a pocket guide to cgmp sampling

A Pocket Guide to cGMP Sampling2

Introduction to cGMPSampling: The Basics

“Sampling” is a key currentGood ManufacturingPractice (cGMP) activity

that impacts nearly every activity ofmanufacturing pharmaceutical prod-ucts. Sampling is used during theassessment of:

• Raw materials, labeling, andcomponents prior to release

• Validation of equipment, pro-cesses, systems, and products

• Products during production• Finished products prior to release• Products during stability studies,

and• Data before, during, and after pro-

duction

The appropriate knowledge andapplication of cGMP requirements forsampling is critical to the developmentof a scientifically sound quality sys-tem.

This article is an attempt to pro-vide both a general overview of sam-pling as it applies to pharmaceuticalmanufacturing, and a series of specif-ic applications of sampling approach-es for various products and activitiesencountered in industry.

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.

byEldon Henson

Director, Quality AssuranceKV Pharmaceutical

Eldon Henson

In this article, a general discussion of cGMP requirements forsampling will be followed by targeted discussions for incomingmaterials and dosage forms. Where applicable, specific examplesand experiences of the author are provided to address typical situ-ations that can arise.

The purpose of this article is not to provide a statistical tutorialon the mathematical principles of sampling plans, or to recom-mend definitive sampling plans to use in every circumstance. In-stead, the general principles and approaches that should be con-sidered for cGMP applications of sampling are presented anddiscussed. It is the author’s hope that this report will stimulate al-ternative approaches, introduce new considerations, and answerbasic questions that create hurdles and issues in pharmaceuticalmanufacturing.

Though the final section of this article provides a listing of sev-eral important and useful resources on sampling that may answerspecific questions and concerns, the ultimate reference onacceptance sampling is Juran’s Quality Control Handbook. Thisexhaustive resource should be viewed as a “must-have” for everyQuality Assurance (QA) professional. Juran’s Quality ControlHandbook1 includes sections on sampling risks, implementation ofacceptance sampling programs, attributes versus variables, relia-bility sampling, bulk sampling, and the definitive statistical basisfor all aspects of sampling programs. No sampling plan should bedeveloped without some regard for the approaches and consider-ations 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 perspec-tive. According to the American Heritage Dictionary, a sample (orsampling) as it might relate to cGMPs is defined as:

“… a portion, piece, or segment that is representative of awhole; a specimen; a set of elements drawn from and ana-lyzed to estimate the characteristics of a population…”

A Pocket Guide to cGMP Sampling 3

In short, a sample is a portion that accurately represents thepopulation from which the characteristics of the population can bedetermined.

The cGMPs mention samples, sampling plans, or samplingmethods repeatedly. When reviewed overall, there are four themesthat occur throughout these references:

❶ Sampling plans and methods must be written and defined❷ Samples must be representative of the population❸ Samples or sampling plans must be based on appropriate

statistical criteria, and❹ 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 DefinedAs with all cGMP requirements, sampling plans and meth-ods must be predetermined and written. The most com-mon approaches to written methods for sampling are:

• Develop a single Standard Operating Procedure (SOP)that details the plan to use with predetermined inspectionlevels, sampling sizes, and acceptance limits – then, anyindividual requirement for sampling will simply refer to thesample plan SOP.

• Develop a specific SOP detailing the sampling plan foruse with each individual type of material – for example,an SOP will be written individually for incoming packag-ing components, raw materials, labeling, etc.

Each approach has advantages, but the key consideration is thatyou must pre-determine the specific sampling plan to be used forany type of material to be tested.

❷ Samples Must be Representative of the PopulationTypically, we assume that any sample we obtain will accurately

represent the entire population. However, this is not always thecase. Some materials are not homogeneous due to:

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• Segregation that occurs during blending, transport, orhandling

• Variability occurring during the manufacturing process,especially if the process is prolonged (such as duringcampaigns to manufacture packaging components)

• Part-to-part variability, due to differences in manufacturingcomponents (such as bottles formed on equipment withmultiple heads)

• Changes in operators during manufacturing• A variety of other factors that impact production consis-

tency

Let’s face it… though process validation is a key element in thepharmaceutical manufacturing process, it is not always consid-ered by vendors producing raw materials, packaging components,excipients, or labeling. Thus, the importance of an appropriatesampling plan is heightened for materials supplied by others.

❸ Samples or Sampling Plans Must be Based on AppropriateStatistical CriteriaThe use of an appropriate statistically-based sampling plan is

important to ensure our sample is truly representative of the popula-tion. In other words, a solid sampling plan based on statistical crite-ria 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 sam-pling plan must be complex, and use extensive statistical tables,formula, and calculations. Though in some cases, it is appropriateto utilize and perform more complex data manipulations (for exam-ple, with Design Of Experiments [DOE] studies), sampling plansfor routine uses can and should be simple and easy to use.

Likewise, some feel that the use of a “universally accepted sam-pling plan,” such as Square Root of N plus one, fulfills the burdenof a statistically-based sampling plan.There is actually no statisticalbasis for this particular sampling plan. Additionally, the use of MIL-STD 105E or American Society for Quality/American National

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Standards Institute (ASQ/ANSI) Z1.4 sampling plans does notensure that the plan is statistically-based. Some sampling plansderived from these widely used programs would actually allowacceptance of some lots with critical defects. Each sampling planmust be developed to consider the specific attributes being meas-ured, and the risks associated with accepting a defective lot.

❹ Samples Must be Properly Identified and HandledFinally, cGMPs mention, in several locations, the need to proper-

ly identify and handle samples. Despite the relative simplicity ofthis requirement, most firms routinely fail product or material lots,or undergo Out-of-Specification (OOS) investigations due to eitherimproper sample identification or poor handling of samples priorto testing. Any testing program and sampling plan must includeappropriate requirements for labeling and handling.

Now that we have discussed general cGMP requirements forsamples or sampling, we will look in more detail at someapproaches for sampling plans for specific materials and productdosage forms. In the following pages, approaches for samplingplans 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 andsampling plans.

Basics of Sampling and Sampling Plans

Several concepts of sampling and sampling plans should bediscussed briefly before we launch into a discussion on specific

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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 require-ments. 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 sam-pler discretion, and better ensure an appropriate and ade-quate sample.

• Method of sampling – The exact manner in which samplesare to be taken, and the sample location must be included.

• Tests or assessments – The testing, inspection, or assess-ment required will be specified in the plan. Because the sam-pling (and testing) plan is pre-determined and written, thetests conducted will be directed toward determination of con-formance to requirements.

• Criteria for acceptance/rejection – Specific criteria for deter-mining whether the material is acceptable or fails require-ments must be specified. Again, unless this is pre-deter-mined, the tendency to compromise for borderline situationswill arise.

■ Must Sampling be Random or Specified?In general, samples taken for pharmaceutical purposes are cho-

sen randomly. Random sampling means that the samples are chosenwithout regard for appearance, ease of sampling, location, etc.Random samples must be truly random with the method for selec-tion specified. However, there are situations (such as for determi-nation of blend uniformity – see section below) in which the exactlocation of sampling is specified. In each case, the plan for selectingsamples must be specified in the sampling plan.

■ What is Sampling Bias?When an error occurs in the sampling process or post-sam-

pling handling that yields testing or inspection results that do notrepresent the population, an effect called sampling bias has

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occurred. This bias can lead to acceptance of non-conforming lotsor rejection of conforming lots. Thus, caution must be exercisedwhen designing a sampling plan to ensure that bias is not intro-duced. The use of sampling devices, such as a sample thief, oftenintroduces biases that cannot be predicted or easily eliminated.Thus, care must be used to either eliminate the bias or identify itsimpact.■ What is Meant by Batch Homogeneity and Batch Uniformity?

Batch homogeneity means that each increment or portion of abatch is visually or analytically the same as all others. Batch uni-formity means that the trend of results, not necessarily all individ-ual results, is similar through all portions of the batch. Thoughthese terms are not the same, they are similar and used nearlyinterchangeably.

Concepts of Sampling Risk

Any discussion of sampling and sampling plans must also con-sider the elements of risk associated with any inspection involvingless than 100% of the population. Two types of risks are inherentin any acceptance sampling plan. These risks are illustrated inFigure 1.

A Type I risk is called a “Producer’s Risk,” because the impactwould be primarily financial to the manufacturer – that is, a lot that

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Eldon Henson

actually would have met acceptance criteria if 100% of the unitswould have been evaluated. In actual practice, this “risk” is mini-mized because most pharmaceutical manufacturers utilize a retest-ing process to fully investigate results that are initially OOS.However, this process of investigating OOS results is time consum-ing and adds expense.

A Type II risk is called a “Consumer’s Risk” because the impactwould be that the ultimate consumer would actually receive adefective or nonconforming product. This risk is certainly ofgreater concern, both because of the potential for harm, but alsobecause an acceptable test result is rarely questioned – in otherwords, there is no “back-up” opportunity for recognition of a con-sumer’s risk that exists for a producer’s risk (i.e., retesting).

Neither type of risk can be totally eliminated. Thus, the sam-pling plan for pharmaceutical products must include a risk assess-ment of the potential for making an incorrect disposition decisionand the likely outcome if incorrect decisions are made. For evalu-ating product attributes (items classified as either good versusdefective, such as tablet appearance), this risk is usually deter-mined by a management decision or corporate philosophy, and isexpressed as Acceptable Quality Level (AQL). AQL is the maxi-mum average percent defective that is acceptable for the productbeing evaluated.

So, let’s see how this risk assessment might be expressed asan AQL by looking at two examples dealing with labels:

❶ Correct label print text – because the “risk” associated withaccepting as-good labels that are defective is significant(both to the consumer, and because this would be a directcGMP violation), the AQL for this type of defect would bevery low. The lowest AQL typically defined in sampling plansis 0.01, meaning that a larger sample would be required todetect even a low level of defects. No defects would be toler-ated in the sample population. Thus, the consumer’s risk issignificantly minimized.

❷ Correct label print color – because the “risk” associated withaccepting as-good labels with off-color is insignificant (noconsumer or cGMP concerns), the AQL for this defect would


be higher. In this case, the firm may choose an AQL of 6.5,which would require a smaller sample needed to assess thepopulation, and more tolerance for random defects.

For product variable characteristics (parameters that are meas-ured, such as analytical test results on products), this risk assess-ment is usually alleviated by the overall process design, processvalidation, and analytical method validation combined to providean acceptable level of confidence in product released. For exam-ple, if a process is incapable of consistently yielding product withdrug active results 90-110% (the product specification range), theconsumer’s risk increases. Or, if the analytical method has amethod variability of + or -3%, can you have confidence releasinga batch with a final drug active result of 91%? Thus, this risk is atleast partially alleviated, in this case, by establishing a releasespecification outside the “danger zone.” In other words, in the caseof a release range of 90-110% and an analytical variability of + or-3%, the actual release specification may be established as 94-106%. Thus, even if the method is biased by 3%, with a result of94%, the actual result (91%) would still be acceptable.

So, the selection of any sampling plan for a pharmaceuticalproduct must be a considered decision. The plan must consider theproducts, processes, test/inspection methods, as well as, thepotential producer’s and consumer’s risks the firm is willing toaccept. It is generally inappropriate to merely select a “typical” sam-pling plan without a proper consideration of these factors.

Incoming Packaging Components

A sampling plan for incoming packaging components mustconsider many factors:

• The criticality of the component as it relates to ultimate prod-uct quality (i.e., primary packaging components versus sec-ondary packaging)

• Typical lot sizes• Confidence in the vendor manufacturing process• Ease of detecting defects

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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 packagingcomponents must utilize knowledge of the material usage, alongwith the potential risks posed by defects in the components.

Most sampling plans for packaging components classifydefects into three categories:

❶ Critical Defects – these are defects that would almost certainlyimpart 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 orunder certain conditions, could render product unacceptable orunusable (i.e., issues during use). Examples of major defectsinclude:

• Bottles out-of-round or with uneven molding or form• Chips, bubbles, cracks, or other defects that may result in pro-

duction 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 pro-duction problems, cosmetic issues, or other non-product critical


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 requiredfor each defect type (it is possible that the number of samples exam-ined will be different for each defect type), testing or inspection per-formed, and number of defects above which the lot would be rejectedor require further inspection.

So, the question that must be answered in developing a samplingplan is how to ensure that the sample is representative of the entirelot, and that the plan is statistically-based.The best approach forensuring representative sampling is to remove samples uniformlyfrom across the batch. For example, if the plan requires a sample sizeof 80 units, these units should be taken from all points in the lot.

NOTE: When removing samples from a batch, it is important toidentify the location of samples taken. One approach often used is toplace a sticker with a statement, such as, “This Case SampledBy/Date __________” on each case or unit from which a sample wasremoved.

How can you best satisfy the cGMP requirement that a samplingplan is statistically-based? Answering this question can be especiallydifficult if a variety of packaging components with various uses indosage forms are received within the firm. For example, is it possibleto establish a statistically-based plan – a simple one – for a firm thatproduces liquids, powders, capsules, and creams encompassing >100product formulations and another >250 packaging configurations?

One approach to developing such a sampling plan would be toutilize ASQ/ANSI Z1.4 criteria, and select a “typical” plan thatcovers most of your product needs. However, this becomes diffi-cult if you can receive lots of 50 to 500,000 units. An interestingstatistically-based plan that may prove useful would be onebased on the Army and Air Force Exchange Service Plan

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Eldon Henson


(AAFES Plan) that incorporates continuing inspection criteria,depending upon what results are obtained. This double samplingplan (located at www.aafes.com/qa/docs/supqap-sampling_plans_home_page.htm) utilizes levels of acceptable quality (or AQL – theprocess average percent defective) that could be equated to criti-cal, major, and minor defects. This plan is summarized in Figure 2and Figure 3.

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Eldon Henson

The example plan outlined above (AAFES Plan) has theadvantage that it is simple, is statistically-based, and providesan opportunity to conduct additional inspection for initial fail-ures. However, from a practical standpoint, the continuinginspections scenario requires that an additional sample betaken from the lot, unless the maximum possible sample istaken initially. Either way, the need for continuing inspection isa productivity concern.

Many other potential sampling plans that would meet cGMPrequirements could be selected. The key to developing anysampling plan is to be able to answer the question that theFood and Drug Administration (FDA) investigator might ask:

“What justification can you provide to ensure that this sam-pling plan will disqualify any lot that could result in defectivefinished product?”

One additional key to sampling plans for incoming packagingcomponents is to consider the potential for remediating or cor-recting lot concerns identified during inspection. In other words,oftentimes, a lot that fails incoming inspection is desperatelyneeded for production. Can you design a procedure that allowsfor inspection/rework of the nonconforming lot, then release thelot? The answer is, “Yes, under certain circumstances.” If thedefect that resulted in failure of the lot can be inspected, and eas-ily detected and removed, it may be possible to result in arelease disposition after inspection. This process must be speci-fied in SOPs, and documentation must exist to demonstrate thatthe lot was acceptable after rework/inspection.

Incoming Raw Materials

Despite the fact that there is no statistical basis for a “squareroot of n plus one” sampling plan, most firms utilize this approachfor incoming raw materials. This plan can be argued as represen-tative of the batch when the sampling requirement ensures that allportions of the batch will be included in the sampling. An addition-al requirement used by most is that for any lot with fewer than fivecontainers, all units will be sampled. With this approach, illustrated


in Figure 4, the plan makes “apparent” statistical sense.

Note: Some raw materials, such as bagged ingredients, will con-tain more than 500 units. When lots of materials are greater than500 units, an alternate sampling plan should be considered.

In each case above, the sampling plan must specify that all por-tions of the batch, beginning, middle, and end, must be sampled.Even in the worst-case scenario above, the batch can be well repre-sented in the final sample.

It must also be pointed out that some materials and productrequirements specify that more rigorous sampling regimens be fol-lowed. For example, if a material is microbiologically sensitive and/orpotentially non-homogeneous, it may be prudent to sample everycontainer regardless of lot size. Knowledge of the material and theprocess must be included in the risk assessment associated withselecting a sampling plan.

For other materials, samples taken are eventually compositedinto a single container and mixed. Several issues exist for thisapproach:

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Eldon Henson

• Does the “mixing” of individual samples into a composite reallyproduce 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 mate-rial.

• Can a non-homogeneous lot actually “pass” incoming testingusing a composite, though it may have locations of high or lowresults?

Despite these concerns, the use of a composite sample to repre-sent 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 rawmaterials:

• Temperature sensitivity must be considered – some samplesmust be stored in cool conditions

• Other factors that could impact material quality must be consid-ered, such as moisture and light

• As discussed earlier, proper sample identification is alwaysrequired

In summary, the simple “square root of n plus one” sampling planis usually acceptable for raw materials.Though not statistically signif-icant from a mathematical viewpoint, this plan does provide for arepresentative sample, and is easy to implement and use. Many ofthe problems and rejections associated with incoming materials areoften traced to poor sampling technique or sample handling. Pro-visions for proper technique is a must for sampling SOPs.

Labeling Materials

Sampling plans and inspection approaches for labeling materi-als must typically consider several factors:


• 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 areconsidered unit labels, packaging instructional inserts, unit car-tons with labeling information, and other printed materials thatcontain product usage, dosage, or warning information.

Let’s look at each of these in more detail.

Label Printing ProcessThe printing process and procedures in place at the label man-

ufacturer are significant in developing a sampling and inspectionprocess. The key aspects of the printing process that must beconsidered include:

How are printed labels cut? How many replicates of each labelare printed for each “shot?”

For label manufacturers that print multiple “shots” of each label,the sampling and inspection plan for incoming labels must ensurethat all representatives of the “shot” be inspected. A “shot” wouldbe a multi-lane printing system that prints multiple versions of thesame label (i.e., four different print mats, for example) that arethen cut and combined. In these cases, it is important that thesampling plan include an inspection of consecutive labels thatrepresent all members of the “shot.”

For example, a label printing press prints four labels across ona sheet of label paper. The four labels are eventually cut into fourseparate rolls. In this case, the incoming sampling plan mustinclude at least minimal samples from each roll. In other cases,the print “shot” might include four across and six down for eachprinting event. In this case, the sampling plan must include repre-sentative samples from each roll, plus at least six consecutivelabels from each roll inspected. This plan will ensure that at least

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Eldon Henson

every separate printing event is represented in the inspection.

How does the printer handle splices in label rolls? What con-trols exist?

Several recalls occur each year when label manufacturersimproperly splice the end of one label roll to the beginning of thenext. These splices must be properly handled and controlled toavoid splice errors. Label manufacturers must ensure propercGMP practice, such as line clearance and double-checks, toavoid these concerns. Incoming sampling plans should include aninspection of these splices, or at least some minimal number ofthem. Ideally, label manufacturers will avoid entirely, or at leastminimize, the number of these splices required.

Is it possible for labeling to change after approval? What comput-er systems are used, and what controls exist to ensure that thelabel approved will be the label printed and delivered?

The label manufacturer’s processes and procedures for con-trolling changes to master labels is critical. Unless the label manu-facturer has superior controls for ensuring that the approved labelis the printed label, the incoming sampling plan and inspectionmust include a thorough review of each printed label lot againstthe master label.

Confidence in the Label ManufacturerOf 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 andinspection plan can be reduced. Key questions that must be answer-ed for label manufacturers include:

Do adequate controls exist to ensure segregation of eachlabeling type and lot?

Because most label manufacturers produce many different labelsfor many different products, it is essential that procedures exist to


detail label segregation. On-site audits are necessary to ascertainthis. The audit should assess how labels are controlled after print-ing, during storage, and at shipment. Ideally, labeling should havea strict chain of custody throughout the manufacturing and han-dling process.

Are the individuals involved in the manufacturing and control ofthe label manufacturing process experienced in pharmaceuticaloperations, controls, and procedures? Do employees receivetraining in cGMP?

At this point in time, most label manufacturers for pharmaceuti-cal companies are well-versed in cGMP requirements, and haveincorporated these concepts into their own operation. An on-siteaudit should assess cGMP essentials, such as the presence ofadequate procedures, training, documented production records,material segregation and controlled access, routine in-processinspection, and strict control of “masters.” Failure to have good con-trols in any of these areas would be an item of concern for a poten-tial pharmaceutical customer.

Is the firm innovative and progressive in developing controls toensure printed label quality?

Today, the use of automated manufacturing and inspectionequipment has become commonplace, and even essential toremain competitive with respect to label quality and productivity. Aproactive approach to improvement and enhanced controls pointsdirectly toward a high and consistent level of quality. The higher thedemonstrated quality, the less incoming inspection is potentiallyrequired.

Does the label manufacturer have a solid history in providinghigh quality materials?

Despite all controls, procedures, and high-quality attitude, themost important factor relating to reducing incoming inspection oflabeling is results. Has the manufacturer demonstrated consistent-

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Eldon Henson

ly that they have systems and procedures in place to control bothlabel manufacturing and segregation? Any effort to reduce or min-imize incoming inspection should consider the historical results ofthe supplier.

Label Control and Verification Procedures in Place in YourFirm

In addition to knowledge and confidence in the label manufac-turer, the controls and verification systems in place at your firmalso play a role in the sampling plan for incoming labeling. Keyquestions that must be answered include:

Do you have 100% label verification systems in place? Havethese systems been validated and proven reliable? Has redun-dancy been designed into these systems?

In today’s pharmaceutical manufacturing world, all manufacturersshould have systems to 100% verify label correctness. However, doyou have confidence that these systems always function properly?The more rigorous the validation, the more confidence you might havein these systems.Thus, the level of incoming inspection may bereduced. Likewise, redundancy in inspection or verification systemscan provide justification for less rigorous incoming inspection.

Does your firm use many different labels of similar size andshape, 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 yournumber of labeling materials is low, or if each label is clearly of a dif-ferent size, shape, or color, the risk for failure might be relatively low.In these cases, less incoming inspection may be warranted.Thereverse would, of course, also be true.

Can you devise a scenario in which the incorrect label deliveredby the label manufacturer could be used and undetected?

Again, how easily could an incorrect label be received,


approved, and used? Would this scenario require multiple systemsfailures, or be essentially impossible? If so, less inspection rigor iswarranted.

Level of Technology Available for Label Inspection and ControlFinally, the type and level of inspection technology available to

your label inspection group may have an impact on the samplingand inspection plan you develop. For example:

Do you use an optical comparator or similar “intelligent” instru-mentation to verify all incoming labeling prior to release?

The use of “intelligent” instrumentation to inspect incominglabeling may provide significant confidence that incorrect labelingcould not be used. Care must be exercised, however, to not usetechnology as an excuse to minimize incoming inspection withoutmerit.

Are all labels electronically inspected and verified “off-line”prior to release and use?

One approach used by many pharmaceutical firms is to con-duct 100% inspection prior to release. This approach, thoughseemingly overkill to some, does provide assurance that the cor-rect label was received and released, and provides added redun-dancy with on-line verification systems.

Do you have other systems in place for 100% inspection oflabeling prior to use to circumvent the need for sampling andinspection?

Again, the greater the level of inspection and verification inplace, the less incoming inspection is needed.

In summary, the level of incoming inspection and the samplingplan used is directly dependent upon many factors. The level ofinspection must be determined based on the overall risks associ-ated with or posed by the labeling. One word of caution… misla-

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Eldon Henson

beling has been one of the top ten causes for pharmaceuticalproduct recalls in each of the last ten years. Despite the fact thatcGMP requirements for labeling and label control have remainedessentially unchanged since issuance in 1978, firms still strugglewith 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, notsuspensions, emulsions, or creams – are among those withfewest special concerns. If the product is a true solution (all mate-rials in solution – no possibility of separation under normal condi-tions – each sample is, by definition, the same as every othersample), no special concerns for sampling usually exist. Certainly,proper handling of samples after collection is important. As with allproducts and all sampling approaches, exercise proper samplingplan design and execution to ensure that results obtained repre-sent the product evaluated.

Sterile Products

Several special sampling concerns exist for sterile products.These products require additional controls for the production envi-ronment, product protection, and product handling to ensure thatsterility is assured. With these products, product and environmen-tal protection has been engineered into the process. For example,protection from environmental contamination is controlled by theuse of filtration to remove essentially all particulates, control of air-flow and direction, sterilization of equipment, containers, potentialproduct contact surfaces, and rigorous controls to prevent “peo-ple” contamination. Sampling plans for these products typically areused to assess the proper function of these systems. The follow-ing aspects of the process are usually sampled and monitored:

• Air• Equipment sterilization• Personnel• Materials


These systems are sampled via environmental monitoringplans and procedures. Sampling plans are designed and executedto comprehensively test each aspect of these systems. For exam-ple, air is tested for both non-viable and viable (microorganisms)contamination in the manufacturing environment. Samples aretaken from the hands and clothing of personnel to ensure thatsystems and personnel practices are properly followed.

It is not the intent of this article to discuss these sampling pro-grams in detail. In short, however, the typical cGMP requirementsdiscussed in the introductory section of this report (statisticallyvalid, written, representative, sample identification, etc.) are alsorequired for each of these sampling efforts.

Creams, Suspensions, and Emulsions

Creams, suspensions, emulsions, and other products that areprone to separation or settling pose special concerns for samplingand testing. During each process step in which separation or set-tling could occur, comprehensive sampling and testing must beperformed to ensure that the process is performing as designed.Validation studies will usually provide the documentation needed toprove the process, and establish the critical process parametersthat must be achieved in order to produce conforming product.Routine sampling and testing during commercial production shouldmerely verify that expected processing parameters are beingachieved.

Each process must be evaluated to determine the proper vali-dation and ongoing verification sampling and testing approach.You must determine this for each individual product. A detaileddiscussion on aspects of this determination will not be reviewed inthis article because each product is unique. However, the follow-ing represents some of the author’s experience relating to sam-pling and testing these products:

■ Sampling TechniquesCare must be taken when specifying the sampling technique for

products prone to separation. For example, for most of theseproducts, prior to packaging, the bulk material must remain under

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Eldon Henson

mixing or agitation conditions. To remove a sample, the mixing oragitation should cease when sampling open containers (to ensuresafety of the sampler). Samples must be removed quickly whensafe to ensure the sample is representative, and that settling hasnot occurred. In addition, samples from open containers should notnecessarily be removed only from the upper few inches of the prod-uct batch. Validation studies should identify from what portion of thebatch the sample should be taken.

Even when sampling closed systems (i.e., samples taken from asampling port or other device, and not taken directly from an opencontainer) requires precautions. In most of these cases, it is impor-tant to purge the sampling port before removing the sample foranalysis. Discharging a small portion of material prior to removingthe sample can avoid samples that are not representative.

■ Handling of SamplesIt is imperative that in-process samples for these products be

properly handled. Handling must ensure that degradation of thesample integrity does not occur. If the intent of the sample is to testthe exact attributes of the product at that point, it may be necessaryto avoid further mixing of the sample. For these products, a samplethat completely fills the sample container to a point that no head-space exists will usually protect sample integrity. Without head-space, inadvertent mixing is unlikely.

However, samples taken to analyze the integrity of the samplemixture may require further mixing prior to analysis. In these cases,collecting the sample in a container that has adequate headspaceto allow further agitation prior to analysis may be required.

The key point here is that you must consider the purpose of thesamples taken. What attributes are you attempting to analyze? It isimportant that you “pre-determine” this purpose, and design a sam-pling approach and sample handling “protocol” to ensure that thesample taken will yield the information required.

■ Validation of Mix FailuresDespite rigorous equipment design, tightly controlled process-

es, and superbly trained personnel, failures in mixing processeswill occasionally occur (i.e., power failures, etc.). Unless validation


data are available that define the length of downtime of mixing sys-tems without affecting the mixture (or emulsion, etc.), the batchmay be in jeopardy. Thus, it may be useful during validation tointentionally cease mixing at key points in the process, sample atvarious time points, and test the product to determine the length of

time the mixingstep can bedown withoutnegativelyimpacting theproduct.

■ Composite SamplesCan cream, emulsion, and suspension samples be composited

and tested? In most cases, composite samples can be used toassess the overall quality of the product. Individual samples can becollected, then combined to produce an overall sample reflectingthe quality of the batch. However, you must use caution with theseproducts to ensure that the mixing of individual samples does notintroduce additional variability in the process that can mask prod-uct issues.You should validate the sample compositing process.This can occur by analyzing the individual samples, then compar-ing results (or average results from all individuals) to the compositesample result. A failure to yield statistically comparable results canindict the compositing process.

In short, if you produce emulsions, creams, or suspensions, youalready know that these products pose special concerns. The sam-pling plan designed to either validate the processes for these prod-ucts, or to assess ongoing production, must consider these specialconcerns and greater effort to “pre-determine” the purpose ofeach set of samples is warranted.

Powder Blends

Perhaps the area of sampling that has caused the most contro-versy is how sampling is applied to powder blends. In other words,what sampling plan is required to demonstrate, in a consistent,

Eldon Henson

Despite all controls, procedures, and high-quality attitude, the most important

factor relating to reducing incoming inspection of labeling is results.


Eldon Henson

reproducible way, homogeneity of the powder blend prior to furtherprocessing? Let’s explore some key considerations.

Following publication of FDA’s Guidance for Industry, ANDAs:Blend Uniformity Analysis (August 3, 1999), significant industryconcerns were raised regarding FDA’s requirements for demon-strating blend uniformity when United States Pharmacopeia (USP)content uniformity testing is required on the product. Some ofthese concerns included:

• Current limitations in sampling technology – specifically, theuse of sample thief technology has been proven prone to errorand inconsistency

• Powder segregation of samples after sampling• Weighing errors can occur during preparation of blend sam-

ples for analysis• Difficulty in proving that the blender sample plan will be truly

representative – demonstrating that all worst-case locationsare included in the sample, and

• Blender sampling fails to consider segregation that can occurduring discharge, storage, and transport prior to final pro-cessing

Despite these concerns, the current cGMP requirement in 21CFR 211.110(a)(3) states:

“…control procedures shall include… adequacy of mixing toassure uniformity and homogeneity.”

This requirement, thus, applies to development, process vali-dation, and post-validation commercial batches for solid oral drugproducts.

Most firms continue sampling plans that involve the removal ofa minimum of ten samples from all primary areas of the blenderusing a sample thief. Many variations in sample thief technologyexist and are in use, including: multiple chamber units, variationsin probe design, and alternatives designed to minimize productdisturbance during sampling. Some firms demonstrate blend uni-


formity by sampling at the discharge stage, or from final in-process blend storage units (i.e., drums, totes, etc.). In all cases,firms uniformly utilize unit-dose sampling sizes to fulfill BarrDecision and FDA current expectations.

Because of the numerous issues mentioned above with thiefsampling of oral drug blends, dealing with blend sample failures isan ongoing concern. In other words, the uncertainty of blend sam-pling technology and approaches often lead to blend analysis fail-ures. So, we face the age-old question, “How do I know these fail-ing results are real? What additional testing is needed to overturnthese failing results?” Some firms universally interpret blend sam-ple failures as “true failures,” and reject any study exhibiting failingresults. Other firms attempt to discredit failing results through aninvestigation that can involve OOS investigations, resampling,retesting, utilization of scientific rationale, or a combination ofthese. The risk of this approach to overturning failing blend resultscan be a delayed regulatory approval or FDA inspection issues.

As a result of these issues and industry concerns, the ProductQuality Research Institute (PQRI) Blend Uniformity Working Groupdeveloped an approach to demonstrating blend uniformity by com-bining blend testing and compendial dosage unit testing. Thisapproach (stratified sampling) postulates that the analysis ofdosage units (i.e., finished tablets) can supplement or provide sta-tistical evidence that a failing blend result was due to poor sam-pling or handling technique. This approach has not been officially“accepted” by FDA, though several members of FDA served on thePQRI expert committee that developed the recommendation. De-spite this lack of official acceptance, several firms have utilized strat-ified sampling to justify acceptance of failing blend data.

For a full copy of the stratified sampling approach and rationalesupporting it, reference the PQRI web site (listed in the final sec-tion of this document).

Tablets, Capsules, and Other Solid Dosage Forms

Solid dosage forms typically pose many opportunities for apply-ing appropriate and scientifically sound sampling approaches.

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Eldon Henson

Figure 5 illustrates the following example process.This example process depicts a coated tablet produced from a


wet granulation process. In this process, the following steps andsampling approaches are typical, as shown in Figure 6.

Eldon Henson


Eldon Henson

Detailed approaches for sampling of materials up through stepfive are discussed earlier in this article. Following are additionalconsiderations for the finishing steps involved in tablet production:

■ Compression into Tablets

There are several key sampling/testing considerations regard-ing the tablet compression process:

• Start-up: It is critical that initial tablets produced be carefullysampled and tested to ensure that equipment set-up is cor-rect, granulation was produced as expected, and the combi-nation of equipment and product are functioning well to-gether. During the initial period of production, additionalsamples should be taken and tested for conformance tophysical requirements (analytical conformance should havebeen assessed and proven during validation). During start-up of routine, commercial production, samples should bereviewed from each set of compression tooling. In otherwords, you should remove at least two consecutive cycles oftablets, and carefully inspect (and document) physical ap-pearance, dimensions, and functionality. Inspection shouldinclude:

i. Appearance – complete tablets, no capping, no chips, andcomplete and correct embossing (if performed)

ii. Dimensions – tablet thickness, weight, and other criticalparameters should be measured

iii. Functionality – tablet hardness, friability, etc. should bechecked

The combination of this initial early inspection is essential toa successful compression run.

• During the run: Samples should be taken at regular intervalsduring the batch to ensure that tablets continue to conformto requirements

• After adjustments: Samples should be taken after any


adjustment of the press that could alter physical dimensionsor characteristics of the tablets

• At the end of the run: Often, the end of the batch is the timewhen nonconforming tablets frequently are produced – thus,it may be prudent to remove and analyze additional samplesnear the end of the run

• Validation: Extensive sampling and testing must occur duringvalidation studies that include analytical testing, in addition tophysical inspection. Because many granulation formulas aresensitive to de-blending or segregation, analytical verificationof blend homogeneity must be verified at all stages of thebatch, with special attention given to start-up, after adjust-ments, when the compression hopper is depleted or nearingdepletion, and at the end of the batch.

■ Tablet CoatingThe tablet coating process must be carefully sampled and eval-

uated to ensure proper application of coating. It is imperative thatthe process be monitored throughout, with additional samplingand evaluation after adjustments or during times deemed critical,such as at the beginning of the process and near the end.

■ Tablet PackagingSampling and analysis of solid dosage forms should occur at

various points during the packaging process. Two key aspects ofpackaging quality are usually considered:

❶ Tablet Integrity❷ Fill Accuracy

Product should be sampled and inspected at the filler and aftereach critical process (blistering, for example) to ensure that tabletdamage is not occurring.

In addition, fill accuracy is important from both a consumercomplaint perspective and economic standpoint. Sampling andverification of fill count are important both during packaging vali-dation and during routine commercial production.

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Eldon Henson

In summary, sampling of all aspects of the tablet productionprocess is important to ensure at all stages that tablet integrity con-forms to requirements. Each process must be carefully evaluated,usually via review of a process flow chart prior to validation, toascertain critical process steps, or points at which defects couldoccur. After identifying these points, a sampling plan must bedeveloped to prove both during validation and routine productionthat tablets meet all requirements.

Guide to References on Sampling Plans

A recent search on the Yahoo internet web site for “samplingplans” revealed 617,000 sites that include some reference to sam-pling or sampling plans. In addition, hundreds of reference bookshave been written that are either dedicated to sampling or samplingplans. So, the availability of information on this subject is abundant.What are the best locations to find needed information that willassist those in the pharmaceutical industry? Though the authordoes not claim to have knowledge of all or even most of the bestinformation sources, the following are good resources for additionalhelp or information on this subject:

Web SitesSeveral 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 sec-tion on “Incoming Packaging Components.” On this site, you canlocate the AAFES approach using continuing inspection criteriabased 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 sta-tistical novice to locate and learn more about these plans.

❷ www.samplingplans.comThis site is administered by H&H Servicco and provides an

excellent tutorial on basic statistics of sampling plans (Operating


Characteristics [OC] Curves, control charts, etc.), and can providevaluable information on getting started on sampling plans.This siteprovides excellent examples of sampling plans, challenge questions,and an extensive glossary of terms and definitions.

❸ www.cqeweb.comThis 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 chapterdeals specifically with the topic, “Sampling.” This chapter providesanother excellent review of the basic and more detailed statistics thatserve as the basis for many sampling plans. It includes a very goodglossary of terms with excellent graphics and examples.

❹ www.iso.chThis is the web site for the International Organization for

Standardization (ISO).This is an extensive web site detailing stan-dardized approaches for many quality topics, including sampling andsample plans. Any effort to develop sampling plans for products forglobal marketing should consider the procedures already developedand in use by the ISO.

❺ www.pqri.orgThis is the Product Quality Research Institute (PQRI) site that

includes the complete Blend Uniformity Working Group report, “Theuse of stratified sampling of blend and dosage units to demonstrateadequacy of mix for powder blends.” In addition to this report, the let-ter provided to FDA introducing this report and blend uniformity dataused to support the recommendations are available.

❻ Many other pharmaceutical organizations have valuable infor-mation on web sites that provide further details and discussions onsampling:

• www.ivthome.comThe Institute of Validation Technology (IVT) includes manyarticles, papers, and additional resources to aid in the develop-ment of sampling plans or approaches to cGMP compliance.

• www.pda.orgThe Parenteral Drug Association (PDA) is another excellentresource for additional information.

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Eldon Henson

• www.ispe.orgThe Society for Life Science Professionals (formerly Institute forPharmaceutical Engineers) provides excellent technical andindustry information regarding aspects of cGMP compliance.

• www.gmp1st.comThe GMP Institute provides a wealth of helpful cGMP compli-ance information.

• www.asq.orgThe American Society for Quality is one of the largest and old-est organizations dedicated to providing information for profes-sionals involved in quality.

This discussion could never identify all of the excellent organiza-tions providing information on cGMP compliance and, specifically,sampling and sampling plans. If the above web sites cannot providethe information required, query other web site search engines to findthe specific information desired.

Textbook ReferenceSeveral classic textbooks provide extensive information on the

development and use of sampling plans for quality assurance pur-poses. However, the ultimate resource is Juran’s Quality ControlHandbook (A. Blanton Godfrey and Joseph M. Juran (coeditors-in-chief), 5th Edition, McGraw-Hill, 1999). is the universal reference bookfor information about quality control sampling plans. All quality practi-tioners should have, and refer often to, this excellent resource. ❏

About the AuthorEldon Henson is a frequent contributor to Institute of ValidationTechnology publications. He has authored IVT’s AuditingHandbook, Quality Improvement Handbook, Topic of the Day GMPTraining Program, and, most recently, the GMP Toolbox. Henson is amember of the Editorial Advisory Board of the Journal of ValidationTechnology, and has written many GMP training modules forEduneering, a web-based training content provider. He holds B.A.


and M.A. degrees in microbiology from Southern IllinoisUniversity-Carbondale, and has worked in various quality andmanufacturing roles at Abbott Laboratories, Novartis, Boehringer-Ingelheim, Sigma-Aldrich, and is currently Director, QualityAssurance at KV Pharmaceutical in St. Louis, MO. Henson can bereached at [email protected].

Reference1. A. Blanton Godfrey and Joseph M. Juran (coeditors in-chief). Juran’s

Quality Control Handbook. 5th Edition. McGraw-Hill. (1999).

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Eldon Henson


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