone.” In other words, in the case
of a release range of 90-110% and an analytical variability of + or
-3%, the actual release specification may be established as 94106%. Thus, even if the method is biased by 3%, with a result of
94%, the actual result (91%) would still be acceptable.
So, the selection of any sampling plan for a pharmaceutical
product must be a considered decision. The plan must consider the
products, processes, test/inspection methods, as well as, the
potential producer’s and consumer’s risks the firm is willing to
accept. It is generally inappropriate to merely select a “typical” sampling plan without a proper consideration of these factors.
Incoming Packaging Components
A sampling plan for incoming packaging components must
consider many factors:
• The criticality of the component as it relates to ultimate product quality (i.e., primary packaging components versus secondary packaging)
• Typical lot sizes
• Confidence in the vendor manufacturing process
• Ease of detecting defects
10
A Pocket Guide to cGMP Sampling
Eldon Henson
• Reactivity of the component with product
• Potential for “fatal” defects
• Potential for foreign material contamination, and
• Other specific factors relating to material use
In other words, any plan for sampling and testing packaging
components must utilize knowledge of the material usage, along
with the potential risks posed by defects in the components.
Most sampling plans for packaging components classify
defects into three categories:
❶ Critical Defects – these are defects that would almost certainly
impart risks to product utility or compliance to specifications.
Examples of critical defects include:
• Foreign bottles mixed with the lot
• Incorrect materials of construction
• Defects with glass containers that would likely result in glass
contamination of the product
• Holes or other defects that would result in leaking containers
or jeopardize product sterility
❷ Major Defects – these are defects that, in sufficient quantity or
under certain conditions, could render product unacceptable or
unusable (i.e., issues during use). Examples of major defects
include:
• Bottles out-of-round or with uneven molding or form
• Chips, bubbles, cracks, or other defects that may result in production or product quality issues
• Failed dimensions (i.e., height, diameter, etc. – dimensions
that would not necessarily result in critical product defects,
such as failed sterility)
• Incorrect color that is not cosmetic-only
• Foreign material contamination
❸ Minor Defects – these are defects that may result in minor production problems, cosmetic issues, or other non-product critical
A Pocket Guide to cGMP Sampling
11
Eldon Henson
concerns. Examples of minor defects include:
• Color variation
• Dirt on exterior containers
• Minor extraneous plastic in molded bottles or caps
• Other defects that are cosmetic-only
The sampling plan should identify the number of samples required
for each defect type (it is possible that the number of samples examined will be different for each defect type), testing or inspection performed, and number of defects above which the lot would be rejected
or require further inspection.
So, the question that must be answered in developing a sampling
plan is how to ensure that the sample is representative of the entire
lot, and that the plan is statistically-based. The best approach for
ensuring representative sampling is to remove samples uniformly
from across the batch. For example, if the plan requires a sample size
of 80 units, these units should be taken from all points in the lot.
NOTE: When removing samples from a batch, it is important to
identify the location of samples taken. One approach often used is to
place a sticker with a statement, such as, “This Case Sampled
By/Date __________” on each case or unit from which a sample was
removed.
How can you best satisfy the cGMP requirement that a sampling
plan is statistically-based? Answering this question can be especially
difficult if a variety of packaging components with various uses in
dosage forms are received within the firm. For example, is it possible
to establish a statistically-based plan – a simple one – for a firm that
produces liquids, powders, capsules, and creams encompassing >100
product formulations and another >250 packaging configurations?
One approach to developing such a sampling plan would be to
utilize ASQ/ANSI Z1.4 criteria, and select a “typical” plan that
covers most of your product needs. However, this becomes difficult if you can receive lots of 50 to 500,000 units. An interesting
statistically-based plan that may prove useful would be one
based on the Army and Air Force Exchange Service Plan
12
A Pocket Guide to cGMP Sampling
Eldon Henson
A Pocket Guide to cGMP Sampling
13
Eldon Henson
(AAFES Plan) that incorporates continuing inspection criteria,
depending upon what results are obtained. This double sampling
plan (located at www.aafes.com/qa/docs/supqap-sampling_plans_
home_page.htm) utilizes levels of acceptable quality (or AQL – the
process average percent defective) that could be equated to critical, major, and minor defects. This plan is summarized in Figure 2
and Figure 3.
14
A Pocket Guide to cGMP Sampling
Eldon Henson
The example plan outlined above (AAFES Plan) has the
advantage that it is simple, is statistically-based, and provides
an opportunity to conduct additional inspection for initial failures. However, from a practical standpoint, the continuing
inspections scenario requires that an additional sample be
taken from the lot, unless the maximum possible sample is
taken initially. Either way, the need for continuing inspection is
a productivity concern.
Many other potential sampling plans that would meet cGMP
requirements could be selected. The key to developing any
sampling plan is to be able to answer the question that the
Food and Drug Administration (FDA) investigator might ask:
“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.
Incoming Raw Materials
Despite the fact that there is no statistical basis for a “square
root of n plus one” sampling plan, most firms utilize this approach
for incoming raw materials. This plan can be argued as representative of the batch when the sampling requirement ensures that all
portions of the batch will be included in the sampling. An additional requirement used by most is that for any lot with fewer than five
containers, all units will be sampled. With this approach, illustrated
A Pocket Guide to cGMP Sampling
15
Eldon Henson
in Figure 4, the plan makes “apparent” statistical sense.
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:
16
A Pocket Guide to cGMP Sampling
Eldon Henson
• Does the “mixing” of individual samples into a composite really
produce a homogeneous, thus, representative, sample?
• Does the mixing process actually degrade or harm the sample?
For example, if the sample is tested for particle size distribution,
the rigors of mixing can destroy the “real” condition of the material.
• Can a non-homogeneous lot actually “pass” incoming testing
using a composite, though it may have locations of high or low
results?
Despite these concerns, the use of a composite sample to represent the entire lot is routinely used. And, unless the questions (i.e.,
concerns) noted in the questions above are properly considered,
FDA will likely raise questions about the plan.
Several precautions must be taken to protect samples of raw
materials:
• Temperature sensitivity must be considered – some samples
must be stored in cool conditions
• Other factors that could impact material quality must be considered, such as moisture and light
• As discussed earlier, proper sample identification is always
required
In summary, the simple “square root of n plus one” sampling plan
is usually acceptable for raw materials. Though not statistically significant from a mathematical viewpoint, this plan does provide for a
representative sample, and is easy to implement and use. Many of
the problems and rejections associated with incoming materials are
often traced to poor sampling technique or sample handling. Provisions for proper technique is a must for sampling SOPs.
Labeling Materials
Sampling plans and inspection approaches for labeling materials must typically consider several factors:
A Pocket Guide to cGMP Sampling
17
Eldon Henson
• Label printing process
• Confidence in the label manufacturer
• Label control and verification procedures in place in your firm,
and
• Level of technology available for label inspection and control
Note: For the sake of this discussion, labeling materials are
considered unit labels, packaging instructional inserts, unit cartons with labeling information, and other printed materials that
contain product usage, dosage, or warning information.
Let’s look at each of these in more detail.
Label Printing Process
The printing process and procedures in place at the label manufacturer are significant in developing a sampling and inspection
process. The key aspects of the printing process that must be
considered include:
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
18
A Pocket Guide to cGMP Sampling
Eldon Henson
every separate printing event is represented in the inspection.
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 manufacturer’s 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.
Confidence in the Label Manufacturer
Of equal importance to understanding the label printing
process is a basic confidence or trust in the label manufacturer.
As trust and experience increase, the incoming sampling and
inspection plan can be reduced. Key questions that must be answered for label manufacturers include:
Do adequate controls exist to ensure segregation of each
labeling type and lot?
Because most label manufacturers produce many different labels
for many different products, it is essential that procedures exist to
A Pocket Guide to cGMP Sampling
19
Eldon Henson
detail label segregation. On-site audits are necessary to ascertain
this. The audit should assess how labels are controlled after printing, during storage, and at shipment. Ideally, labeling should have
a strict chain of custody throughout the manufacturing and handling process.
Are the individuals involved in the manufacturing and control of
the label manufacturing process experienced in pharmaceutical
operations, controls, and procedures? Do employees receive
training in cGMP?
At this point in time, most label manufacturers for pharmaceutical companies are well-versed in cGMP requirements, and have
incorporated these concepts into their own operation. An on-site
audit should assess cGMP essentials, such as the presence of
adequate procedures, training, documented production records,
material segregation and controlled access, routine in-process
inspection, and strict control of “masters.” Failure to have good controls in any of these areas would be an item of concern for a potential pharmaceutical customer.
Is the firm innovative and progressive in developing controls to
ensure printed label quality?
Today, the use of automated manufacturing and inspection
equipment has become commonplace, and even essential to
remain competitive with respect to label quality and productivity. A
proactive approach to improvement and enhanced controls points
directly toward a high and consistent level of quality. The higher the
demonstrated quality, the less incoming inspection is potentially
required.
Does the label manufacturer have a solid history in providing
high quality materials?
Despite all controls, procedures, and high-quality attitude, the
most important factor relating to reducing incoming inspection of
labeling is results. Has the manufacturer demonstrated consistent20
A Pocket Guide to cGMP Sampling
Eldon Henson
ly that they have systems and procedures in place to control both
label manufacturing and segregation? Any effort to reduce or minimize incoming inspection should consider the historical results of
the supplier.
Label Control and Verification Procedures in Place in Your
Firm
In addition to knowledge and confidence in the label manufacturer, the controls and verification systems in place at your firm
also play a role in the sampling plan for incoming labeling. Key
questions that must be answered include:
Do you have 100% label verification systems in place? Have
these systems been validated and proven reliable? Has redundancy been designed into these systems?
In today’s pharmaceutical manufacturing world, all manufacturers
should have systems to 100% verify label correctness. However, do
you have confidence that these systems always function properly?
The more rigorous the validation, the more confidence you might have
in these systems. Thus, the level of incoming inspection may be
reduced. Likewise, redundancy in inspection or verification systems
can provide justification for less rigorous incoming inspection.
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.
Can you devise a scenario in which the incorrect label delivered
by the label manufacturer could be used and undetected?
Again, how easily could an incorrect label be received,
A Pocket Guide to cGMP Sampling
21
Eldon Henson
approved, and used? Would this scenario require multiple systems
failures, or be essentially impossible? If so, less inspection rigor is
warranted.
Level of Technology Available for Label Inspection and Control
Finally, the type and level of inspection technology available to
your label inspection group may have an impact on the sampling
and inspection plan you develop. For example:
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
merit.
Are all labels electronically inspected and verified “off-line”
prior to release and use?
One approach used by many pharmaceutical firms is to conduct 100% inspection prior to release. This approach, though
seemingly overkill to some, does provide assurance that the correct label was received and released, and provides added redundancy with on-line verification systems.
Do you have other systems in place for 100% inspection of
labeling prior to use to circumvent the need for sampling and
inspection?
Again, the greater the level of inspection and verification in
place, the less incoming inspection is needed.
In summary, the level of incoming inspection and the sampling
plan used is directly dependent upon many factors. The level of
inspection must be determined based on the overall risks associated with or posed by the labeling. One word of caution… misla22
A Pocket Guide to cGMP Sampling
Eldon Henson
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.
Non-Sterile Liquid Products
Sampling of liquid products – those that are true solutions, not
suspensions, emulsions, or creams – are among those with
fewest special concerns. If the product is a true solution (all materials in solution – no possibility of separation under normal conditions – each sample is, by definition, the same as every other
sample), no special concerns for sampling usually exist. Certainly,
proper handling of samples after collection is important. As with all
products and all sampling approaches, exercise proper sampling
plan design and execution to ensure that results obtained represent the product evaluated.
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
A Pocket Guide to cGMP Sampling
23
Eldon Henson
These systems are sampled via environmental monitoring
plans and procedures. Sampling plans are designed and executed
to comprehensively test each aspect of these systems. For example, air is tested for both non-viable and viable (microorganisms)
contamination in the manufacturing environment. Samples are
taken from the hands and clothing of personnel to ensure that
systems and personnel practices are properly followed.
It is not the intent of this article to discuss these sampling programs in detail. In short, however, the typical cGMP requirements
discussed in the introductory section of this report (statistically
valid, written, representative, sample identification, etc.) are also
required for each of these sampling efforts.
Creams, Suspensions, and Emulsions
Creams, suspensions, emulsions, and other products that are
prone to separation or settling pose special concerns for sampling
and testing. During each process step in which separation or settling could occur, comprehensive sampling and testing must be
performed to ensure that the process is performing as designed.
Validation studies will usually provide the documentation needed to
prove the process, and establish the critical process parameters
that must be achieved in order to produce conforming product.
Routine sampling and testing during commercial production should
merely verify that expected processing parameters are being
achieved.
Each process must be evaluated to determine the proper validation and ongoing verification sampling and testing approach.
You must determine this for each individual product. A detailed
discussion on aspects of this determination will not be reviewed in
this article because each product is unique. However, the following represents some of the author’s experience relating to sampling and testing these products:
■ Sampling Techniques
Care must be taken when specifying the sampling technique for
products prone to separation. For example, for most of these
products, prior to packaging, the bulk material must remain under
24
A Pocket Guide to cGMP Sampling
Eldon Henson
mixing or agitation conditions. To remove a sample, the mixing or
agitation should cease when sampling open containers (to ensure
safety of the sampler). Samples must be removed quickly when
safe to ensure the sample is representative, and that settling has
not occurred. In addition, samples from open containers should not
necessarily be removed only from the upper few inches of the product batch. Validation studies should identify from what portion of the
batch the sample should be taken.
Even when sampling closed systems (i.e., samples taken from a
sampling port or other device, and not taken directly from an open
container) requires precautions. In most of these cases, it is important to purge the sampling port before removing the sample for
analysis. Discharging a small portion of material prior to removing
the sample can avoid samples that are not representative.
■ Handling of Samples
It is imperative that in-process samples for these products be
properly handled. Handling must ensure that degradation of the
sample integrity does not occur. If the intent of the sample is to test
the exact attributes of the product at that point, it may be necessary
to avoid further mixing of the sample. For these products, a sample
that completely fills the sample container to a point that no headspace exists will usually protect sample integrity. Without headspace, inadvertent mixing is unlikely.
However, samples taken to analyze the integrity of the sample
mixture may require further mixing prior to analysis. In these cases,
collecting the sample in a container that has adequate headspace
to allow further agitation prior to analysis may be required.
The key point here is that you must consider the purpose of the
samples taken. What attributes are you attempting to analyze? It is
important that you “pre-determine” this purpose, and design a sampling approach and sample handling “protocol” to ensure that the
sample taken will yield the information required.
■ Validation of Mix Failures
Despite rigorous equipment design, tightly controlled processes, and superbly trained personnel, failures in mixing processes
will occasionally occur (i.e., power failures, etc.). Unless validation
A Pocket Guide to cGMP Sampling
25
Eldon Henson
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,
26
A Pocket Guide to cGMP Sampling
Eldon Henson
reproducible way, homogeneity of the powder blend prior to further
processing? Let’s explore some key considerations.
Following publication of FDA’s Guidance for Industry, ANDAs:
Blend Uniformity Analysis (August 3, 1999), significant industry
concerns were raised regarding FDA’s requirements for demonstrating blend uniformity when United States Pharmacopeia (USP)
content uniformity testing is required on the product. Some of
these concerns included:
• Current limitations in sampling technology – specifically, the
use of sample thief technology has been proven prone to error
and inconsistency
• Powder segregation of samples after sampling
• Weighing errors can occur during preparation of blend samples for analysis
• Difficulty in proving that the blender sample plan will be truly
representative – demonstrating that all worst-case locations
are included in the sample, and
• Blender sampling fails to consider segregation that can occur
during discharge, storage, and transport prior to final processing
Despite these concerns, the current cGMP requirement in 21
CFR 211.110(a)(3) states:
“…control procedures shall include… adequacy of mixing to
assure uniformity and homogeneity.”
This requirement, thus, applies to development, process validation, and post-validation commercial batches for solid oral drug
products.
Most firms continue sampling plans that involve the removal of
a minimum of ten samples from all primary areas of the blender
using a sample thief. Many variations in sample thief technology
exist and are in use, including: multiple chamber units, variations
in probe design, and alternatives designed to minimize product
disturbance during sampling. Some firms demonstrate blend uniA Pocket Guide to cGMP Sampling
27
Eldon Henson
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).
Tablets, Capsules, and Other
Solid Dosage Forms
Solid dosage forms typically pose many opportunities for applying appropriate and scientifically sound sampling approaches.
28
A Pocket Guide to cGMP Sampling
Eldon Henson
Figure 5 illustrates the following example process.
This example process depicts a coated tablet produced from a
A Pocket Guide to cGMP Sampling
29
Eldon Henson
wet granulation process. In this process, the following steps and
sampling approaches are typical, as shown in Figure 6.
30
A Pocket Guide to cGMP Sampling
Eldon Henson
Detailed approaches for sampling of materials up through step
five are discussed earlier in this article. Following are additional
considerations for the finishing steps involved in tablet production:
■ Compression into Tablets
There are several key sampling/testing considerations regarding the tablet compression process:
• Start-up: It is critical that initial tablets produced be carefully
sampled and tested to ensure that equipment set-up is correct, granulation was produced as expected, and the combination of equipment and product are functioning well together. During the initial period of production, additional
samples should be taken and tested for conformance to
physical requirements (analytical conformance should have
been assessed and proven during validation). During startup of routine, commercial production, samples should be
reviewed from each set of compression tooling. In other
words, you should remove at least two consecutive cycles of
tablets, and carefully inspect (and document) physical appearance, dimensions, and functionality. Inspection should
include:
i. Appearance – complete tablets, no capping, no chips, and
complete and correct embossing (if performed)
ii. Dimensions – tablet thickness, weight, and other critical
parameters should be measured
iii. Functionality – tablet hardness, friability, etc. should be
checked
The combination of this initial early inspection is essential to
a successful compression run.
• During the run: Samples should be taken at regular intervals
during the batch to ensure that tablets continue to conform
to requirements
• After adjustments: Samples should be taken after any
A Pocket Guide to cGMP Sampling
31
Eldon Henson
adjustment of the press that could alter physical dimensions
or characteristics of the tablets
• At the end of the run: Often, the end of the batch is the time
when nonconforming tablets frequently are produced – thus,
it may be prudent to remove and analyze additional samples
near the end of the run
• Validation: Extensive sampling and testing must occur during
validation studies that include analytical testing, in addition to
physical inspection. Because many granulation formulas are
sensitive to de-blending or segregation, analytical verification
of blend homogeneity must be verified at all stages of the
batch, with special attention given to start-up, after adjustments, when the compression hopper is depleted or nearing
depletion, and at the end of the batch.
■ Tablet Coating
The tablet coating process must be carefully sampled and evaluated to ensure proper application of coating. It is imperative that
the process be monitored throughout, with additional sampling
and evaluation after adjustments or during times deemed critical,
such as at the beginning of the process and near the end.
■ Tablet Packaging
Sampling and analysis of solid dosage forms should occur at
various points during the packaging process. Two key aspects of
packaging quality are usually considered:
❶ Tablet Integrity
❷ Fill Accuracy
Product should be sampled and inspected at the filler and after
each critical process (blistering, for example) to ensure that tablet
damage is not occurring.
In addition, fill accuracy is important from both a consumer
complaint perspective and economic standpoint. Sampling and
verification of fill count are important both during packaging validation and during routine commercial production.
32
A Pocket Guide to cGMP Sampling
Eldon Henson
In summary, sampling of all aspects of the tablet production
process is important to ensure at all stages that tablet integrity conforms to requirements. Each process must be carefully evaluated,
usually via review of a process flow chart prior to validation, to
ascertain critical process steps, or points at which defects could
occur. After identifying these points, a sampling plan must be
developed to prove both during validation and routine production
that tablets meet all requirements.
Guide to References on Sampling Plans
A recent search on the Yahoo internet web site for “sampling
plans” revealed 617,000 sites that include some reference to sampling or sampling plans. In addition, hundreds of reference books
have been written that are either dedicated to sampling or sampling
plans. So, the availability of information on this subject is abundant.
What are the best locations to find needed information that will
assist those in the pharmaceutical industry? Though the author
does not claim to have knowledge of all or even most of the best
information sources, the following are good resources for additional
help or information on this subject:
Web Sites
Several Internet web sites provide helpful information that can aid
the pharmaceutical practitioner develop an appropriate sampling plan:
❶ 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.
❷ www.samplingplans.com
This site is administered by H&H Servicco and provides an
excellent tutorial on basic statistics of sampling plans (Operating
A Pocket Guide to cGMP Sampling
33
Eldon Henson
Characteristics [OC] Curves, control charts, etc.), and can provide
valuable information on getting started on sampling plans. This site
provides excellent examples of sampling plans, challenge questions,
and an extensive glossary of terms and definitions.
❸ www.cqeweb.com
This site provides a wealth of information on many subjects that
comprise the body of knowledge for the American Society for Quality
(ASQ) Certified Quality Engineer Certification process. One chapter
deals specifically with the topic, “Sampling.” This chapter provides
another excellent review of the basic and more detailed statistics that
serve as the basis for many sampling plans. It includes a very good
glossary of terms with excellent graphics and examples.
❹ www.iso.ch
This is the web site for the International Organization for
Standardization (ISO). This is an extensive web site detailing standardized approaches for many quality topics, including sampling and
sample plans. Any effort to develop sampling plans for products for
global marketing should consider the procedures already developed
and in use by the ISO.
❺ www.pqri.org
This is the Product Quality Research Institute (PQRI) site that
includes the complete Blend Uniformity Working Group report, “The
use of stratified sampling of blend and dosage units to demonstrate
adequacy of mix for powder blends.” In addition to this report, the letter provided to FDA introducing this report and blend uniformity data
used to support the recommendations are available.
❻ Many other pharmaceutical organizations have valuable information on web sites that provide further details and discussions on
sampling:
• www.ivthome.com
The Institute of Validation Technology (IVT) includes many
articles, papers, and additional resources to aid in the development of sampling plans or approaches to cGMP compliance.
• www.pda.org
The Parenteral Drug Association (PDA) is another excellent
resource for additional information.
34
A Pocket Guide to cGMP Sampling
Eldon Henson
• 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 Juran’s 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. ❏
About the Author
Eldon Henson is a frequent contributor to Institute of Validation
Technology publications. He has authored IVT’s Auditing
Handbook, Quality Improvement Handbook, Topic of the Day GMP
Training Program, and, most recently, the GMP Toolbox. Henson is a
member of the Editorial Advisory Board of the Journal of Validation
Technology, and has written many GMP training modules for
Eduneering, a web-based training content provider. He holds B.A.
A Pocket Guide to cGMP Sampling
35
Eldon Henson
and M.A. degrees in microbiology from Southern Illinois
University-Carbondale, and has worked in various quality and
manufacturing roles at Abbott Laboratories, Novartis, BoehringerIngelheim, Sigma-Aldrich, and is currently Director, Quality
Assurance at KV Pharmaceutical in St. Louis, MO. Henson can be
reached at ehenson@kvph.com.
Reference
1. A. Blanton Godfrey and Joseph M. Juran (coeditors in-chief). Juran’s
Quality Control Handbook. 5th Edition. McGraw-Hill. (1999).
36
A Pocket Guide to cGMP Sampling
Eldon Henson
A Pocket Guide to cGMP Sampling
37