FDA Seminar Materials on Importation of API Requirements

The material below may be found here.
Importation of Active Pharmaceutical Ingredients (APIs) Requirements
7-16-08 FDA NYK-DO API Seminar Presentation Notes (Tab A)
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TAB CONTENTS
A. GENERAL IMPORTATION: Definitions (Page 1)
B. REGISTRATION AND LISTING: FRN (Page 2)
C. API EXEMPTIONS (Page 4)
D. MISBRANDING: Labeling Requirements & Exemptions (Page 6)
E. MARKETING: Requirements & Useful Information (Page 6)
OTC, Pharmacy Compounding, Pre-Submission Batches, and Rx
F. DATABASE: Drug Master Files (DMFS)/Establishment Evaluation
System (EES) (Page 8)
G. PRE-LAUNCH ACTIVITIES IMPORTATION REQUEST (PLAIR)
(Page 9)
H. CONTACTS (Page 9)
Importation of Active Pharmaceutical Ingredients (APIs) Requirements
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A. DEFINITIONS:
1. “Drug” [FD&C Act Section 201(g)(1)]:
• Articles intended to diagnose, cure, mitigate, treat or prevent disease in man
or other animals
• Articles (other than food) intended to affect the structure or any function of
the body of man or other animals
• Articles intended for use as a component of a drug
2. "New" drug [FD&C Act Section 201 (p) & 505]:
• "any drug.... the composition of which is such that such drug is not generally
recognized, among experts qualified by scientific training and experience....,
as safe and effective for use under the conditions prescribed, recommended
or suggested in the labeling."
• A “new drug” must be covered by an approved new drug application
(NDA/ANDA) to be marketed in the U.S. or by an investigational new drug
application (IND)
• Applies to both Rx and OTC drugs
3. Over-the-counter drug products (OTC):
• All other drugs that can be used safely without medical supervision
Example: Medications for fever such as aspirin and acetaminophen,
preparations for the common cold or allergies, antacids, and some
first aid antibiotics
4. Prescription (Rx) drug products (Rx) [FD&C Act Section 503(b)(1)]:
• These drugs cannot be used safely without medical supervision
Example: Injectable drugs or drugs to treat serious conditions like heart
disease, cancer, or fertility problems
Importation of Active Pharmaceutical Ingredients (APIs) Requirements
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5. Active Pharmaceutical Ingredient (API) a.k.a. bulk drug substance
[21 CFR 207.3]
• "any substance that is represented for use in a drug and that, when used in
the manufacturing, processing, or packaging of a drug, becomes an active
ingredient or a finished dosage form of the drug“
• "term does not include intermediates used in the synthesis of such
substance"
6. Adequate Directions for Use [21 CFR 201.5]: “directions under which a
layman can use the drug safely….”
B. REGISTRATION & LISTING:
1. Requirements for Foreign Establishments:
• FFDCA Section 510(i) [21 U.S.C. 360]
• 21 CFR 207.40
• FFDCA Section 502(o) [21 U.S.C. 352]
• FFDCA Section 801(o) [21 U.S.C. 381]
2. Foreign firms that manufacture, prepare, propagate, compound, or process
a drug imported or offered for import into the U.S. are required to…
a. Register name and place of business
b. List all drugs imported or offered for import into the U.S.
c. Designate a U.S. Agent
- Each foreign drug establishment shall designate only one United States
agent
- Must be physically located in the U.S.
- Point of contact between FDA and foreign firm on all drug registration &
listing matters and requirements
- Letter of designation must:
o Be prepared on the foreign firm's letterhead
o Signed by authorizing official of the firm
o Contain: Name of the firm's designated U.S. Agent, Address,
Telephone/ fax numbers, and E-mail address
Importation of Active Pharmaceutical Ingredients (APIs) Requirements
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3. Registration must be renewed annually
4. Registration required before any application is approved
5. Listing information must be updated:
a. Every June and December or
b. Discretion of the registrant or
c. When any change occurs
6. National Drug Code Number (NDC #):
a. Assigned to each listed product
b. Identifies manufacturer/distributor, drug, and trade package size/type
c. FDA requests but does not required to appear on the product label or
labeling:
- If the NDC # appears on the label it must comply with
21 CFR 207.35 (b)(3)
7. Does not indicate FDA’s approval of a firm or its products
8. The Bioterrorism Act of 2002:
Requires foreign drug establishments whose drugs are imported into the U.S. to
submit certain information with the annual registration (This is in addition to
the regular registration requirements):
- Each importer/consignee of each drug in the U.S. known to the manufacturer
at time of registration
- Each person who imports or offers to import the manufacturer’s drugs
- The name and contact information of U.S. Agent
9. Non-listed products are misbranded [502(o)] & in violation of 801(a)(3)
10. Firms that are not in compliance with 510(i) are in violation of 801(o)
11. Listing Requirements – Exemptions:
a. Inactive ingredients
b. Intermediates (non-API)
c. Drug products not for importation into the U.S.
d. Drugs imported or offered for import under an Investigational New Drug
Application (IND) [21 CFR 312]
e. Components of drugs imported under 801(d)(3) - Import for Export (IFE)
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12. Information:
a. FDA Forms: www.psc.gov/forms
b. NDC Directory: www.fda.gov
c. Guidance Annual Registration:
www.fda.gov/cder/drls/registration_listing.htm
d. Annual Registration Status: www.fda.gov/cder/dfars/default.htm
e. Registration & Listing contact number: 301-210-2840
f. Draft Guidance: E-Registration & Listing: FRN Vol. 73, No. 134, 7/11/08,
Page 39964
SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of a draft guidance for industry entitled ``Providing Regulatory
Submissions in Electronic Format--Drug Establishment Registration and
Drug Listing.'' This draft guidance document establishes a Pilot Program for
industry to voluntarily submit drug establishment registration and drug
listing information in an electronic format that FDA can process, review, and
archive. The document provides guidance on what required and FDArecommended
information related to drug establishment registration and
drug listing to submit and on how to electronically prepare and submit the
information to FDA.
C. API EXEMPTIONS:
1. 21 CFR 201.122(a):
a. API is intended for use in a product approved in a NDA, ANDA, or
supplement
b. API is manufactured by the supplier approved in the new drug application
c. Prescription (Rx) and over-the-counter (OTC) drugs covered by an approved
application
d. Labeling (Must):
• “Caution: for manufacturing, processing, or repacking” &
• “Rx only”- when most dosage forms in which the API may be used are
subject to prescription [503(b)(1)]
e. Useful Information:
• API product name and NDC number
• Name and address of the API manufacturer
• Number of approved NDA/ANDA or supplement
• Finished dosage drug product name and NDC number
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2. 21 CFR 201.122(b):
a. API is intended for use in a product subject to an IND (for clinical use)
b. Must be covered by an active IND
c. Must be going to person(s) authorized in the IND
d. Labeling (Must):
• “Caution: for manufacturing, processing, or repacking in the preparation
of a new drug or new animal drug limited by federal law to
investigational use”
e. Useful Information:
• IND number
• Sponsor’s name
• Name of the product
3. 21 CFR 201.122(c):
a. API is intended for use in a product subject to a pending NDA or ANDA or
supplement
b. API is manufactured by the supplier included in the pending NDA, ANDA,
or supplement.
c. Applies to prescription (Rx) and over-the-counter (OTC) drugs
d. Labeling (Must):
• “Caution: for manufacturing, processing, or repacking” &
• “Rx only”- when most dosage forms in which the API may be used are
subject to prescription [503(b)(1)]
e. Useful Information:
• API product name and NDC number
• Name and address of the API manufacturer
• Number of pending NDA/ANDA or supplement
• Finished dosage drug product name and NDC number (if applicable)
• Written commitment that products manufactured with the API will not be
introduced in commercial distribution until they are approved
4. 21 CFR 201.125:
a. API is intended for use in teaching, law enforcement, research, and analysis
b. Includes both APIs and finished drug products
c. Cannot be used in human research
d. API product name and NDC number
e. Name and address of the API manufacturer
f. Name and address of U.S. Consignee
g. Written commitment that the quantity offered for import is reasonable for
the contemplated research, teaching, analysis, etc.
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5. 21 CFR 312.160:
a. API is intended for investigational (IND) use in laboratory research animals
or in-vitro testing
b. To conduct R&D work prior to the submission of an IND
c. Product cannot be used in humans
d. Must comply with all the requirements under 21 CFR 312.160
e. Includes both APIs and finished drug products
f. Labeling (Must):
• “Caution: Contains a new drug for investigational use only in laboratory
research animals, or for tests in-vitro. Not for use in humans”
g. Useful Information:
• API product name
• Name and address of API manufacturer
• API label content demonstrating compliance with 21 CFR 312.160
D. MISBRANDING - Adequate Directions for Use [502(f)(1) & 21 CFR
201.5]: “directions under which a layman can use the drug safely”
1. All drugs, including APIs, must bear “adequate directions for use” or meet one
of the exemptions. If not, then misbranded [502(F)(1)].
2. Only OTC finished drug products can meet this requirement. All other drugs
must meet one of the exemptions
E. MARKETING – REQUIREMENTS & USEFUL INFORMATION:
1. OTC pending and final monograph drugs:
a. Labeling (Must):
• “Caution: for manufacturing, processing, or repacking”
b. Useful Information:
• Name and NDC # of product to be manufactured with the API
• A statement justifying why an approval is not required for the finished
drug product
• API label content demonstrating compliance with 21 CFR 201.122
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2. Pharmacy Compounding
a. Labeling (Must):
• “For Prescription Compounding”
• “Rx only”
b. Useful Information:
• API is a component of an FDA approved drug
• API meets official compendial requirements when applicable
Example: Certificate of Analysis
• Drug has not been withdrawn or removed from the U.S. market for public
health reasons (list in CPG 460.200)
• API product name and NDC #
• Name of API manufacturer and registration number
• A written commitment that the API will be sold and used solely for
pharmacy compounding by a state licensed pharmacy or federal facility
• A written commitment that the drug has not been withdrawn or removed
from the U.S. market for public health reasons
3. Pre-Submission Batches: (Batches used to conduct the studies necessary to
generate data required to submit an application or supplement
Example: Bioequivalence, bioavailability, and stability batches)
a. Useful Information:
• API product name and NDC #
• Name and address of the API manufacturer
• Name and address of U.S. consignee
• Product must be labeled as per 21 CFR 201.122
• For supplements - may include number of NDA/ANDA to be
supplemented and NDC # of finished product
b. Written commitment that product manufactured with API will not be
introduced in commercial distribution until approved
c. Explanation that API is intended to generate data to submit an application/
supplement
Example: Bioequivalence and/or bioavailability batches
Importation of Active Pharmaceutical Ingredients (APIs) Requirements
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4. Prescription (Rx) drugs not currently subject to application requirements:
a. Labeling (Must):
• “Caution: For manufacturing, processing, or repacking”
• “Rx only”
b. Useful Information:
• Name and NDC # of product to be manufactured with the API
• A statement justifying why an approval is not required for the finished
drug product
• API label content demonstrating compliance with 21 CFR 201.122
F. DATABASES:
1. Drug Master Files (DMFs):
a. Contain API chemistry and manufacturing control information
b. Are submitted to FDA voluntarily by the API manufacturer
c. NDA/ANDA sponsors may elect to refer to a an API DMF in their
application
d. Are not approved by FDA
e. They are reviewed by FDA in reference to a submission and are judged to be
either adequate or inadequate with regard to that submission
f. May be referenced in multiple applications
g. May be associated with both approved and unapproved applications
h. A DMF number is not sufficient to show that the API supplier is approved in
an application

Criminalization of Medication Errors; Mistakes by Pharmacists

The following article appears at http://www.uspharmacist.com/content/c/16572/

Jesse C. Vivian, BS Pharm, JD

Professor, Department of Pharmacy Practice
College of Pharmacy and Health Sciences
Wayne State University
Detroit, Michigan

11/19/2009

US Pharm. 2009;34(11):66-68. Here is a sobering thought. A pharmacist makes a mistake. The error results in the death of a patient, and the pharmacist is charged with negligent homicide. He is found guilty of involuntary manslaughter and faces up to 5 years in prison and a maximum fine of $10,000. Of course, his pharmacist license is revoked and chances are he will never work in the profession again. His crime? He did not check the accuracy of calculations used by a pharmacy technician under his charge to compound the concentration of sodium chloride in a prescription for a cancer chemotherapy solution.
Negligent? Yes. Accountability and responsibility? Yes and Yes. Malpractice? Yes. Loss of license? Yes. Guilty? Yes. But a crime? Prison term? For a mistake, albeit a mistake with a worst-case outcome? That is tough medicine to swallow. More important, how is justice served by putting this pharmacist in jail? The message to pharmacists and perhaps all other health care practitioners—watch out. There may be prosecutors out there just itching to put you away.

Facts of the Case

On February 24, 2006, while working at the Rainbow Babies and Children’s Hospital in Cleveland, Ohio, licensed pharmacist Eric Cropp received a prescription for a chemotherapy solution of Eposin (etoposide phosphate) that was supposed to be mixed in an IV bag of normal saline containing 0.9%

USA: Doctor jailed over misbranded drugs

USA: Doctor jailed over misbranded drugs

bnd.com on May 25, 2012 reported that a St. Louis County cancer doctor has been sentenced to probation for two years, fined $25,000 and ordered to pay $1 million for misbranded prescription drugs. The penalties for Dr. Abid Nisar of Town and Country, Mo., were announced Friday. He pleaded guilty to federal charges earlier this year. As part of an agreement with prosecutors, Nisar will pay $1 million to resolve allegations that he submitted false claims for payment through several programs, including Medicare. Nisar is also banned from participation in federal health care programs for seven years.

Corporate HGH Smuggler Gets Fine

From the Steroids Bodybuilding Peptides and SARMS Blog:


Corporate HGH Smuggler Gets Tiny Fine

A Plattsburgh pharmaceutical company and its president, a Canadian citizen, were fined $15,000 this week for mislabeling more than $1 million worth of human growth hormone that was imported from China and distributed to pharmacies around the country.


The case has ties to a 2007 investigation by the Albany County district attorney's office targeting pharmaceutical companies that illegally sold steroids and other anti-aging drugs.


Antonio Dos Santos, 63, of Montreal and Plattsburgh-based Medisca, Inc., also must forfeit $1.76 million to the U.S. government. Dos Santos and the company pleaded guilty to misdemeanor federal drug charges last October in Albany.


U.S. Magistrate David R. Homer this week ordered Dos Santos to pay a $5,000 fine and the company to pay $10,000.


A former Orlando pharmacy, Signature Compounding Pharmacy, whose owners and operators are under indictment, was among the customers of Medisca, Inc., which also has a corporate office in St. Laurent, Quebec.


John L. Pacht, an attorney from Burlington, Vt., entered a guilty plea on behalf of Medisca last fall.


Plea agreements signed by Dos Santos and Pacht said that between July 2004 and February 2007 Medisca imported 1,737 grams of human growth hormone from China. The criminal accusation is that the company marketed the drug as an "FDA approved drug" which is false, federal prosecutors said.


Dos Santos founded Medisca in 1989. The $1.76 million forfeiture represents the company's gross profits from the unlawful drug sales.


The company ceased importing human growth hormone in February 2007. That month, a multi-agency task force raided Orlando's Signature Compounding Pharmacy. The arrests of Signature's operators were made on warrants filed by Albany County prosecutors who obtained felony indictments against Signature's operators related to the alleged sale of performance-enhancing drugs, including steroids, to customers that included pro athletes and celebrities.


Albany County prosecutors have said Medisca was a primary supplier of Signature pharmacy.


Albany prosecutors allege in their charges that Signature was selling growth hormone to people nationwide who had no legitimate medical reason for the drug.


The plea agreements require Medisca face spot checks by the U.S. Food and Drug Administration for one year. The company must pay the costs of those inspections.


Dos Santos had faced up to a year in prison and a fine of up to $100,000.


Records show Dos Santos, who founded Medisca in 1989, pleaded guilty to a similar charge for illegally importing shipments of minoxidil (Rogaine), a hair-growing product, from Canada into the United States in 1989, when it was prohibited.


The Minnesota conviction was vacated in 2007 after Dos Santos' lawyers filed a motion arguing his plea was flawed and that minoxidil is now approved for distribution in the United States.

C.R. Pharmacy Services d/b/a Fifth Avenue Pharmacy and Fifth Avenue Compounding Litigation in Iowa; Doctor Sued

Iowa court denies new trial in pharmacy lawsuit

DAVID PITT, Associated PressCopyright 2012 Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.

DAVID PITT, Associated Press

Updated 07:13 p.m., Friday, June 29, 2012inShare

Page 1 of 1

DES MOINES, Iowa (AP) — A woman left with eye problems when she didn't get the right medication after surgery won't get a new trial in her lawsuit against a pharmacy, even though new evidence that surfaced as the trial was beginning surprised her attorney, the Iowa Supreme Court ruled Friday.

The case centered on medication prepared by C.R. Pharmacy Service, which does business as Fifth Avenue Pharmacy. The medication was to be applied by Misty Whitley's doctor immediately after surgery. However, after Whitley developed problems, it was discovered she did not get the right medication.

Whitley, of Marengo, sued Dr. Lee Birchansky and the Cedar Rapids pharmacy in 2007 but dropped Birchansky from the lawsuit and pursued a malpractice and negligence claim against the pharmacy claiming it supplied the wrong product for her surgery. A jury found a verdict in favor of the pharmacy.

Whitley has since filed a new lawsuit against Birchansky after the pharmacy manager discovered documents that indicated the medication ordered by Birchansky had not been picked up by his office from the pharmacy until after the surgery had been completed.

Those documents were at the heart of the appeal that led to the Supreme Court's decision Friday. The manager who discovered the documents a few weeks before the trial told his attorney. However, that information was not passed on to Whitley's attorney.

The Supreme Court found the pharmacy's attorney violated a duty to disclose the new information, but it said the judge did nothing wrong in allowing the evidence. The judge delayed the trial so Whitley's attorney could explore the new evidence and interview additional witnesses.

The saga began when Whitley went to the Fox Eye Clinic in Cedar Rapids in 2005 hoping to improve nearsightedness with a procedure that involves using a laser to sculpt the shape of the cornea. Then, in March 2006, she had a corneal scraping procedure to repair scarring of the cornea in both eyes, a common risk with laser eye surgery.

After that surgery, her eyes developed signs of cataracts and glaucoma. An investigation and testing revealed the substance applied to her eyes after surgery was not the medicine ordered by her ophthalmologist Birchansky.

She had to undergo corneal transplant surgery. After a subsequent accident, she lost her left eye.

Whitley asserted the pharmacy delivered the wrong prescription, which the doctor applied to her eyes. The pharmacy maintained it delivered the correct prescription and the doctor mistakenly applied the wrong substance.

Then, at the beginning of the trial, the pharmacy's attorney said it could not be at fault because it didn't deliver the medication before the surgery took place. The attorney disclosed the documents on the second day of the trial during questioning of the doctor.

Whitley's attorney wanted the evidence excluded from the trial, but the district court judge denied that request.

The Iowa Court of Appeals ordered a new trial, finding that the surprise Whitley's attorney encountered by the new evidence was too prejudicial for the district court to refuse to exclude the evidence.

The Supreme Court reversed that decision and agreed with the district court judge that the evidence should have been allowed.

"The district court did not abuse its discretion when it made its decision to grant a continuance and deny the request to exclude the evidence," the justices wrote. "Based on the circumstances existing at the time the decision was made, the trial court pursued a reasonable course of action."

Robert Breckenridge, of Ottumwa, who represented Whitley, said he continues to believe the conduct of the pharmacy's attorneys should not have been rewarded by the court.

Court records show a scheduling conference in the lawsuit against Birchnasky is set for July 24.

Birchansky's attorney, Hayward Draper, of Des Moines, said the case was dropped against the doctor the first time because Whitley's attorneys concluded the doctor provided good care and did nothing wrong in his treatment of her.

"The new lawsuit is completely without merit because Dr. Birchansky did provide good care and did do nothing wrong," Draper said.

An attorney for the pharmacy, Chris Bruns, of Cedar Rapids, said the pharmacy had not authorized him to comment further about the case.

Read more: http://www.mysanantonio.com/news/article/Iowa-court-denies-new-trial-in-pharmacy-lawsuit-3674230.php#ixzz1zHhIPTy1

To review the Iowa Supreme Court decision click here.