The ABCs of Importing and

Exporting Products, Samples and Biologics across International

Borders

Olive J Sturtevant, MHP,MT (ASCP)SBB, CQA

Director of CTQA

Dana Farber Cancer Institute, Boston, Ma

Quality and Operations Track 4 – Transport, Import and Export of Cell Therapy Products Fri 4/27/14 07:30 - 08:30

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

Types of Products

• HPC and other novel cell products (351 & 361)

• Vectors

• Other biologics –

– Cytokines

– Platelet lysates

– Retronectin

• Medical Specimens

– Research samples

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

• Category A - Infectious substances,

– (UN 2814) affecting humans

– (UN 2900) affecting animals

• 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

CDC Categories:

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

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”

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 73.16 or 9 CFR 121.16.

– 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 71.56.

– 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. §§ 151-159).

• 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 known to contain or suspected of containing an infectious biological agent, or has been rendered noninfectious.

CDC Application Process

• Request permit to Import http://www.cdc.gov/od/eaipp

• Biological Agent or Vector

• Permit to Import or Transport Live Bats

• Guidance documents online

• Permittee (Section A)

• Senders (Section B)

• Final Destination (Section D

Category A

Biosafety Measures

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

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.

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.

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.

USDA Statement Date: Shipper Address Responsible party Telephone # Consignee Address Responsible party Telephone # Contents PHS Permit n 2011-11-021 For Clinical trial Number of samples 25, number of mls 25, Lot # 12345 25 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

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.

Labeling / Documentation

• Proper shipping name must be supplemented with the technical name (the recognized biological/scientific name of the micro-organism).

• 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

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.

Documents

• Labels and labeling

– Product

– Shipping containers

• Other documents

– COA

– Package inserts

• CDC Importation permits

• DOT

• Importation Customs

– USDA Statement

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

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

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

Port of Entry • http://www.cbp.gov/xp/cgov/toolbox/contact

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

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

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

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 199621. It also provides contacts for additional information.

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.

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.

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

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, 2001.

• 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.

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.

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

Useful Links

• Centers for Disease Control and Prevention http://www.cdc.gov • U.S. Customs and Border Protection http://cbp.gov/xp/cgov/trade/

• U.S. Department of Transportation Pipeline and Hazardous Materials

Safety Administration http://www.phmsa.dot.gov/home

• CDER Small Business and Industry Assistance: Import and Export of Human Drugs and Biologics

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/ucm052787.htm • International Air Transport Association http://www.iata.org