Amendment with Respect to Misbranding Contained in Senate Bill 3187

The final version of Senate Bill 3187 as passed and headed ot the President's desk can be read by clicking here. 

One amendment provided for in the bill is an amendment to the misbranding provision as follows:

SEC. 306. AMENDMENT WITH RESPECT TO MISBRANDING.

Section 502 (21 U.S.C. 352) is amended by adding at the end the following:

‘(aa) If it is a drug, or an active pharmaceutical ingredient, and it was manufactured, prepared, propagated, compounded, or processed in a facility for which fees have not been paid as required by section 744A(a)(4) or for which identifying information required by section 744B(f) has not been submitted, or it contains an active pharmaceutical ingredient that was manufactured, prepared, propagated, compounded, or processed in such a facility.’.

FDA Alert 66-66; "APIs That Appear To Be Misbranded Under 502(f)(1) Because They Do Not Meet The Requirements For The Labeling Exemptions In 21 CFR 201.122"

(Note: This import alert represents the Agency's current guidance to FDA field personnel regarding the
manufacturer(s) and/or products(s) at issue. It does not create or confer any rights for or on any person,
and does not operate to bind FDA or the public).

Import Alert # 66-66

Published Date: 04/10/2012

Type: DWPE

Import Alert Name:

"APIs That Appear To Be Misbranded Under 502(f)(1) Because They Do Not Meet The
Requirements For The Labeling Exemptions In 21 CFR 201.122"

Reason for Alert:

OASIS records indicate that a large volume of bulk chemicals which can be used as APIs in human
medicines that require NDAs, ANDAs, or INDs are being offered for entry into the U.S.

NDA Imported APIs labeled for further manufacturing and processing or labeled as chemical
substances are frequently destined for pharmaceutical processors that formulate finished drug
products. These drug substances, consigned to individuals or processors who formulate and
distribute human drugs, may be misbranded under Section 502(f)(1).

AIND Sponsors of investigational new drug applications frequently import from foreign
countries either the dosage form or the API for use in laboratory research or clinical trials.

Some persons importing APIs have found that they could obtain entry of these articles if they
simply supply an NDA or IND number at the point of entry. Districts should be alert to the
possibility that: 1) the NDA or IND number provided does not cover the source of the particular
API or 2) the persons importing the API have no authorization to refer to the particular NDA or
IND number. In the past, the persons importing an API have referred to legitimate numbers to
get their APIs released, but the APIs were not destined for use in the application referenced.

CDER and ORA are in the process of making the Establishment Evaluation System (EES)
available to the field. When available, field offices should utilize EES to search and verify the
status of an API, its manufacturer, whether it has been referenced in a valid NDA or whether
it is the subject of a valid IND. Districts that do not have access to EES should contact
DIOP, 301-443-6553 to verify this status.

(OASIS entry records can be compared to CDER records for NDAs, ANDAs, and IND
exemptions to verify the source and status of an API.)

EXEMPTION UNDER 21 CFR 201.122

API labeling invariably lacks adequate directions for use as required by Section 502(f)(1)
of the Act. However, such drugs may be subject to an exemption under 21 CFR subpart 201.122.
This regulation requires specific labeling on the package when adequate directions for use are
missing, such as "Caution: For manufacturing, processing, or repacking."

However, the exemption under 21 CFR 201.122 will not apply to a substance intended for a
use in the manufacture, processing, or repacking of the API which causes the finished article
to be a new drug, unless:

A. an approved NDA covers the production and delivery of the API to the application holder
by persons named in the application; or

B. if no application is approved with respect to the API, the label statement "Caution: For
manufacturing, processing, or repacking" is immediately supplemented by the words "in the
preparation of a new drug or new animal drug limited by Federal law to investigational use,"
and the delivery is made for use only in the manufacture of such new drug or new animal
drug limited to investigational use as provided in 21 CFR part 312 or part 511.1.

The API/manufacturer combinations listed in Attachment A appear to represent importations
of APIs to be used for the manufacture, processing, or repacking of drugs which the Act
and regulations require to be the subject of an approved NDA or a valid IND. However,
either the person receiving the API or the person importing the API appears not to meet the
statutory and/or regulatory requirements regarding labeling. Further, it appears that the Agency
has never inspected the declared manufacturer's GMPs for that imported API.

Guidance:

Detain without physical examination the APIs from the manufacturers identified in the
Red List to this Import Alert.

Districts may detain without physical examination APIs from the persons identified in the
Red List because it appears that the API is misbranded based on its lack of adequate
directions for use as required by section 502(f)(1) of the Act and its failure to meet the
requirements of the exemption found in 201.122. Persons importing these APIs may obtain
release of the detained articles if these persons can supply evidence establishing that the article is:

1. intended for pharmacy compounding that meets the requirements of section 503A of the
Act, including that the API:

a. is accompanied by a valid certificate of analysis,

b. is manufactured by an establishment registered under section 510 of the Act,

and

c. does not appear on a list of drugs identified in 21 CFR 216.24, that have been withdrawn or
removed from the market for reasons of safety or effectiveness.

2. intended for use in the manufacture, processing, or repacking of an over-the-counter
product or prescription product that does not require an NDA;

or

3. a new animal drug, or intended for use in the manufacture, processing, or repacking of a new
animal drug, subject to an NADA;

and, therefore, the API is not subject to this import alert.

OR

Persons importing APIs may obtain release of the detained articles by supplying evidence
establishing that the article is:

1. intended for use in the manufacture, processing, or repacking of a human drug that is itself
the subject of an approved NDA, and that the API is from the appropriate source; or

2. it is covered by IND requirements at 21 CFR 312.110(a).

For questions or issues concerning science, science policy, sample collection, analysis,
preparation, or analytical methodology, contact the Division of Field Science at (301) 796-6600.

This guidance is not intended to address new animal drugs or investigational new animal drugs addressed
by Import Alert number 68-09. If the imported APIs are intended for use in an NADA or INAD, refer
to Import Alert number 68-09.

If the APIs are intended for the compounding of finished drugs by pharmacies, persons
importing the APIs must comply with the requirements in 503A of the FDCA.

This guidance does not apply to excipients or APIs intended for use in OTC drugs or prescription drugs
that do not require a new drug application.

Product Description:

Active Pharmaceutical Ingredients (APIs)

Charge:

"The article is subject to refusal of admission pursuant to section 801(a)(3) in that it appears to be misbranded in that it lacks adequate directions for its intended use. [Misbranding, Section 502(f)(1)]."

OASIS Charge Code - DIRECTIONS

NOTE: Under 502(f)(1), an API must have labeling that lists adequate directions for its use unless the API is subject to exemptions from labeling found in 201.122.

For a list of firms and their products subject to detention without physical examination (DWPE) under this import aller (a.k.a. Red List), click here and scroll to the bottom of the page.

Criminal Charges in a Compounding Case: Exercise of Federal Authority

The Criminal Information filed against ApothéCure, a major compounder in the United States, and Gary D. Osborn charges violations of 21 U.S.C. Section 331(a), 352(a) and 333(a)(1)--all criminal, class A misdemeanors.  Basically, the information charges that  ApothéCure and Gary D. Osborn introduced in interstate commerce a misbranded drug in that its label was false and misleading.  Criminal misdemeanors under the federal system are criminal offenses eligible for terms of imprisonment that do not exceed one year but are more than six months in length by federal statute. See 18 U.S.C. 3559(a)(6)  Under the federal system, the district court also uses the advisory United States Sentencing Guidelines to determine the range and actual punishment.  Both the criminal charges in ApothéCure and the attempt to obtain an injunction in Franck's show the FDA and DOJ attempting to exercise its federal jurisdiction to regulate and punish compounders who step out of bounds.  It will be interesting to see how far the federal courts allow the FDA and DOJ  to exercise this power against other compounders who violate the law.   The appeal  in Franck's while only binding on those states in the 11th Circuit Court of Appeals--Alabama, Florida, and Georgia--will be precedent setting with the possibility, no matter the outcome, of making its way to the United States Supreme Court.  The other possibility if DOJ/FDA loses the appeal is for there to be a legislative fix attempting to define the parameters of federal jurisdiction to regulate this area of the law.