Drug Imports & Exports

1. Drug Imports & Exports

2. Import/Export of Drugs Chicago District-Import TeamAugust 26,2010 Michael Giammanco, CSO Sherea L. Dillon, CSO

3. Topics to Cover • Drug Imports and Exports • Errors Commonly Seen at O’Hare • What is required for Review • Affirmation of Compliance • Registration and Listing • NDA/ANDA/ • Manufacture Name and Location • Reason for USRG

4. Definition: “Drug” [201(g)(1)] Article… • Intended to diagnose, cure, mitigate, treat or prevent disease in man or other animals • Intended to affect the structure or any function of the body of man or other animals (other than food) • Recognized in the USP/NF, HPUS or any supplements • Intended for use as a component of a drug

5. Drug Imports & Exports

6. IMPORTED DRUG PRODUCT • 80% APIs • 40% finished drugs • Heparin sodium adulteration • DEG • Melamine • Drug Diversion (ketamine)

7. Registration and Listing

8. R & L Requirements [510(j) & 21 CFR 207] All foreign firms that manufacture, prepare, propagate, compound, or process a drug imported or offered for import into the U.S. are required to… • Register their name and place of business • List all drug products imported or offered for import into the U.S. (FDA form 2657) • Designate a U.S. Agent

9. R & L Requirements • Manufacturers: APIs & finished drug products • Repackers and relabelers • Control laboratories: registration only • Domestic manufactures that pack/repack, label/relabeled, etc. drugs under the Import for Export (IFE) requirements • NDC #: • FDA requests but not require that it appears on the product label or labeling • If NDC # appears on the label it must comply with regulation [21 CFR 207.35 (b)(3)] • Registration & Listing does not indicate FDA’s approval of a firm or its products [21 CFR 207.39]

10. R & L Requirements • Registration must be renewed annually • Registration required before any application is approved • Listing information must be updated: • Every June and December or • Discretion of the registrant or • When any change occurs

11. R & L Requirements U.S. Agent (21 CFR 207.40(c)) • Each foreign drug establishment must designate only one U.S. 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

12. R & L Requirements U.S. Agent (21 CFR 207.40(c)) Letter of designation must: • Be prepared on the foreign firm's letterhead • Be signed by authorizing official of the firm • Contain the following: - Name of the firm's designated U.S. Agent - Address - Telephone/fax numbers, and - E-mail address

13. R & L Requirements • Listed products: assigned National Drug Code number (NDC #) • NDC # identifies the following: • Manufacturer or distributor • Drug • Trade package size and type • Un-listed products are misbranded [502(o)]

14. Listing Exemptions • Component of a drug (e.g. ingredients or non-API intermediates used to synthesize APIs) • Drugs not for importation into U.S. (i.e. FTZ) • Drugs offered under Investigational New Drug (IND) [21 CFR 312] • Research for own study only andnot for research in humans (If distributed by someone and research is conducted by someone else then, not exempt)

15. R & L Information FDA Forms: http://www.hhs.gov/forms NDC Directory: www.fda.gov

16. Drugs: Approved/ DESI/ Investigational/ OTC

17. Importation Commercial Shipments transmitted to Chicago Approved Drugs Unapproved Drugs Investigational New Drugs Over the Counter OTC DESI Drugs for Research and Development PLAIR (Pre-Launch Activities Importation Requests) 17

18. Prescription (Rx) drugs [503(b)(1)] • These drugs cannot be used safely without medical supervision Examples: • Injectable* drugs or • drugs to treat serious conditions like heart disease, cancer, or fertility problems * Generally, injectable drugs are Rx, but insulin is not Rx in every state.

19. MR:IND vs. NDA vs. ANDA NDA vs. ANDA: The differences in the two are noted in Green. IND eventually becomes NDA (Generic Drug) ANDA Requirements 1-3. Bioequivalence 4. Chemistry 5. Manufacturing 6. Controls 7. Labeling 8. Testing (Brand Name Drug) NDA Requirements 1. Animal Studies* 2. Clinical Studies* 3. Bioavailability Studies 4. Chemistry 5. Manufacturing 6. Controls 7. Labeling 8. Testing

20. Marketing requirements (NDA/ANDA) Approved new drug must be: • Manufactured, packaged, or labeled at a facility covered in the application using the formulation and process approved • Manufactured using an API supplied by a manufacturer covered in the application

21. Definition:Over-the-counter (OTC)drug • All other drugs that can be used safely without medical supervision Examples: • Medications for fever such as aspirin and acetaminophen • Preparations for the common cold or allergies • Antacids, and • Some first aid antibiotics

22. Definition:Over-the-counter (OTC)drug • Do some OTC products have NDA/ANDAs? • Yes • No

23. OTC DRUGS • Most OTC drugs on market not covered by approved NDAs • Large number of OTC drugs on market in 1972 did not have FDA approval • Agency decided to have a class-by-class review for OTC drugs instead of NDAs • Final rules in effect 21 CFR 331-358 • Negative monographs found in 21 CFR 310

24. OTC DRUGS • Where there is a final monograph (FM), OTC drug must meet the FM including labeling and formulation • Product must also comply with all other labeling requirements of the FDCA • Drug must be manufactured under cGMPs • Firm is registered and the product is listed • Some drugs switched from Rx to OTC still require NDA (ibuprofen, Advil) • Timed-release drugs require approval 21 CFR 310.502(a)(14)

25. Chemical or Drug • Per the FDCA, chemicals can be drugs, but not all chemicals are drugs • • Regulation 21 CFR 201.128, concerns the meaning of “intended uses”– Intent is determined by labeling, advertising matter, oral or written statements • GHB, GBL, DMSO, Procaine

26. API Use inClinical Studies(a.k.a. IND)[21 CFR 201.122(b)] • Must be covered by an active IND • Must be going to person(s) authorized in the IND • Drugs for clinical studies may not be used for manufacturing.

27. Marketing Requirements (MR):DESI • Review initiated in response to the Drug Amendments of 1962 to assess the effectiveness of drugs that had been previously found to be safe under the Act • DESI drugs are drugs that were the subject of pre-1962 (safety only) NDAs and drugs that are identical, related, and similar to such drugs [21 CFR 310.6]

28. MR:DESI • Once final order issued and any appeals exhausted, application approval required for continued marketing • Continued marketing permitted (exercise enforcement discretion per CPG 7132C.02 (Sec. 440.100)) while administrative process and any judicial appeals are pending (DESI pending) and may be recognized as part of the "DESI" drug • CDER's policy: There are no such drugs as "grandfathered drugs"

29. Import for ExportForeign Trade Zones

30. MR: The 1996 Export Reform Act Import for Export (IFE) [801(d)(3)] • Allows importation of violative articles (including finished drugs) intended for export [801(e) & 802] only if further processed • FDA must be provided with certain information: • Written statement article is to be further processed, id manufacture, processor, packer, distributor or any entity that had possession of the article • COA to identify the article • Records when requested • Must execute a bond for any liquidated damages • Must maintain records of use and/or destruction • Must destroy any article not used in production

31. MR: The 1996 Export Reform Act Import for Export (IFE) [801(d)(3)] • Article can be refused admission if credible evidence that it is not intended to be further processed • Prohibited Acts [301(w)]: Exempts exportation • False information and statement • Introduction into interstate commerce any article (including finished) • Not submitting and maintaining records and COA

32. MR: Foreign Trade Zone (FTZ) • CBP’s designation to exempt from payment of duties, taxes and bonds and considered by them to be outside U.S. • Articles not offered for consumption, thus not considered “imported or offered for import” • If in FTZ, subject to FDA laws since considered within the “territory” of the U.S. • 801 does not apply until article is out of FTZ • Introducing unapproved new drugs into FTZ violates new drugs [355(a)] and prohibited [301(d)] • Can bring into FTZ articles (bulk or finished) pending approval

33. How we see your entry

34. Affirmations of Compliance Human Rx • NDA/ANDA • DLS/NDC • Registration • Animal Rx • NADA/ANADA • DLS/NDC • Registration • OTC • DLS/NDC • Registration • NDA/ANDA*

35. Affirmations of Compliance PLAIR (Pre-Launch Activities Importation Request) • CDER Approval Investigational • IND Research Use • Statement of Intended Use

36. Common Errors Made on Drugs • Submitting Affirmation of Compliance for Animal and Human Drugs in the Affirmation Section • Many Brokers put the NDA/ANDA in the product description. This is incorrect. It should go in the Affirmation of Compliance Section • Multiple NDAs and uses should be filed on different lines of the entry. • Different NDAs should be on different lines, to avoid errors, different purposes

37. Common Errors Made on Drugs • Drug Compounding information should be submitted to FDA when entry is made and should have the proper documents for release. • Drugs not listed • Imported Drug does not reflect Product code • Quantity Description • Bulk API vs. Finished Drug

46. Importer given opportunity to bring product into compliance. Products which are not brought into compliance are refused admission into the U.S. Refused articles must either be destroyed or re-exported Drug Imports & Exports (cont)

47. Thank you! QUESTIONS?