Guidance for Industry 256: Understanding Impacts on the Compounding Industry
Guidance for Industry 256:
Understanding Impacts on the Compounding Industry
By Sarah Taylor, PharmD
What is Guidance for Industry
(GFI) 256?
GFI 256 is a guidance for industry intended to provide
clarification from the FDA on compounding animal drugs from bulk drug
substances. The guidance does not apply to animal drugs compounded from
FDA-approved animal or human drugs, which the FDA generally considers to be
legal extra label uses of such drugs.1 The FDA considers compounding
animal drugs from bulk substances by pharmacists and veterinarians to violate
aspects of the FD&C Act. Given the wide range of animal species and their
varying needs, the FDA acknowledges that in some circumstances there may be no
medically appropriate commercially available treatment options or commercially
available FDA approved drugs may not be suitable for use as a source of active
pharmaceutical ingredient (API) in some circumstances. This guidance lays out
the circumstances in which the FDA generally does NOT intend to take
enforcement action for those compounding animal drugs from bulk API.
1.
See
the Animal Medicinal Drug Use Clarification Act of 1994 for further information
What are the circumstances in
which the FDA states that they do NOT intend to take enforcement action against
those compounding animal drugs for non-food producing animals from bulk APIs?
The GFI 256 document should be referenced for a full
explanation, but the below is a summarized list of the circumstances listed in
the guidance document:
1.
The drug is compounded under the supervision of
a veterinarian or pharmacist in a state or federally licensed facility
2.
The compounding is done in compliance with
relevant state laws and regulations
3.
Bulk APIs, excipients, and finished drug
products used meet the standards set forth in applicable USP-NF monographs and
other FD&C requirements
4.
The drug is dispensed by a pharmacy after the
receipt of a valid script for a specific patient or by the veterinarian to the
owner/caretaker of the patient
5.
The compounded drug is not a copy of an FDA
approved drug or if it is a copy, there is a documented reason why the
compounded product will produce a clinical difference in the identified patient
as determined by the treated veterinarian and this rationale is documented on
the prescription or a document kept with the prescription
6.
If the animal drug has the same API as one or
more FDA approved drugs, the compounder has determined and documented reasons
why the FDA approved drug cannot be used as the bulk source of API
7.
Upon becoming aware of any adverse event or
product defect associated with any compounded animal drug from bulk API, the
pharmacist or veterinarian who compounded the product files a Form FDA 1932a
within 15 business days
8.
The labeling includes
a.
Name of drug
b.
Strength of drug
c.
Species of patient
d.
Patient ID (ex: name of animal)
e.
Name, address, and contact info of compounding
facility
f.
A beyond-use-date
h. The
statement “This is a compounded drug. Not an FDA approved or indexed drug” is
included on the label
i.
The statement “Caution: Federal law restricts
this drug to use by or on the order of a licensed veterinarian” is included on
the label
What counts as a “clinical
difference”?
The FDA clarifies in the guidance that “clinical difference”
may encompass a wide range of potential reasons including harmful ingredients
in an FDA approved medication for certain animals, or strength or concentration
change to accommodate wide variations in size in different species, as well as
aspects such as dosage form or flavoring. The FDA states that they generally do
not intend to question a veterinarian’s determination that a commercially
available product is unsuitable for a given animal or species so long as
appropriate documentation regarding rationale is noted.
Example:
Pimecrolimus ophthalmic drops are determined to be necessary for management of
cyclosporine-resistant keratoconjunctivitis sicca in a canine patient. There
are no FDA approved animal drugs containing pimecrolimus and the FDA approved pimecrolimus
products for human use are creams that are non-sterile and contain excipients
that are inappropriate for ophthalmic use.
What are the required changes to
my documentation and labeling for patient specific prescriptions in non-food
producing animals?
The FDA will require that the below statements be added to labels
of compounded drugs from bulk APIs:
1.
“Report suspected adverse reactions to the
[pharmacist or veterinarian who compounded the drug] and to the FDA using
online Form FDA 1932a”
2.
“This is a compounded drug. Not an FDA approved
or indexed drug”
3.
“Caution: Federal law restricts this drug to use
by or on the order of a licensed veterinarian”
You will also be required to document veterinarian
justification of “clinical difference” or other reason for compounding (such as
the specific API not being present in an FDA approved drug product that may be
used as the source of API) on the prescription or on a document kept with the
prescription.
What are the requirements for
reporting adverse effects to the FDA?
If a compounder has compounded an animal drug from bulk substances,
the FDA will require the compounder to report any adverse reactions or product
defects associated with the compounded drug to the FDA by filling out a form
FDA 1932a within 15 business days. A copy of the form can be found here: How
to Report Animal Drug and Device Side Effects and Product Problems | FDA
Which bulk APIs meet the criteria
for compounding for office use for non-food producing animals?
In addition to many of the restrictions applied to
compounded veterinary medications from bulk pursuant to a patient-specific
prescription, including specific labeling and reporting requirements, compounds
for office stock must also be included on the FDA’s “List of Bulk Drug Substances
for Compounding Office Stock Drugs for Use in Non-Food Producing Animals”. A
full list of APIs that may be compounded for office use can be found here List
of Bulk Drug Substances for Compounding Office Stock Drugs for Use in
Nonfood-Producing Animals | FDA. The FDA also has a list of substances
currently under review, and substances that have been reviewed but were not
added to the list of bulk drug substances. The FDA is accepting additional
submissions, if there are bulk APIs that you believe should be considered for
this list as their lack of availability for immediate use may result in animal
suffering or death, consider submitting the substance for evaluation to the FDA
by following the instructions listed here: Federal
Register :: Lists of Bulk Drug Substances for Compounding: Office Stock Drugs
for Use in Nonfood-Producing Animals or Drugs for Use in Food-Producing Animals
or Free-Ranging Wildlife Species; Request for Nominations
Which animals are considered to
be “Food-Producing” or “Free-Ranging”?
The FDA does not provide a complete list of “food-producing”
animals, but includes as examples cattle, swine, chickens, turkeys, sheep,
goats, fish (excluding ornamental/aquarium fish), other aquatic animal species,
gamebirds, and wildlife raised or harvested for food as well as honeybees.
Which bulk APIs meet the criteria
for compounding for food producing animals?
Compounding for food-producing animals is subject to increased
scrutiny. Among other requirements, drugs compounded from a bulk substance for
use in food producing animals must be on the “List of Bulk Drug Substances for
Compounding Drugs for Use in Food-Producing Animals or Free-Ranging Wildlife
Species”. The list may be found here: List
of Bulk Drug Substances for Compounding Drugs for Use in Food-Producing Animals
or Free-Ranging Wildlife Species | FDA. The FDA is accepting additional
submissions, if there are bulk APIs that you believe should be considered for
this list as their lack of availability for immediate use may result in animal
suffering or death, consider submitting the substance for evaluation to the FDA
by following the instructions listed here: Federal
Register :: Lists of Bulk Drug Substances for Compounding: Office Stock Drugs
for Use in Nonfood-Producing Animals or Drugs for Use in Food-Producing Animals
or Free-Ranging Wildlife Species; Request for Nominations
When does GFI 256 go into effect?
The FDA released draft GFI 256 in 2019 and took into
consideration comments made by veterinarians, pharmacy compounders, and other
stakeholders. The draft GFI was further revised and was slated to be subject to
enforcement as of October 1st 2022. Due to stakeholder concern and
requests for clarification, enforcement has been further delayed until April 2023.
Though requests for clarification from the Alliance for Pharmacy Compounding
(APC) and other organizations are still outstanding, the FDA has not stated
that enforcement will be further delayed.
Who will enforce GFI 256?
The FDA states in GFI 256 that it will ordinarily rely on
compounding pharmacies’ home state licensing boards to provide oversight of
routine compounding practices, but that the FDA may also provide oversight when
considered appropriate by the agency.
Where can I go to learn more?
The full GFI 256 may be found here: CVM
GFI #256 - Compounding Animal Drugs from Bulk Drug Substances | FDA
The FDA’s Official Q&A on GFI 256 may be found here: Q&A:
GFI #256 - Compounding Animal Drugs from Bulk Drug Substances | FDA
Information from our industry partner the Alliance for
Pharmacy Compounding may be found here: APC:
Issue: GFI #256 (a4pc.org)
A Recent letter from the FDA describing their thinking on
enforcement roll out may be found here: Letter
to Industry: Phase-In of Inspectional Activities Related to Compounding of
Animal Drugs from Bulk Drug Substances | FDA
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