FOOD AND DRUG ADMINISTRATION

OFFICE OF REGULATORY AFFAIRS

Office of Regulatory Science

Document Number:

MAN-000067

Revision #: 03

Revised: 

27 Jul 2022

Title: 

ORA Lab Manual Vol. IV Section 14 - Consumer Complaints and Product 

Tampering (IV-14)

Page 1 of 24

For the most current and official copy, check QMiS.

Sections in This Document

1. Purpose ................................................................................................................................ 1

2. Scope.................................................................................................................................... 1

3. Responsibility ...................................................................................................................... 2

4. Background.......................................................................................................................... 2

5. References ........................................................................................................................... 3

6. Procedure............................................................................................................................. 4

6.1. Preliminary Information and the Analytical Strategy.............................................. 4

6.1.1. During the manufacturing process ............................................................ 4

6.1.2. During distribution or at the retail location ............................................... 5

6.1.3. After the product is in the possession of the consumer .......................... 5

6.1.4. Prior to starting an analysis........................................................................ 5

6.2. Safety ......................................................................................................................... 6

6.3. Sample Handling ....................................................................................................... 7

6.4. Initial Observations ................................................................................................... 8

6.5. Analytical and Instrumental Methods .................................................................... 10

7. Glossary/Definitions.......................................................................................................... 19

8. Records .............................................................................................................................. 20

9. Supporting Documents ..................................................................................................... 20

Document History ................................................................................................................ 21

Change History........................................................................................................................... 22

Attachments......................................................................................................................... 24

1. Purpose

This document provides a framework for the analysis of samples which are 

obtained during the investigation of consumer complaints, or which are 

associated with alleged instances of product tampering.

2. Scope

The Agency’s consumer complaint system is a crucial source of information on 

potentially unsafe products in the US marketplace. Complaints involving death, 

serious illness, or injury are given the highest priority and demand an 
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Document Number:

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Revision #: 03

Revised: 

27 Jul 2022

Title: 

ORA Lab Manual Vol. IV Section 14 - Consumer Complaints and Product 

Tampering (IV-14)

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immediate response. Complaints about infant formula, baby food and medical 

foods are especially sensitive due to the vulnerability of the population that 

consumes these products. Product tampering is an intentional adulteration of a 

product that is frequently brought to the Agency’s attention through consumer 

complaints.

Laboratory examination and analysis of complaint/tampering samples allows 

the Agency to begin to assess the severity and scope of the potential problem. 

Producing analytical results in a timely manner is paramount to developing a 

response that will minimize risk to public health.

3. Responsibility

A. Analyst 

1. Review available background information, including complaint form 

and collection report

2. Obtain appropriate control/comparison samples as needed

3. Take appropriate safety precautions

4. Document sample examination and analysis in analytical 

worksheet(s)

B. Supervisor/Management

1. Communicate results to investigator, Office of Emergency 

Operations, District/Program Compliance Branch, Complaint 

Coordinators as applicable

4. Background

A complaint serves as notification that a product in commercial distribution 

may be in violation of FDA laws and regulations. FDA is authorized to 

investigate reported tampering of FDA regulated products under the Federal 

Anti-Tampering Act, Title 18, United States Code, Section 1365. Note that the 

Act not only makes tampering a crime but also identifies as criminal “whoever 

knowingly communicates false information about product tampering” and 

“whoever threatens.” The Office of Criminal Investigations (OCI) has the 

primary responsibility for all criminal investigations of tampering/threat 

incidents.
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Tampering (IV-14)

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5. References

A. Gosselin, R.E., Smith, R.P. and Hodge, H.C. (1984). Clinical Toxicology of 

Commercial Products (5th ed.). Baltimore: Williams & Wilkins.

B. Bryson, P.D. (1996). Comprehensive Review in Toxicology (3rd ed.). 

Aspen, CO: Raven Press.

C. Saferstein, R. (Ed.). Forensic Science Handbook, Volumes I, II and III (2nd

ed.).

D. U.S. Pharmacopeia and National Formulary. 

E. Hummel, D.O. (2000). Handbook of Surfactant Analysis – Chemical, 

Physico-chemical and Physical Methods. New York: Wiley & Sons.

F. Rosen, M.J. and Goldsmith, H.A. (1972). Systematic Analysis of Surfaceactive Agents (2nd ed.). New York: Wiley-Interscience.

G. Schonfeldt, N. (1969) Surface Active Ethylene Oxide Adducts. Pergamon 

Press.

H. Kato, H., Nagai, Y., Yamamoto, K., Sakabe, T. “Determination of 

Polysorbates in Foods by Colorimetry with Confirmation by Infrared 

Spectrophotometry, Thin Layer Chromatography and Gas 

Chromatography”, J. AOAC, 72 (1989) 27-29.

I. Mulligan, K.J. “A Procedure to Determine Diethylene Glycol (2,2’-

oxybisethanol) and Ethylene Glycol (1,2-ethanediol) in Glycerin and 

Selected Products”, Laboratory Information Bulletin No. 4042 (1996). Also 

at https://www.fda.gov/Food/FoodScienceResearch/LaboratoryMethods

J. U.S. Environmental Protection Agency, Methods for Chemical Analysis of 

Water and Wastes, Method 335.2, “Cyanide, Total (Titrimetric; 

Spectrophotometric).”

K. Moffat, A.C., Jackson, J., Moss, M.S. and Widdop, B. (Eds.). (1986). 

Clarke’s Isolation and Identification of Drugs (2nd ed.). London: The 

Pharmaceutical Press.

L. Feigl, F. and Anger, V. (1972). Spot Tests in Inorganic Analysis (6th ed.). 

New York: Elsevier Publishing Company Inc.

M. Kolb, B. and Ettre, L.S. (1997). Static Headspace–Gas Chromatography: 

Theory and Practice. New York: Wiley-VCH.

N. ASTM International E1387-01, “Standard Test Method for Ignitable Liquid 

Residues in Extracts from Fire Debris Samples by Gas Chromatography”.
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O. Mulligan, K.J. and McCauley, H.A., “Factors that Influence the 

Determination of Residual Solvents in Pharmaceuticals by Automated 

Static Headspace Sampling Coupled to Capillary GC-MS”, J. Chromatogr. 

Sci., 33 (1995) 49-54.

P. AOAC Official Method 993.30, “Inorganic Anions in Water by Ion 

Chromatographic Method.” 

Q. Wang, F., Dicinoski, G.W., Zhu, Y., Haddad, P.R. “Simultaneous 

Determination of Monofluoroacetate, Difluoroacetate and Trifluoroacetate in 

Environmental Samples by Ion Chromatography.” J. Chromatogr. A, 1032 

(2004) 31-35.

R. Jackson, D.S., Crockett, D.F., Wolnik, K.A. “The Indirect Detection of 

Bleach (Sodium Hypochlorite) in Beverages as Evidence of Product 

Tampering.” J. Forensic Sci., 51 (2006) 827-831.

S. Dionex Application Note 143, “Determination of Organic Acids in Fruit 

Juices.” 

T. Dionex Application Note 243, “Determination of Common Anion and 

Organic Acids using Ion Chromatography-Mass Spectrometry.”

U. Food Emergency Response Network, “BSL-3 High-Risk Unknown Agent 

Screening Procedure for Food”, SOP No: FERN.RES.0001.01. Current 

version available from eLEXNET.

6. Procedure

6.1. Preliminary Information and the Analytical Strategy

Many complaints allege product tampering; however, facts uncovered during the 

investigation may not support the allegations. Unless there is prevailing 

investigational information prior to laboratory examination and analysis, it is difficult 

to differentiate manufacturing problems from intentional tampering. Consequently, 

a similar analytical approach is taken for both.

There are several different ways or points in the supply chain at which a product 

may be adulterated, either unintentionally or intentionally:

6.1.1. During the manufacturing process

Instances initially thought to be tampering (because only a few units were 

affected) may later be linked to manufacturing problems after an 

investigation. This could include the contamination of a product with 

cleaning solution due to incomplete rinsing of processing equipment, or the 
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Title: 

ORA Lab Manual Vol. IV Section 14 - Consumer Complaints and Product 

Tampering (IV-14)

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presence of foreign objects such as metal fragments or machine parts due 

to equipment failure. Other problems may result from an incorrectly labeled 

or contaminated component used as an ingredient, or an incorrect product 

inside a container due to labeling mix-ups.

One example of a contaminated ingredient occurred in 1996. Drums 

labeled “USP Glycerine” were used in Haiti to produce children’s cough 

syrup. The glycerin was contaminated with 24% diethylene glycol, the 

main component of antifreeze, and caused the deaths of many children.

6.1.2. During distribution or at the retail location

The appearance of adulteration may result from improper storage 

conditions. If the product is intentionally adulterated, it may often be 

disguised so that the product appears “normal”. One of the most infamous 

examples is the 1982 case in which seven people in the Chicago area died 

after taking Tylenol capsules containing cyanide.

6.1.3. After the product is in the possession of the consumer

“Copycat” or false report cases may follow a highly publicized tampering. 

Product substitution is another type of tampering in which the consumer will 

empty the contents of the container, refill it with another substance, and 

return it to the retail store for a refund. Intentional poisoning of a person is 

another example. There can also be instances in which the consumer 

unknowingly contaminates the product himself, when the suspicious tablet 

found in a beverage is determined to be the same as the tablet the 

consumer was attempting to swallow.

The objectives of the investigation and analysis of complaint/tampering 

samples are to determine if the product is adulterated or substandard, 

determine the nature/identity and extent of the adulteration, and evaluate, if 

possible, which adulteration scenario is most likely and/or which can be 

ruled out. This assessment represents an ideal situation. In reality, the 

ability to resolve these issues with absolute certainty is often limited by the 

details of the complaint and the history and condition of the sample 

received by the laboratory.

6.1.4. Prior to starting an analysis

Review the available background information. Read the complaint form, 

collection report and affidavits and discuss the sample with the 

investigators. It is important to differentiate facts from allegations and 

theories. Facts include when a product was manufactured (as determined 

from code/lot number/expiration date) and when the complaint was made. 
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Tampering (IV-14)

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Allegations, e.g., the product tasted bitter or made the consumer nauseous, 

may or may not be accurate or true. Information obtained from the 

manufacturer on previously encountered packaging or product defects, or 

additional complaints is beneficial. Medical records can provide important 

clues in cases involving death, serious illness, and injuries. For example, 

medical tests may indicate that the consumer ingested a reversible 

cholinesterase inhibitor in which case it would be sensible to screen the 

sample for carbamate pesticides. Some guidance in this area can be 

obtained from toxicology textbooks or through consultation with local Drug 

and Poison Information Centers, toxicology laboratories or appropriate FDA 

Center subject matter experts. 

Whenever possible, obtain a control sample of the product for comparison 

to the suspect sample. For the most meaningful comparison, the control 

should closely match the suspect with respect to product, packaging, 

manufacturing location, and time. There should also be some assurance 

between the product and the packaging manufacturer, that the control is 

intact and free of contamination. In the absence of a well-matched control, 

one alternative is to use a comparison sample with nominally the same 

suspect sample matrix, but is manufactured by a different manufacturer, as 

a comparison control for chemical tests.

General guidance on the examination of materials for forensic purposes 

can be found in various monographs. It is also important to plan an 

analytical approach while considering that many times the amount of 

sample available for analysis is limited. The choice of destructive versus 

non-destructive techniques and the possibility of using one sample 

preparation for more than one analysis are options that should be 

considered.

The FDA Forensic Chemistry Center (FCC) located in Cincinnati, Ohio, has 

extensive experience in dealing with product tampering samples. Contact 

them whenever there are questions about an analytical approach, methods 

to use, or whether the FCC has prior experience with the type of 

complaint/tampering situation under investigation.

Forensic Chemistry Center (FCC)

Phone 513/679-2700 

FAX: 513/679-2761

6.2. Safety

Treat complaint/tampering samples with extra precaution because they may 

present unidentified/unforeseen hazards. Background information from the 
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complaint form and collection report may help the analyst anticipate hazards 

including biological (e.g., bloodborne pathogens like HIV), chemical (e.g., cyanide, 

fentanyl or toxic or carcinogenic compounds) and/or physical (e.g., needles, 

syringes, razor blades, etc.). Choose the laboratory location or analysis site for the 

suspect sample with care. Use biological safety cabinets, chemical fume hoods or 

sealed glove boxes as needed. Personal protection should include safety glasses, 

gloves, respiratory protection if needed, and protective clothing ranging from 

laboratory coats to safety suits and face shields. Before starting the initial 

examination all containment, clean-up and disposal supplies should be ready and 

on-hand. Special care should be exercised if any odors, leaks or discoloration 

associated with the sample container are noted. Be aware that some adulterants 

may react with the product containers and alter the sample if the sample is not 

transferred to a resistant container for storage. Suspect samples should only be 

examined/analyzed when other trained laboratory personnel can monitor the 

analyst in the event of an accident.

Although detectable odors may be unavoidable, the sample should be moved 

immediately to a chemical fume hood. Organoleptic testing, i.e., purposefully 

smelling the sample, is not recommended. Particulates that are present may also 

be inhaled, and compounds such as fentanyl and carfentanil are highly toxic in 

very low quantities. Do not, under any circumstances, taste the sample!

6.3. Sample Handling

It is important that judicious attention to detail occur in sample handling to maintain 

sample integrity and avoid overlooking or damaging evidence. Carefully document 

chain of custody and storage conditions. Preserve as much suspect material and 

forensic evidence as possible. Unless otherwise notified by submitting officials, 

protect fingerprint evidence by wearing vinyl, nitrile or latex gloves and using tongs 

or forceps to handle the sample on edges, seams, and corners (i.e., away from 

potential fingerprint regions). As much of the packaging and product as possible 

should be left undisturbed. It is imperative to document each step of the 

examination and every observation in writing or through photographic 

documentation.

Perform a thorough physical examination (Section 6.4) before proceeding to 

chemical analysis (Section 6.5). There may be a point at which it is best to stop the 

examination and refer the sample to another law enforcement agency or laboratory 

with more familiarity with certain forensic techniques, such as fingerprinting, 

analyzing adhesives, or identifying particles in situ. Any suspicious findings should 

be discussed with laboratory management immediately to determine a best course 

of action.
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6.4. Initial Observations

6.4.1. Comparisons between suspect and control samples 

It is often advantageous to examine the suspect sample in parallel with the 

control or comparison sample but is imperative that the sample be 

separated physically from the control, and care taken to minimize the risk of 

cross-contamination (for example by changing gloves between handling of 

items). Control samples should be processed using the same procedures 

as the suspect sample, and any discrepancies should be noted and 

documented. Record the manufacturing code and any codes printed on the 

labels, containers, and closure systems for both the suspect and the 

control.

Obtain a gross sample weight before proceeding with the analysis. The 

sample may be weighed in the original container and the container weight 

subtracted later if needed. The weight/volume may be needed for 

comparison to control samples, to determine the amount of product 

remaining, or to substantiate the amount consumed, the amount of 

adulterant added, etc.

6.4.2. Examination of packaging

Intact suspect sample cartons, boxes, bags, plastic film covers, etc. should 

be opened in a region that is not suspected as being the site of entry. Avoid 

opening along manufacturer seams or seals. Record and document any 

observations and sample treatment used in the examination of suspect 

samples.

The observation process should proceed in a logical manner working from 

the external surfaces to the inside, only opening the product container after 

all external examinations are completed. Written and photographic 

documentation of the suspect product should be obtained for the product 

packaging (box, carton, package, wrapper, bottle, etc.) and any other

sample-related items. Include a measurement scale (preferably metric 

units) in every photographic image at the same focus level as the sample. 

Examination may include visual observations using the unaided eye and 

closer examination using a hand lens, stereoscopic light microscope (SLM) 

and/or compound light microscope. The suspect sample should be 

examined using short-wavelength and long-wavelength ultraviolet light 

and/or a variable wavelength light source (e.g., Crimescope®, Video 

Spectral Comparator® or CDx device) and all findings documented.

Check for any surface anomalies such as punctures, tears, cuts, holes, slits 

and abrasions. Thoroughly examine all container closure seams, folds, 
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crimps, caps, tops, lids and liners, and note any irregularities. Document 

the condition of tamper-evident closures such as safety seals, tear-away 

ring bottle caps and vial flip-off caps. Look for chips or cracks in glass and 

damaged threads on screw caps. Examine packaging joints and seams 

closely for excess glue, glue smears, glue tear pattern and multiple glue 

types. Any extraneous surface marks (paint, ink, pencil, marker, scratches) 

should be documented. Note any discoloration, dust, powders, crystals, 

debris, or leakage. Evaluate the product for color, clarity, fluidity, layering, 

clumping, marks, chips, stains, orientation (e.g., capsule parts askew, units 

out of place in a sectioned package) and foreign objects.

6.4.3. Documentation of anomalies

The location of any unusual findings or foreign objects should be 

diagrammed or photo documented. Removal of any portion of the suspect 

sample should take place only after the initial observations and photodocumentation have been completed. Once photographed in situ, the 

object or questionable portion of the sample may be isolated for additional 

characterization and/or chemical analysis.

6.4.4. Additional considerations

When sampling any portion of the suspect sample for analysis, use as little 

as possible to conserve the sample for confirmatory analysis or further 

testing that may need to be performed by other specially equipped 

laboratories such as the Forensic Chemistry Center. Ensure that the 

condition of the sample has been well documented before sampling. 

Ordinarily, the sample should not be homogenized. For example, if the 

sample consists of a liquid in a bottle with some particulate on the bottom, 

remove a portion of the liquid and remove a portion of the particulate and 

analyze them separately.

If portions of the sample are removed prior to homogenizing, quantitative 

work will not be able to be performed.

If an odor is detected unavoidably, move the sample to a chemical fume 

hood immediately to prevent exposure to toxic vapors or gases (see 

Section 6.2). Make a note of the odor because it may suggest the 

presence of bleach, ammonia, amines or a petroleum product such as 

gasoline, thinner or a vehicle for an emulsifiable concentrate of a pesticide.
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Title: 

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Tampering (IV-14)

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6.5. Analytical and Instrumental Methods

6.5.1. Preliminary considerations

Experience with tampering cases has shown that the contaminant is 

typically present in relatively large amounts. However, when the 

examination reveals no remarkable differences, it is important to be aware 

of the adequacy of the screening procedure. The United Nations Globally 

Harmonized System of Classification and Labeling of Chemicals (revision 

4, 2007) provides a convenient classification of relative toxicity based on 

the probable oral lethal dose (LD50). However, significant clinical illness can 

be expected at doses well below the probable lethal dose. To minimize the 

risk of sensitivity-based false negative screening results, a Level of 

Concern Concentration equivalent to 3% of the probable oral lethal dose, 

can be calculated by the following equation:

Level of Concern (mg/kg) = 0.03 X oral LD50 (mg/kg body weight) X body 

weight (kg) X portion size-1 (kg or L)

Using a body weight of 70 kg (average adult) with a portion size of 355 mL 

(e.g., a 12 oz. beverage), the table below can serve as a guide to the 

required sensitivity of the analytical methods. This equation can be 

adjusted in keeping with additional information, for example, a good 

estimate of the amount of product ingested by a child of known body weight 

and an identified poison with a known lethal dose. 

Toxic Classification of Chemicals and Desirable Method Sensitivity

Description GHS Range for Probable Level of 

Concern

Toxicity Oral Lethal Dose For the Lower 

Limit

Class (mg / kg. body weight) (mg/L)

Practically 

Non-toxic

>5,000

Slightly Toxic 5 2,000 to 5,000 12,000
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It is also important to bear in mind that LD50 values are primarily set based on 

assumptions of acute exposure. Substances with relatively low acute toxicity 

may present a significantly higher risk under chronic exposure. 

Where available, Minimal Risk Levels (MRLs) set by the Agency for Toxic 

Substances and Disease Registry, Lowest Observed Adverse Effect Levels 

(LOAELs), No Observed Adverse Effect Levels (NOAELs), or chronic 

Reference Dose (RfD) may provide reasonable estimates of the level of 

concern which should be achieved:

Level of Concern (mg/kg/day) = MRL (mg/kg body weight/day) X body weight 

(kg) X portion size-1 (kg)

6.5.2. Chemical analyses

6.5.2.1. Methodology

Complaint/tampering samples can require numerous analytical 

approaches, including physical examinations, visual analyses, chemical 

spot tests, micro/molecular biological analyses, and instrumental 

techniques such as microscopy, chromatography, mass spectrometry and 

spectroscopy. Published methods such as those in the Pesticide Analytical 

Manual (PAM), Microbiological Methods & Bacteriological Analytical 

Manual (BAM), Elemental Analysis Manual for Food and Related Products 

(EAM), United States Pharmacopoeia (USP) and the Official Methods of 

Analysis of AOAC International are good resources. Frequently, however, 

the analytes of interest are unknown, and these established methods may 

not be applicable to, or may require modification for, the sample matrix 

received. Sources for alternate analytical methods include technical 

organizations (ASTM International, ISO, etc.), scientific journals, Laboratory 

Information Bulletins (LIBs), internet resources, Food Emergency 

Moderately 

Toxic

4 300 to 2,000 1,800

Very Toxic 3 50 to 300 300

Extremely 

Toxic

2 5 to 50 30

Super Toxic 1 <5 0.601

1Calculated using a LD50 of 0.1 mg/kg. 
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Response Network (FERN), and technical procedures. When nonstandard matrices or sample requests are received, the analyst must verify 

the accuracy and reliability of the chosen method for the intended purpose. 

Method validation studies will demonstrate the method can be used to 

support the conclusions of the analysis and the situation to which it was 

applied.

6.5.2.2. Analytical approach

Depending on the nature of the suspected contaminant, the sample-related 

information supplied by the submitter, or the information needed to address 

public health aspects, it must be determined whether the sample is to be 

analyzed by single or multiple disciplines. If multiple analytical disciplines 

are required, it will be necessary to determine whether the analyses should 

run consecutively or concurrently. Consecutive analyses will require that 

one type of analysis be completed before another may be initiated. For 

example, a suspect vial of liquid may require consecutive analyses if 

determination of evidence of tampering and screens of the liquid were 

requested, or if the product must be sampled for microbiological 

contamination before aliquots are removed for chemical analyses. 

Concurrent analyses of the same suspect vial might be appropriate if the 

analyses to be performed do not depend on completing one before 

initiating another, such as examination of an opened carton and 

identification of the liquid contents.

6.5.2.3. Sampling considerations

Sample preparation should be minimized to speed the progress of analyses 

and retain information. Non-destructive techniques may be preferred 

initially, particularly if the amount of suspect sample is limited. Whenever 

possible, direct analysis is preferred to extraction/clean-up. Good judgment 

on the part of the analyst(s) should be exercised when deciding which 

methodologies will be used and the order in which they will be performed.

6.5.2.4. Initial characterizations

If moderate shaking of the sample (see Section 6.4 before shaking) 

produces a persistent foam, this may indicate the presence of a surfactant 

which might be associated with a cleaning product. This form of tampering 

is relatively common and there are a variety of tests to determine which 

class of surfactant is present. If the formation of foam is suppressed when 

the sample is acidified, this may indicate the presence of a soap. If, on the 

other hand, foaming is relatively unaffected by pH, then the presence of a 

detergent is likely. Additional characterization utilizing color tests can 
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distinguish among nonionic, anionic or cationic surfactants. Further 

analysis, if necessary, can proceed after consulting the chemical literature.

Another chemical test is the measurement of pH. A significant difference in 

sample pH relative to a control sample indicates a change in the sample 

which should be explored. If the pH is less than 2 or greater than 10, then 

the presence of a corrosive acid or base is likely. Further investigation 

might include examination by ion chromatography (IC) for anions such as 

chloride or nitrate which would correspond to the acids HCl or HNO3, 

respectively, or inductively coupled plasma atomic emission spectroscopy 

(ICP-AES) or mass spectroscopy (ICP-MS) for metals or cations to indicate 

the presence of a metalloid and/or complex anion (such as PO43-). IC can 

also be used to detect some organic acids and cations including 

ammonium, and gas chromatography-mass spectrometry (GC-MS) can be 

used to detect organic acids or bases.

Exposing the sample to ultraviolet light may indicate that a component of 

the contaminant is a fluorescent material. Identification of the fluorescent 

compounds may help focus the analytical approach. For example, dyes 

which are associated with antifreeze may suggest the sample should be 

analyzed using GC-MS for the presence of ethylene glycol or diethylene 

glycol.

Another simple chemical test might include a cyanide screen using 

Cyantesmo test paper. Positive results for the presence of cyanide would 

require confirmatory analysis, for example, using ultraviolet-visible 

spectroscopy.

Spot tests for the presence of oxidizing agents using diphenylamine in 

sulfuric acid or Starch/Iodide paper can provide useful information.

6.5.3. Instrumental methods and techniques

The following sections contain brief overviews of the use of instrumental 

methods to compare the suspect sample and the control sample. It is 

recognized that not all the instrumentation that will be discussed is found in 

every laboratory. A basic understanding of each technique on the part of 

the analyst is assumed.

A. Particle analyses using stereoscopic light microscopy (SLM), 

polarized light microscopy (PLM), scanning electron microscopy with 

energy dispersive x-ray spectroscopy (SEM/EDS), Fourier-transform 

infrared (FT-IR) spectroscopy or Raman spectroscopy. 

B. Vibrational spectroscopic techniques (FT-IR and Raman)
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C. Gas chromatography-mass spectrometry (GC-MS) with headspace 

sampling for volatile materials

D. GC-MS for volatile and semi-volatile materials

E. Ion chromatography (IC) or IC-MS for anions and cations 

F. Liquid chromatography-mass spectrometry (LC-MS) with 

DART/ESI/APCI/other ion sources 

G. Inductively-coupled plasma-atomic emission spectroscopy (ICPAES) or –mass spectrometry (ICP-MS) for minerals, metals and 

metalloids

It is also necessary to be aware that detected compounds may be 

indicative of other contaminants that may not be found using the 

instrumental methods described above. For example, the detection of 

ricinine using LC-MS, or ricinoleic acid using GC-MS, may indicate the 

presence of ricin. The determination of this protein requires specific tests 

such as enzyme-linked immunosorbent assay (ELISA) or protein/peptide 

LC-MS.

6.5.3.1. Stereoscopic Light Microscopy (SLM), Polarized Light

Microscopy (PLM) and Scanning Electron Microscopy with Energy 

Dispersive X-ray Spectroscopy (SEM/EDS)

In general, SLM and PLM are used to examine solids, semi-solids, 

powders, liquids, and packaging materials visually. Samples can be 

examined independently or compared to controls and standards. 

Stereoscopic and polarizing light microscopes can be equipped with 

cameras to document observations with digital images.

Stereoscopic light microscopes are designed to examine large areas of a 

sample using low magnifications and various lighting conditions. SLM is 

used typically to determine the heterogeneity or homogeneity of a sample, 

examine packaging for evidence of tampering (e.g., additional adhesives or 

tears) and isolate particles and materials physically from samples for 

further analysis. Individual or small groups of particles can be examined at 

higher magnifications using PLM, to determine physical characteristics 

(e.g., particle/material morphology, surface texture) and other optical 

properties which can be used to identify a sample when compared to 

known standards or literature references.

SEM is used to visualize samples at even higher magnifications (10X500,000X). An SEM image can provide morphological information about a 
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sample. An EDS attachment to an SEM can be used to obtain qualitative 

elemental information about the sample.

If the sample is limited in size or volume, SLM, PLM, and SEM/EDS are 

useful techniques for initial characterizations because they are often nondestructive to the sample and can be helpful in preparing the sample for 

further analyses.

6.5.3.2. Vibrational Spectroscopic Techniques (FT-IR and Raman

Spectroscopy)

The selection of an FT-IR or Raman spectroscopy is generally dependent 

on the physical form of the sample, the quantity or size of sample, and 

sample information available. These techniques can be used to analyze 

single crystals, amorphous solids, conglomerate/ aggregate particles, films, 

fibers, semi-solids, single- and multi-component solids, liquids and gases. 

In general, the instrument’s lack of sensitivity limits the usefulness for the 

analysis of solutions except in instances of gross contamination. However, 

FT-IR and Raman may be utilized in conjunction with a microscope for the 

examination of individual particles or for characterization of substances 

isolated by physical means. FT-IR and Raman can determine the 

composition of samples by comparing spectral features with libraries of IR 

or Raman spectra from reference compounds. FT-IR and Raman can also 

provide indications of the presence of functional groups to supplement 

other analytical information.

In certain instances, some sample preparation (e.g., liquid extraction, 

filtration) may be necessary to isolate the analyte(s) of interest from the 

sample matrix. Therefore, FT-IR or Raman spectral information about the 

sample matrix, as well as literature information about the specific 

analyte(s), should be used to determine the optimum sample preparation 

conditions.

6.5.3.3. Headspace Sampling combined with Gas ChromatographyMass Spectrometry (GC-MS) 

The technique is used for the detection and characterization of volatile 

materials (boiling points approximately below 200°C). It is very useful for 

detecting solvents (e.g., alcohols, chlorinated hydrocarbons, other organic 

solvents), fragrances associated with cleaning products which frequently 

appear as contaminants, and petroleum products. Petroleum products may 

occur as contaminants in their own right or may be associated with 

pesticides in emulsifiable concentrates.
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This technique can also be used to screen for toxic anions, such as azide, 

cyanide, or fluoroacetate by forming their ethyl derivatives prior to analysis.

Mass spectra which are associated with observed differences between the 

suspect sample and control sample are compared to reference spectra to 

obtain tentative identification. This identification may be subsequently 

confirmed through the analysis of standards concurrently with the sample. 

6.5.3.4. Gas Chromatography-Mass Spectrometry (GC-MS) 

This technique is applicable to a variety of matrices being screened for 

evidence of tampering or adulteration. Direct injection of the sample or an 

extract/solution of the sample in methanol or acetonitrile is the first choice, 

with the understanding that other volatile solvents could be utilized as 

needed. The range of applicability can be extended to functionally nonvolatile materials by silylating the extracts to form trimethylsilyl (TMS) 

derivatives. Silyl derivatives are formed by replacement of active hydrogens 

from acids, alcohols, thiols, amines, amides, and enolizable ketones and 

aldehydes with the TMS group. Derivatization is typically performed after 

solvent exchange into pyridine by the addition of N, O-bis-

(trimethylsilyl)trifluoroacetamide (BSTFA) which contains 1% 

trimethylchlorosilane with incubation at 70°C for 15-30 min and repeating 

the analysis. Other derivatization reagents (e.g., N-methylbis(trifluoroacetamide), MBTFA) may be used when selective replacement 

of active hydrogens is desired.

In addition, an acid/base extraction should be considered for samples with 

high fat, sugar, and/or protein content. The sample solution should be 

between pH 5 and 9 to minimize column damage. Minimizing the amount 

of water in the sample/extract solution will limit the creation of active sites in 

the injection port liner, which may prevent loss in sensitivity of an 

analyte. If the nature of the sample precludes this or if some preconcentration is needed, then the sample may be extracted with acidified 

aqueous acetonitrile (pH = 3) and the acetonitrile subsequently isolated by 

“salting out” for analysis by GC-MS. Isolation of a basic extract is obtained 

using the same procedure with basic aqueous acetonitrile (pH = 10). 

Additional sensitivity can be obtained by evaporative concentration of the 

acetonitrile extracts.

The suspect and control samples are compared to expose differences. The 

mass spectra associated with these differences are compared to reference 

spectra to provide tentative identification. This identification may be 

subsequently confirmed through the analysis of standards concurrently with 

the sample. Occasionally, available mass spectral libraries do not contain 
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spectra of the compound(s) observed, and tentative identification proceeds 

from mass spectral interpretation.

6.5.3.5. Ion Chromatography (IC)

Ion chromatography can be used to detect common anions such as 

chloride, bromide, nitrate, and phosphate, as well as more toxic anions 

such as fluoride, fluoracetate, azide and nitrate.

It is worth noting that a reactive contaminant, such as bleach, may produce 

additional peaks in a suspect sample that can only be properly 

characterized through experiments that monitor the impact of the addition 

of the nominal contaminant to a control sample through time. The probable 

presence of bleach in the suspect sample at some point in time is implied 

by elevations in the chloride and chlorate levels along with high pH and the 

presence of excess sodium.

Ion chromatography is also useful for identifying sugars, sugar alcohols, 

and amino acids. The wrong label on an infant formula which contains

lactose might put a child who is lactose intolerant at risk. For 

pharmaceutical formulations in which lactose, mannitol, or glycine is used, 

IC may be a useful tool to verify the authenticity of a manufacturer based 

on the profile of components detected. Lower levels of components in a 

formulation may be an indication that the product has been diluted or 

counterfeited.

6.5.3.6. High Performance Liquid Chromatography-Mass Spectrometry 

(HPLC-MS)

HPLC- or ultra-HPLC (UHPLC)-MS offers versatility, sensitivity, selectivity, 

mass accuracy, and rapid screening of samples for drugs, poisons, toxins, 

peptides, and proteins. It is versatile because it offers many different 

ionization sources (e.g., ESI (electrospray ionization), APCI (atmospheric 

pressure chemical ionization), DART (direct analysis in real time)) and 

positive or negative ionization modes.

HPLC-MS is the method of choice for detecting non-volatile or thermally 

unstable compounds (e.g., cardiac glycosides, alkaloids, proteins) which 

are not amenable to determination using GC-MS. HPLC-MS is especially 

useful as a screening tool if a comparison sample is available. Due to the 

ever-growing compilation of reference spectra (MS/MS libraries), mass 

spectra which are associated with observed differences between the 

suspect and control sampled can be compared to obtain tentative 

identification with subsequent verification through the analysis of standards.
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If still needed and available, high-resolution accurate mass (HRAM) can be 

utilized to aid in determination of unknowns by generating potential 

chemical formulae with subsequent verification through the analysis of 

standards.

6.5.3.7. Inductively Coupled Plasma (ICP)-Atomic Emission 

Spectroscopy (AES) or -Mass Spectrometry (MS) 

Methods and procedures outlined in the EAM should be followed in 

principle to the extent they are appropriate. Elevated levels of minerals, 

metals, and metalloids relative to the native levels in comparison samples 

may serve as an indicator of adulteration. In contrast, the concentration of 

minerals, metals or metalloids “missing” relative to the native levels in 

closely matched comparison samples can sometimes be useful in 

estimating the extent to which the adulterant has diluted the original 

sample.

While some minerals, metals and metalloids have significant toxicity, in 

tampering scenarios the adulterant would typically be added as a salt or 

molecular complex which may have significantly different toxicity than the 

elemental or ionic form.

Minimal Risk Levels of Selected Elements and Desirable Method 

Sensitivity

Oral MRL1 Elements

Desirable Method 

Sensitivity2

0.001 – 0.01 

mg/Kg/day

Sb, As, Cd, Cr, Pb, Hg, 

P, Se, Tl, U

0.2 μg/g 

0.01 – 0.1 mg/Kg/day Be, Co, Cu, Au, I, Li, 

Mo, Ni, Pd, Ag, V

2 μg/g

0.1-1 mg/Kg/day Ba, B, Mn, Sn 20 μg/g

≥ 1 mg/Kg/day Al, Sr, Zn 200 μg/g

1Based on highest risk chemical form for which acute (≤ 14 days) or 

intermediate (15-365 days) MRL was established. Elements without 

established MRLs were classified based on published relative Oral PDE 

values.

2 Calculated as MRL • 70 Kg / 0.355 L
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The chemical form of the element defines its toxicity. For example, 

phosphorous as yellow phosphorous (Toxicity Class 1) is a significant 

hazard but phosphorous as phosphate (Toxicity Class 5) is commonly 

encountered in foods. Barium (Toxicity Class 2), when present as the 

insoluble sulfate salt, is not considered harmful. Inorganic arsenic is highly 

toxic (toxicity class 1), but arsenic as arsenobetaine, which is found in 

seafood, is considered non-toxic. Although most forms of silicon are 

innocuous, silicon is significant as an indicator of the possible presence of 

fluorosilicate. Consequently, it may be necessary to couple separation 

techniques with atomic spectroscopy, often called speciation, or to 

compare the total elemental content with results from ion chromatography 

or molecular mass spectrometry to fully evaluate the associated risk.

Additionally, vulnerable populations, may be more sensitive to high levels 

of certain elements or salts. For example, very high levels of sodium 

chloride or iron in infant formula have resulted in significant toxicity.

6.5.4. Suspected biological contamination

If the suspected contamination is unknown or microbiological in nature, the 

way in which the sample is processed and analyzed will depend on 

whether the contamination is deemed routine or high-risk (Biosafety Level 3 

[BSL-3]). Guidance can be found in the BAM and FERN.RES.0001.01.

7. Glossary/Definitions

A. AES – Atomic Emission Spectroscopy

B. AOAC – Association of Official Analytical Chemists

C. APCI – Atmospheric Pressure Chemical Ionization

D. ASTM – American Society for Testing and Materials

E. BAM – Microbiological Methods & Bacteriological Analytical Manual

F. BSL-3 – Biosafety Level 3

G. BSTFA – N,O-bis(trimethylsilyl)trifluoroacetamide

H. CDx – Counterfeit Detection Device, version x

I. DART – Direct Analysis in Real Time

J. EAM – Elemental Analytical Manual for Food and Related Products

K. ELISA – Enzyme-linked Immunosorbent Assay
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L. ESI – Electrospray Ionization

M. FCC – Forensic Chemistry Center

N. FDA – United States Food and Drug Administration

O. FERN – Food Emergency Response Network

P. FT-IR – Fourier-transform Infrared Spectroscopy

Q. GC – Gas Chromatography

R. HPLC – High-Performance Liquid Chromatography

S. HRAM – High-Resolution Accurate Mass

T. IC – Ion Chromatography

U. ICP – Inductively-Coupled Plasma

V. ISO – International Organization for Standardization

W. LIB – Laboratory Information Bulletin

X. MBTFA – N-methyl-bis(trifluoroacetamide)

Y. MS – Mass Spectrometry

Z. OCI – Office of Criminal Investigations

AA. PAM – Pesticide Analytical Manual

BB. PLM – Polarized Light Microscope/Microscopy

CC. SEM/EDS – Scanning Electron Microscopy with Energy Dispersive 

 X-ray Spectroscopy

DD. SLM – Stereoscopic Light Microscope/Microscopy

EE. TMS – Trimethylsilyl

FF. UHPLC – Ultra High-Performance Liquid Chromatography

GG. USP – United States Pharmacopeia

8. Records

A. Analytical Worksheets

B. Sample Summary Reports

9. Supporting Documents
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A. U.S. Food & Drug Administration, Pesticide Analytical Manual (PAM) | 

FDA

B. U.S. Food & Drug Administration, Microbiological and Biological 

Methods Resources 

C. U.S. Food & Drug Administration, Elemental Analysis Manual (EAM) 

for Food and Related Products | FDA 

D. Official Methods of Analysis of AOAC International. Gaithersburg, MD: 

Association of Official Analytical Chemistry International. Available at 

FDA Library Resources 

E. Laboratory Information Bulletins (LIBs) Office of Regulatory Science. 

F. U.S. Food & Drug Administration, Office of Regulatory Affairs 

Investigations Operations Manual | FDA Chapter 8

Document History

Revision

#

Status*

(D, I, R) Date Author Name and Title Approving Official Name and Title

1.2 R 09/01/2005 LMEB LMEB

1.3 R 02/02/2010 LMEB LMEB

1.4 R 02/06/2012 LMEB LMEB

1.5 R 02/14/2013 LMEB LMEB

02 R 05/05/2020 LMEB LMEB

03 R REFER TO 

QMIS OMPTSLO/MPTSS/FCC LMEB

* - D: Draft, I: Initial, R: Revision
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Change History

Revision 

# Change

1.2

• Table of Contents – Section 14.11 added.

• Section 14.8 II. – revised fourth paragraph; Section 14.8 III. removed headers A. & 

B and 1-7 now A-G; revised Section 14.8 III. D. & E.

• References formatted with numbers 22. – 35.

1.3

14.5 – paragraphs 1, 5, and 6 revised

14.8 I. – deleted last sentence

14.8 II. – revised

14.8 III. – paragraphs 1, 2, and 3 revised

14.9 – revised

14.10 - Changed “Division of Emergency Operations” to “Office of Crisis 

Management”

1.4

14.3 – deleted “FATA” in second paragraph

14.4 – updated contact information with weblink

14.7 – added “in order” and updated Section 14.4 to 14.5, Safety in third paragraph

14.8 II – deleted supplier name in fourth and fifth paragraph

14.8 III – revised first sentence in first paragraph

14.8 III A. – added (GC_MS) in heading; defined LODs

14.8 III B. – added (GC-MS) in heading; defined FID

14.8 III C. – added (IC) in heading; defined ICP

14.8 III E. – added (ICP-AES) in heading; corrected spelling of Thallium in Table

14.8 III F. – added (FT-IR) in heading

14.8 III G. – added (UV-VIS) in heading

14.9 – deleted second sentence in second paragraph

1.5

Header – Division of Field Science changed to Office of Regulatory Science

14.11 – Division names removed; ORO change to OO; Division of Field Science 

changed to Office of Regulatory Science
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Revision 

# Change

02

Reformatted SOP to follow current template

“14.1 Objective” renamed “1. Purpose”

“14.2 Introduction” renamed “2. Scope” and updated content

“14.3 FDA Laws and Regulations” renamed “4. Background” and updated content

“14.11 References” renamed “5. References” and updated content

“14.4 Preliminary Information and the Analytical Strategy” moved to section 6.1 under 

“6. Procedure” and updated content

“14.5 Safety” moved to section 6.2 under “6. Procedure” and updated content

“14.6 Sample Handling” moved to section 6.3 under “6. Procedure” and updated 

content

“14.7 Initial Observations” moved to section 6.4 under “6. Procedure” and updated 

content. Subheadings created for: Comparisons between suspect and control 

samples; Examination of packaging; Documentation of anomalies; Additional 

considerations

“14.8 Analytical and Instrumental Methods” moved to section 6.5 under “6. 

Procedure” and updated content

Subheadings under previous 14.8 “I. Simplify the problem if possible”, “II. When there 

isn't much to go on”, and “III. Application of instrumental techniques” updated to 

“6.5.1 Preliminary considerations” and “6.5.2 Chemical analyses” under “6.5 

Analytical and Instrumental Methods.” Updated content.

Under 6.5.2, added subheadings “6.5.2.1 Methodology”, “6.5.2.2 analytical 

approach”, “6.5.2.3 Sampling considerations”, “6.5.2.4 Initial characterizations”, 

“6.5.2.5 Instrumental methods and techniques”. Under 6.5.2.5 created “6.5.2.5.1 

Stereoscopic Light Microscopy (SLM), Polarized Light Microscopy (PLM) and 

Scanning Electron Microscopy with Energy Dispersive X-ray Spectroscopy 

(SEM/EDS)”, “6.5.2.5.2 Vibrational Spectroscopic Techniques (FT-IR and Raman 

Spectroscopy)”, “6.5.2.5.3 Headspace Sampling combined with Gas 

Chromatography-Mass Spectrometry (GC-MS)”, “6.5.2.5.4 Gas ChromatographyMass Spectrometry (GC-MS”, “6.5.2.5.5 Ion Chromatography”, 6.5.2.5.6 High 

Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS)”, “6.5.2.5.7 

Inductively-Coupled Plasma (ICP)-Atomic Emission Spectroscopy (AES) or -Mass 

Spectrometry (MS)”. Deleted “G. UV-Visible Spectrophotometry (UV-VIS).” Updated 

content in all sections.

Added “6.5.3 Suspected biological contamination” under “6.5 Analytical and 

Instrumental Methods.”

Deleted “14.9 Analytical Documentation” and “14.10 Reporting”.

Added “Analytical Worksheets” and “Sample Summary Reports” to “8. Records”

03 Clarified control instructions. Removed use of cloth gloves; added nitrile section. Added information 

on United Nations Globally Harmonized System of Classification and Updated information for Level of 

Concern. Added use of Raman Spectroscopy to Instrumental methods and techniques. Added Minimal 

Risk Levels of Selected Elements table. 
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