misbranding vs adulteration

Question 1

General: Adulteration

F

Answer 1

FILTHY

FAKE

Ingredient in product is a substitute for another ingredient

Question 2

General: Adulteration

I

Answer 2

FILTHY

IMPROPER

Proper is not manufactured according to cGMP

Question 3

General: Adulteration

L

Answer 3

FILTHY

LOWER

Product’s quality, purity, or strength is lower than standard

Question 4

General: Adulteration

T

Answer 4

FILTHY

TARNISH

Container could leech dangerous substance into drug

Question 5

General: Adulteration

H

Answer 5

FILTHY

HUE

Made with unapproved color additives or ingredients

Question 6

General: Adulteration

Y

Answer 6

FILTHY

YUCKY

Made in unsanitary conditions or is dirty or decomposed

Question 7

General: Misbranding

D

Answer 7

DESIGN

DECEIPT

Label is misleading, false, or makes a false health claim

Question 8

General: Misbranding

E

Answer 8

DESIGN

EXCLUDE

Missing required parts of label like quantity or dose

Question 9

General: Misbranding

S

Answer 9

DESIGN

SECRET

Names of active ingredients or name of manufacturer absent

Question 10

General: Misbranding

I

Answer 10

DESIGN

IMPROPER

Label is not filled out following USP/NF standard

Question 11

General: Misbranding

G

Answer 11

DESIGN

GUISE

The product sells a drug under the name of another drug

Question 12

General: Misbranding

N

Answer 12

DESIGN

No Rx

A legend drug is sold without a legal prescription

Question 13

Adulteration is a problem of

Answer 13

composition

Question 14

Misbranding is a problem of

Answer 14

labeling

Question 15

Adulteration in the law text

Answer 15

“A drug or device shall be deemed to be adulterated—
(a)(1) If it consists in whole or in part of any filthy, putrid, or decomposed substance; or (2)(A) if it has been
prepared, packed, or held under insanitary conditions whereby it may have been contaminated with filth, or
whereby it may have been rendered injurious to health; or (B) if it is a drug and the methods used in, or the
facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not
operated or administered in conformity with current good manufacturing practice… or (3) if its container is
composed, in whole or in part, of any poisonous or deleterious substance which may render the contents
injurious to health; or (4) if (A) it bears or contains, for purposes of coloring only, a color additive which is
unsafe… or it is a color additive the intended use of which in or on drugs or devices is for purposes of coloring
only and is unsafe.

(b) If it purports to be or is represented as a drug the name of which is recognized in an official compendium,
and its strength differs from, or its quality or purity falls below, the standard set forth in such compendium…
No drug defined in an official compendium shall be deemed to be adulterated under this paragraph because it
differs from the standard of strength, quality, or purity therefor set forth in such compendium, if its difference
in strength, quality, or purity from such standard is plainly stated on its label…

(c) If it is not subject to the provisions of paragraph (b) of this section and its strength differs from, or its purity
or quality falls below, that which it purports or is represented to possess.

(d) If it is a drug and any substance has been (1) mixed or packed therewith so as to reduce its quality or
strength or (2) substituted wholly or in part therefore
…
(j) If it is a drug and it has been manufactured, processed, packed, or held in any factory, warehouse, or
establishment and the owner, operator, or agent of such factory, warehouse, or establishment delays, denies,
or limits an inspection, or refuses to permit entry or inspection.”

Question 16

Adulteration: Filthy, putrid, or decomposed

Answer 16

this can be summarized as expired or contaminated
substances. It may include, but isn’t limited to, expired substances within a product, the
product itself is expired, degraded materials, precipitation in solution, unclean containers,
contaminants in or on a product, and dropping tablets on the floor.

Question 17

Adulteration: Prepared, packed, or held under unsanitary conditions

Answer 17

this can be summarized as
manufacturing and storage conditions. This may include situations where a product was held at inappropriate temperatures for an inappropriate period, was made in an
inappropriate environment, was repacked under inappropriate conditions, wasn’t tested
appropriately, wasn’t prepared following current good manufacturing practices (cGMP),
and many others. You should take away from this section, and it may be the most
important thing to take away, that a drug is considered adulterated if it’s in conditions
where it may have been contaminated. That means there does not need to be something
wrong with a drug for it to be adulterated, only that there could be something wrong with
it, and we err on the side of caution.

Question 18

Adulteration: Not manufactured under current good manufacturing practices (CGMP or cGMP)

Answer 18

these
regulations establish minimum requirements for manufacturing, packaging, and holding
products. More detail will be provided in a moment, but all our drug products must be
made, packaged, and stored in places that conform to these necessary regulations.1,2 If
it’s not, the drug is adulterated. The book Bottle of Lies by Katherine Eban provides a
shocking review of what happens when CGMP isn’t followed.

Question 19

Adulteration: Container is composed of a deleterious substance

Answer 19

this can better be stated as the
container is problematic. The assumption is that if the container is made of a deleterious
or dangerous substance, it’ll transfer to the drug, and when ingested, the drug can harm
someone. This may not always be the case, but we assume it’s the case since it’s better
to be safe than sorry.

Question 20

Adulteration: Contains an unsafe coloring agent

Answer 20

this is written to include all unsafe coloring agents
when added to a product. This is a simple section to remember and understand; however,
it’s often confused with the misbranding section on coloring agents. Remember,
adulteration is about a coloring agent being part of the product, while misbranding is
about whether it’s listed on the label.

Question 21

Adulteration: Doesn’t meet official standards or isn’t required to meet official standards

Answer 21

products in
the official compendium have standards for strength, purity, and quality, and how a
company tests for or ensures a drug meets these items. Those standards must be met by
any drug that claims to be the official drug. Note that the purity or quality may be better
than required per this section. There are exceptions, such as if the difference is plainly
stated on the label or the product notes something like “not USP” on the label. If
something isn’t an official drug, the manufacturer must meet the standard for strength,
quality, and purity claimed on the label. These provisions are sometimes confused with
misbranding (and they are that too). But this is really about what’s inside the drug being
a problem. Importantly, this is rarely an issue with a prescription or OTC drug; however,
it may be an issue with specific vitamins, herbal supplements, dietary supplements, and
homeopathic drug products, especially those made by disreputable companies. I say it’s
rarely an issue with prescription and OTC drugs, but that also assumes the manufacturer
is reputable. Again, Bottle of Lies by Katherine Eban sheds light on this area.

Question 22

Adulteration: Mixed to reduce quality or substituted

Answer 22

this is not the issue it used to be in decades past,
but there have been times when this was done to make a product last longer or to use
the active ingredient for something else. This provision is about mixing products
differently from the labeled directions. This doesn’t mean mixing as required by the
labeling but instead purposely mixing a product differently than noted in the prescribing
information or purposely mixing to reduce the quality of a product. Consider that
vancomycin for injection must be reconstituted using sterile water and then further
diluted in an infusion bag before being given to a patient (e.g., 250mg vial reconstituted
with 5ml sterile water and added to a 50ml bag for a final concentration of 5mg/ml for
infusion to a patient). Again, this is an appropriate dilution based on the product’s labeling
and not something covered under this provision. Instead, this provision covers situations
where we use the wrong diluent or other vehicle or purposely mix something to reduce
the quality or strength. For example, if the label required sterile water for mixing, and
ethyl alcohol was used by accident, that would be adulteration. It would also be
adulteration if our final concentration should be 5 mg/ml, and we purposely diluted the
product to 0.5mg/ml to make it go further.

Question 23

Adulteration: Inspection refusals

Answer 23

if you refuse to allow an inspector into any facility where drugs are
handled, everything in the warehouse, factory, or another location is considered
adulterated. This is often why pharmaceutical companies have specific entry points and
require you to use them. They don’t want anyone to open a random door somewhere,
and an inspector happens to be there and requests to come in and be denied. The concern
is denial, delay, or limitation to an inspection happens when a company has something to
hide. Inspectors need to see all areas of a facility, potentially without notifying a company
or without a significant delay, to ensure our products are safe for use.

Question 24

Adulteration Villa Paraphrase

Answer 24

Adulteration can be summarized as issues inside or with the product (e.g., recipe, ingredients,
other components). Recognize that most provisions are aimed at preventing issues with our drug
products. The FDA cannot reasonably check all drug products during or after manufacturing.
However, the FDA can regularly check manufacturing facilities, warehouses, containers, and
manufacturer quality testing logs. So, the FDA focuses on preventing adulteration rather than
waiting and removing adulterated products from the market. As we’ll see with recalls, removing
drugs from the market is a more significant task than one might expect.

While drug manufacturers appear to be the focus of these provisions, pharmacies can and do
often violate the provisions and adulterate a product. Pharmacies may adulterate products in
many ways. Here are a few very brief examples:
- In the middle of the summer, the pharmacy’s air conditioning breaks, and temperatures
in the pharmacy reach 95°F. After reading the prescribing information and calling the
manufacturers, you find this temperature exceeds the max excursion temperature for
most pharmacy products. This drug was held under unsanitary conditions.
- A pharmacy intern counts tablets on a counting tray but does not clean the tray before
counting the next prescription drug. Residue from the previously counted drug gets on
the tablets of the current medication.1,2 This drug could be considered both filthy, putrid,
or decomposed and packed under unsanitary conditions.
- A pharmacist reconstitutes a face gel with ethyl alcohol instead of the purified water
specified in the reconstitution instructions. This drug was mixed inappropriately and
against labeling requirements.
- A pharmacy sells an ibuprofen product OTC that has exceeded the expiration date listed
on the packaging. This drug is filthy, putrid, or decomposed.

Question 25

What is current good manufacturing practice?

Answer 25

Current good manufacturing practices (CGMP or cGMP) are regulations that establish the
minimum requirements for manufacturing drug products for administration to humans or
animals. These regulations assure proper design, monitoring, and control of manufacturing
processes and facilities. These regulations apply to manufacturers of drug products but not
pharmacies unless the pharmacy engages in manufacturing. Manufacturers must be registered
with the FDA and generally undergo an inspection process at least once every two years.
Inspections are often delayed for companies in specific locations due to the difficulty of obtaining
visas and traveling internationally. Current good manufacturing practices help prevent
contamination, mix-ups, deviations from protocol, failures, and overall errors to assure drug
products meet quality standards. cGMP applies to all facilities manufacturing products for use in
the United States. So moving a facility overseas does not exempt you from these requirements.
Failure to follow cGMP leads to a product being per se adulterated. Failure to register an
establishment where US drug products are made causes it to be both adulterated and
misbranded, as we’ll discuss next.

Question 26

Misbranding in the law text

Answer 26

“A drug or device shall be deemed to be misbranded—

(a) If its labeling is false or misleading in any particular…

(b) If in package form unless it bears a label containing (1) the name and place of business of the
manufacturer, packer, or distributor; and (2) an accurate statement of the quantity of the contents in terms of
weight, measure, or numerical count…

(c) If any word, statement, or other information required…on the label or labeling is not prominently placed
thereon with such conspicuousness…and in such terms as to render it likely to be read and understood by the
ordinary individual under customary conditions of purchase and use.
…
(e)(1)(A) If it is a drug, unless its label bears, to the exclusion of any other nonproprietary name (except the
applicable systematic chemical name or the chemical formula) (i) the established name (as defined in
subparagraph (3)) of the drug, if there is such a name; (ii) the established name and quantity or, if determined
to be appropriate by the Secretary, the proportion of each active ingredient, including the quantity, kind, and
proportion of any alcohol, and also including whether active or not the established name and quantity or if
determined to be appropriate by the Secretary, the proportion of any bromides, ether, chloroform,
acetanilide, acetophenetidin, amidopyrine, antipyrine, atropine, hyoscine, hyoscyamine, arsenic, digitalis,
digitalis glucosides, mercury, ouabain, strophanthin, strychnine, thyroid, or any derivative or preparation of
any such substances, contained therein, except that the requirement for stating the quantity of the active
ingredients, other than the quantity of those specifically named in this subclause, shall not apply to
nonprescription drugs not intended for human use; and (iii) the established name of each inactive ingredient
listed in alphabetical order on the outside container of the retail package and, if determined to be appropriate
by the Secretary, on the immediate container, as prescribed in regulation promulgated by the Secretary,
except that nothing in this subclause shall be deemed to require that any trade secret be divulged, and except
that the requirements of this subclause with respect to alphabetical order shall apply only to nonprescription
drugs that are not also cosmetics and that this subclause shall not apply to nonprescription drugs not intended
for human use. (B) For any prescription drug the established name of such drug or ingredient, as the case may
be, on such label (and on any labeling on which a name for such drug or ingredient is used) shall be printed
prominently and in type at least half as large as that used thereon for any proprietary name or designation for
such drug or ingredient…(3) As used in subparagraph (1), the term “established name “… means (A) the
applicable official name… or (B) if there is no such name and such drug…is an article recognized in an official
compendium, then the official title thereof in such compendium, or (C) if neither clause (A) nor clause (B) of
this subparagraph applies, then the common or usual name…

(f) Unless its labeling bears (1) adequate directions for use; and (2) such adequate warnings against use in
those pathological conditions or by children where its use may be dangerous to health, or against unsafe
dosage or methods or duration of administration or application, in such manner and form, as are necessary for
the protection of users, except that where any requirement of clause (1) of this paragraph, as applied to any
drug or device, is not necessary for the protection of the public health, the Secretary shall promulgate
regulations exempting such drug or device from such requirement…

(g) If it purports to be a drug the name of which is recognized in an official compendium, unless it is packaged
and labeled as prescribed therein…

(h) If it has…to be a drug liable to deterioration, unless it is packaged in such form and manner, and its label
bears a statement of such precautions…

(i) (1) If it is a drug and its container is so made, formed, or filled as to be misleading; or (2) if it is an imitation
of another drug; or (3) if it is offered for sale under the name of another drug.

(j) If it is dangerous to health when used in the dosage or manner, or with the frequency or duration
prescribed, recommended, or suggested in the labeling thereof.
…
(m) If it is a color additive the intended use of which is for the purpose of coloring only, unless its packaging
and labeling are in conformity with such packaging and labeling requirements..

(n) …unless the manufacturer, packer, or distributor includes in all advertisements and other descriptive
printed matter…a true statement of (1) the established name…printed prominently and in type at least half as
large as that used for any trade or brand name thereof, (2) the formula showing quantitatively each ingredient
of such drug…and (3) such other information in brief summary relating to side effects, contraindications, and
effectiveness…
…
(p) If it is a drug and its packaging or labeling is in violation of an applicable regulation of the Poison Prevention
Packaging Act of 1970
…
(y)If it is a drug subject to an approved risk evaluation and mitigation strategy…and the responsible
person…fails to comply with a requirement of such strategy…
…
(bb) If the advertising or promotion of a compounded drug is false or misleading in any particular.
(cc) If it is a drug and it fails to bear the product identifier as required…”

Question 27

Misbranding: False or misleading labeling

Answer 27

anything false or misleading on a label and within labeling
will cause a product to be misbranded. Recognize this broad statement covers many
things, including wrong information on a label or within labeling, missing information on
a label or within labeling, or added or unapproved information on a label or in labeling.
Recall the definition of labeling; it includes labels, prescribing information, medication
guides, and advertisements, to name a few. All labeling must be FDA-approved, so it’s
crucial variations don’t occur from approved materials. This is why companies are often
cautious about the statements made in advertisements or other items. Similarly,
statements made by individuals representing the company can also be problematic
because verbal statements that differ from approved information can also be
misbranding. That’s why only specific individuals at a drug company, like medical science
liaisons (MSLs), can talk about off-label uses, and even then, it’s still carefully curated
information.

Question 28

Misbranding: Manufacturer information not on label

Answer 28

labels must list the name and place of the
manufacturer, packer, or distributor. Without this information, a drug is misbranded.

Question 29

Misbranding: Quantity information not on label

Answer 29

labels must provide a statement of the quantity of
the product in the container. This will vary depending on the product but might list the
number of tablets, ounces, weight, or another measure.

Question 30

Misbranding: Information not prominently displayed on labels

Answer 30

this provision is really about preventing
someone from hiding information that may need to be seen on a label. This provision
highlights that things must be able to be read and understood by “the ordinary individual
under customary conditions of purchase and use.”5 This doesn’t tell us who is considered
an ordinary individual or what typical conditions are; however, it puts manufacturers and
pharmacies on notice in making sure that they do everything possible to make their
information clear to most people.

Question 31

Misbranding: Established names not on label or in labeling where required

Answer 31

this provision is lengthy
and can be confusing, but it’s written in this way to be as complete as possible. It
addresses both prescription and non-prescription product labels, which are different. This
provision requires the generic name must be on the label, even if the product is branded.
It also requires that all active ingredients be listed on the label or in the labeling and
inactive ingredients when required. This second part is best demonstrated by OTC drugs,
where you see combinations of active ingredients listed and often see inactive ingredients
listed. The final thing to notice about this provision is that it notes that the generic name
must be in type at least half the size as the brand name on the label. We don’t know if
that means half the size measured by a ruler (e.g., 1 inch and ½ inch) or half the font size
(e.g., 20-point font and 10-point font). Again, this is about putting people on notice, so
information isn’t hidden.

Question 32

Misbranding: Adequate directions and warnings not in labeling

Answer 32

drug labeling must contain adequate
directions for use and warnings. Consider that this information is often seen in OTC
labeling since the user is a layperson, and information must be more apparent to them.
Directions for use, when to discontinue a product, and warnings are prominently placed
to ensure the information is accessible to the general population. This information is also
provided for prescription drugs but may be less accessible within the prescribing
information.

Question 33

Misbranding: Official drug not packaged as required

Answer 33

the official compendium lists standards for drugs
as noted in adulteration, but these also list how products should be packaged. These
provisions must be followed, or the drug is misbranded. The official compendium may
provide specific requirements regarding the packaging or storage of a product. Examples
include packaging in a glass vial, light-resistant packages, temperature requirements, or
specific desiccant requirements. Specific packaging may be required for stability or other
issues observed with the drug, so if not followed, the drug may no longer act as we expect.

Question 34

Misbranding: Not labeled for deterioration

Answer 34

some drugs deteriorate over time and must be labeled
with information about the deterioration and how to recognize the product has
deteriorated to prevent use. Some drugs may deteriorate in unique ways, like
precipitating, changing color, or producing a smell. These unique things should be noted
on the label. All drugs deteriorate over time, and expiration dates are the traditional way
things are noted. Any drug missing an expiration date is misbranded since it’s not labeled
for deterioration but is also adulterated because we don’t know that it is still good to use.

Question 35

Misbranding: Misleading container or imitation

Answer 35

this is about a product pretending to be something
it’s not or making you think it’s something it’s not. Counterfeit products and imitations
are pretending to be something they’re not. But misleading containers may be harder to
understand. In these cases, the products often use their name and are marketed as the
correct product, but the layout of information or the label’s design is such that a normal
person would be drawn to certain parts that mislead the reader. This is harder to
understand, so I’ve created a fake label based on a real example.

Question 36

Misbranding: Dangerous to health as prescribed

Answer 36

a drug that’s dangerous to health based on its
standard recommended dosing is misbranded. This occurs after the drug has undergone
the usual clinical trials and received approval. At that time, the drug is used widely across
the population, and that’s when unexpected issues occur. While it doesn’t occur often, it
has happened previously, notably with the drug Vioxx (rofecoxib).

Question 37

Misbranding: Color additive and not labeled

Answer 37

this one is often confused with adulteration, but this is
about a color additive not having information on the label that it is a color additive or not
being packaged as required for the color additive.

Question 38

Misbranding: Established name not in advertising and advertising violates other requirements

Answer 38

have
you ever wondered why advertisements list so many things, including side effects, active
ingredients, generic names, and other things? This is the reason why. The product is
misbranded if the manufacturer doesn’t put this information in advertisements. This is
part of the labeling, and no one wants a patient to be misled.

Question 39

Misbranding: Packaging violates the PPPA

Answer 39

we’ll spend time discussing the Poison Prevention
Packaging Act, but it requires that drugs meeting specific requirements be packaged in
child-resistant packaging. If a drug must be placed in this type of packaging and you
haven’t packaged it as required or received an exemption, the product is misbranded.

Question 40

Misbranding: REMS not followed

Answer 40

if the drug requires risk evaluation and mitigation strategies (REMS)
and you don’t follow the REMS with dispensing, the drug is misbranded. We’ll discuss the
different types of REMS later in this course.

Question 41

Misbranding: Fails to bear product identifier

Answer 41

this was mentioned in the last section, but prescription
medications must bear the identifier “Rx-Only” or “Prescription Only” on the label.
Another option is the statement, “Caution: Federal law prohibits dispensing without a
prescription.” Similarly, controlled substances must have a schedule identifier on the
label, which we’ll discuss in the course’s controlled substance section. If this is missing,
the product is misbranded. The clonazepam bottle label below shows these required
product identifiers for prescription drugs and controlled substances and many other
requirements noted in this section.

Question 42

Misbranding Villa Paraphrase

Answer 42

Misbranding can be summarized as issues outside of the product or issues with the words
associated with the product (e.g., label, labeling, statements made). While adulteration focuses
more on the drug product (strength, purity, quality, manufacturing process), misbranding focuses
more on the label and labeling of a drug product.1,2 As noted previously, all labeling is approved
as part of the FDA drug approval process, and any deviation from approved labeling on the part
of a manufacturer, manufacturer representative, or pharmacy is misbranding.2 I think most of
the misbranding provisions listed here are more transparent than the adulteration provisions,
though there are more provisions to remember.