The ABCs of Importing and Exporting Products, Samples and Biologics across International Borders

Transcription

1 The ABCs of Importing and Exporting Products, Samples and Biologics across International Borders Quality and Operations Track 4 Transport, Import and Export of Cell Therapy Products Fri 4/27/14 07:30-08:30 Olive J Sturtevant, MHP,MT (ASCP)SBB, CQA Director of CTQA Dana Farber Cancer Institute, Boston, Ma

2 Objectives: 1. To outline the basic regulations and requirements to remain compliant with US laws 2. To define key attributes important when selecting a courier and a broker 3. To identify potential risks and how one might mitigate their impact

3 Types of Products HPC and other novel cell products (351 & 361) Vectors Other biologics Cytokines Platelet lysates Retronectin Medical Specimens Research samples

4 Materials Requiring Import Permit and Application Process Animal or Human body fluids, tissues, body parts, blood/blood products, and feces Bacterial isolates, Viral isolates, Fungal isolates, Prions, and toxins Diagnostic or clinical samples (patient samples that will be tested for specific etiologic agent(s)) Environmental samples (air, water, soil, surfaces, etc.) Genomic material (DNA, RNA, genomic vectors, i.e., plasmids) Hosts or vectors (flies, mosquitoes, snails, ticks, etc.) Human tissue/organs used for human transplants or graphs Human remains Vaccines/drugs/reagents Live animals Bats,Non-human primates, All other live animals Select Agents Isolates An Overview of The Types of Material that Require an Import Permit and the Application Process: Meranda D. Bradley, Ph.D., B.S, B.S.Ed., Health Scientist, Etiologic Agent Import Permit Program, Division of Select Agents and Toxins

5 Category A - Infectious substances, (UN 2814) affecting humans (UN 2900) affecting animals CDC Categories: Category B (UN 3373) medical specimen taken from a population where infectious agents (HIV, Hepatitis, etc) are likely Exempt medical specimen taken from a low risk population and / or know to not contain infectious agents if you are not sure of the status, take precautions and use Category B

6 CATEGORY A: An infectious substance in a form capable of causing permanent disability or life threatening or fatal disease in otherwise healthy humans or animals when exposure to it occurs. An exposure occurs when an infectious substance is released outside of its protective packaging, resulting in physical contact with humans or animals. Classification must be based on the known medical history or symptoms of the source patient or animal, endemic local conditions, or professional judgment concerning the individual circumstances of the source human or animal. Category A poses a higher degree of risk than Category B. Infectious substances, affecting animals, UN2900 Infectious substances, affecting humans, UN2814

7 CATEGORY B An infectious substance not in a form generally capable of causing permanent disability or life-threatening or fatal disease in otherwise healthy humans or animals when exposure to it occurs. This includes Category B infectious substances transported for diagnostic or investigational purposes. PROPER SHIPPING NAME AND IDENTIFICATION NUMBER: Biological substance, Category B, UN3373 Examples of Biological substance, Category B can be a Diagnostic Specimen or Clinical Specimen

8 Materials that do not require a CDC import permit: Select agents listed in 42 CFR Part 73 if its importation has been authorized in accordance with 42 CFR or 9 CFR Diagnostic specimen not known by the importer to contain, or suspected by the importer of containing, an infectious biological agent and is accompanied by an importer certification statement confirming that the material is not known to contain or suspected of containing an infectious biological agent, or has been rendered noninfectious. Animal or animal product being imported for educational, exhibition, or scientific purposes and is accompanied by documentation confirming that the animal or animal product is not known to contain (or suspected of containing) an infectious biological agent or has been rendered noninfectious. Nucleic acids that cannot produce infectious forms of any infectious biological agent and the specimen is accompanied by an importer certification statement confirming that the material is not known to contain or suspected of containing an infectious biological agent. Animal or animal product listed in 42 CFR Part 71 if its importation has been authorized in accordance with 42 CFR 71.52, 71.53, or Product that is cleared, approved, licensed, or otherwise authorized under any of the following laws: The Federal Food, Drug, and Cosmetic Act (21 U.S.C. 301 et seq.), or Section 351 of the Public Health Service Act pertaining to biological products(42 U.S.C. 262), or The Virus-Serum-Toxin Act (21 U.S.C ). Please Note: The CDC requires that importers of materials that do not require a CDC import permit, include with the shipment an importer certification statement confirming that the material is not

9 CDC Application Process Request permit to Import Biological Agent or Vector Permit to Import or Transport Live Bats Guidance documents online Permittee (Section A) Senders (Section B) Final Destination (Section D

10 Category A

11 Biosafety Measures

12 Pre-Shipping Obtain all required export permits from the country of origin. Check airline policies. Not all airlines will take infectious material or Dangerous Goods (dry ice >5 lbs is a DG) Check airline flight schedules to find the most direct route. The more connections, the greater the chance of a package being lost or needing re-icing en route, or an animal not surviving Tips for Shipping by Air Sheryl E. Shapiro, MHA, Senior Public Health Advisor, Zoonoses Team Quarantine and Border Health Services Branch, Division of Global Migration and Quarantine, Centers for Disease Control and Prevention

13 Transport by Air Instructions for the Safe Transport of Dangerous Goods by Air are issued by the International Civil Aviation Organization (ICAO) legally binding international regulations. The International Air Transport Association (IATA) issues the Dangerous Goods Regulations (DGR) ICAO rules apply on all international flights. For national flights, national civil aviation authorities apply national legislation which is normally based on the ICAO provisions, but may incorporate variations. State and operator variations are published in the ICAO Technical Instructions and in the IATA Dangerous Goods Regulations.

14 Shippers Declaration Must be completed in English and two copies are required one for aircraft operator and the other kept with the package Should be typed Make sure all sections are completed and form signed Sign any changes or amendments. Air Waybill number, airport of departure and airport of destination maybe left blank for later completion: Shipper s declaration of dangerous goods is not needed for goods classified as UN 3373 but some couriers/countries/airlines may ask for one to be completed.

15 Shippers Declaration Most of the Air Waybill will be completed by the airline but certain information will be needed for completion: If the package contains dangerous goods the words, enter the words Dangerous goods as per attached Shipper s declaration under handling information should be used Include cargo aircraft only if applicable The nature and quantity of goods should contain the words Infectious substances Only BIOLOGICAL SUBSTANCE, CATEGORY B and UN 3373 required if the package does not contain dangerous goods Enter the following information: UN number, proper shipping name, Class or division number, number of packages and net quantity per package.

16 USDA Statement Date: Shipper Address Responsible party Telephone # Consignee Address Responsible party Telephone # Contents PHS Permit n For Clinical trial Number of samples 25, number of mls 25, Lot # x 1 mls Description of Non-replicating immunodeficiency virus type 1 Cultures The material is cell cultures supernatant for ex-vivo human use. Material is recombinant but contains no genes and expresses no product of exotic live stock or poultry disease agents Material is not a tissue culture. The material is sterile and has been purified. The material is not zoonotic 2. Dry ice ()UN1845

17 Labeling number/proper shipping name: UN 2814 INFECTIOUS SUBSTANCE AFFECTING HUMANS UN 2900 INFECTIOUS SUBSTANCE, AFFECTING ANIMALS ONLY Packing instruction Air: PI 620 Triple pack outer packaging must be rigid Road and rail: PI 620 Quantity limits Air: 50ml/50g on passenger & cargo aircraft; 4L/4kg on cargo only aircraft Road: No limits Testing of packaging UN type testing (9m drop test, puncture and water immersion test). Primary receptacle or secondary packaging must be capable of withstanding pressure differential of not less than 95kPa and temperatures in the range -40 C to +55 C.

18 Labeling / Documentation Proper shipping name must be supplemented with the technical name (the recognized biological/scientific name of the microorganism). Infectious substances: suspected Category A infectious substance in parentheses should be used as the technical name. An itemized list of contents and customs statement research materials of no commercial value Also needed are the Shippers Declaration for Dangerous Goods for transport by air (and equivalent for road) and the Air Waybill for transport by air Written emergency response procedures

19 General principles of packaging All infectious substances must be packed using a triple layer system: a. Primary receptacle a primary watertight, leak-proof (or sift-proof for solids) containing the infectious substance, packaged with enough absorbent material to absorb all fluid in case of breakage; b. Secondary packaging a second durable, watertight, leak/sift-proof packaging to enclose and protect the primary receptacle(s). Several cushioned primary receptacles can be placed in one secondary packaging, but sufficient absorbent material should be used to absorb all fluid in case of breakage c. Outer packaging secondary packaging is placed in an outer shipping packaging with suitable cushioning material. Outer packaging should protect contents from physical damage during transit.

20 Documents Labels and labeling Product Shipping containers Other documents COA Package inserts CDC Importation permits DOT Importation Customs USDA Statement

21 Shipping Routes Land, air Time in route Temperature Ambient Cold 2-10 C Frozen 30 or =130 C Other concerns Exposure to light Exposure to irradiation Biohazardous spills / leaks Monitoring Continuous Above / below a given temp Mean kinetic temperature

22 Selection of Courier Local sites near originating source Choose based on: Point of entry for clearing customs Experience Customer service Tracking Validated Containers Monitoring capability Ability to charge dry shipper or add Dry Ice while held in Customs

23 Courier Specifications Full GMP compliant storage facility Storage at appropriate temperature ranges controlled ambient (+15 C to +25 C) refrigerated (+2 C to +8 C) frozen (-20 C) deep frozen (-70 C) on demand Validated areas for kits & recalled drugs Facility to maintain optimum control and confidentiality. Separate area for both active and recalled drugs. Redundant system for temperature detection and data loggers with memory and graphic display for each temperature. Able to open shipping container and recharge (Dry Ice / LN2) Able to serve a Broker

24 Port of Entry s/ports/ A Port of Entry is any designated place at which a CBP officer is authorized to accept entries of merchandise to collect duties, and to enforce the various provisions of the customs and navigation laws (19 CFR 101.1). Operational Hours: Twenty Four (24) Hours A Day Seven Days A Week (7) Brokers : View List

25 FDA's Import Program File entry notice to ensure that FDA is notified of all regulated products imported into the United States, Entry bond filed with Customs. Examine or Not to Examine Compliant with the Act and related regulations, the shipment may be released If found in violation, the product will be detained Notice of Detention and Hearing Refusal of Admission re-export or destroy Application to Recondition - bring it into compliance with the Act. Detention Without Physical Examination

26 PHARMACEUTICALS The U.S. Federal Food, Drug, and Cosmetic Act prohibits the interstate shipment (which includes importation) of unapproved new drugs. Importation of drugs that lack FDA approval, whether for personal use or otherwise, is a violation of the above law Unapproved new drugs are any drugs, including foreign-made versions of U.S. approved drugs, that have not been manufactured in accordance with or pursuant to an FDA approval. Under the Act, FDA may refuse importation of any drug that appears to be unapproved

27 Exports Export of Drugs and Biologics Under the FDA Export Reform and Enhancement Act of 1996 A draft guidance document is available that summarizes and explains the basic requirements and procedures for exporting human drugs (also drug components) and biologics that may not be sold or distributed in the United States. This guidance document also summarizes and explains the requirements for exporting drugs that are approved for marketing in the United States, but which are being exported for an unapproved use. The draft guidance document is available online: Guidance for Industry: Exports Under the FDA Export Reform and Enhancement Act of It also provides contacts for additional information.

28 Formal and Informal Entries to CBP All articles offered for import with a value greater than $2000 are considered by CBP to be formal entries and require a formal entry bond, Under current CBP procedures, entries with a value less than $2000 do not require posting a redelivery bond. FDA is notified of all formal or informal entries of articles under FDA jurisdiction. When informal entries that include articles under FDA jurisdiction are to be sampled, or FDA believes the articles may be in violation of FDA law, FDA may request CBP convert the informal entry into a formal entry, which requires the posting of a redelivery bond. "Section 321 entry" is a term CBP uses for those entries with a value of $200 or less. These entries have a fair retail value of $200 or less, as evidenced by the bill of lading (or other document filed as the entry). They pass free of duty and tax, and are imported by one person on one day.

29 Broker s Power of Attorney The Power of Attorney (POA) is the foundation on which Customs brokerage business is built. In some Customs clearance situations, a properly-executed POA to clear the goods in your name and to prepare the necessary Customs documents to ensure a smooth clearance process. POAs are normally only needed when performing formal entries and restricted informal entries. It helps if your courier has POA. Should have the POA executed well in advance of arrival in order to prevent clearance delay. If courier has POA they become the Importer of Record and they act on your behalf as a representative to US Customs.

30 Broker and Importer Responsibilities Customs brokers are licensed by CBP You can review a list of customs brokers licensed to conduct CBP business in a specific port Even when using a broker, you, the importer of record, are ultimately responsible for the correctness of the entry documentation presented to CBP and all applicable duties, taxes and fees

31 Bioterrorism Act (BTA) Public Health Security and Bioterrorism Preparedness and Response Act of 2002 was signed into law as a direct response to the terrorist attacks of September 11, The BTA amended the Food Drug and Cosmetic Act (FDCA) intended to provide FDA with new inspection and enforcement tools to help the agency prevent and respond to a bioterrorism event.

32 Customs Mission Before September 11, 2001, the major responsibility of the former U.S. Customs Service was to administer the Tariff Act of 1930, as amended. Customs subsequently merged with other border enforcement agencies to become U.S. Customs and Border Protection CBP s priority mission became homeland security: detecting, deterring and preventing terrorists and their weapons from entering the United States.

33 What happens when things don t go as planned Shipment held in customs for paperwork Broker quits Breaks / leakage Product thaws, warms, freezers Pilot refuses boarding They insists on opening or irradiating the package / product No Stem Cells

34 Useful Links Centers for Disease Control and Prevention U.S. Customs and Border Protection U.S. Department of Transportation Pipeline and Hazardous Materials Safety Administration CDER Small Business and Industry Assistance: Import and Export of Human Drugs and Biologics tance/ucm htm International Air Transport Association