AQUACULTURE DRUGS

FDA PROSPECTIVE

Barbara MontwillFDA/CFSAN

Office of Seafood

Shrimp School 2005University of Florida

Aquaculture• Aquaculture – the fastest growing

business (10% per year)• Global aquaculture production

Estimated for 35 million metric tons (~30% of total seafood production)

Estimated production of farm-raised shrimp 2 million metric tons

• U.S. shrimp import: ~75% of total supply

7 countries account for about 70%(Thailand, China, Ecuador, Vietnam, India, Indonesia and Brazil)

AquacultureAquaculture production more intensive larger number of animals per

production unit higher farms density in an

area

Risk of rapid expansion poor water quality disease outbreaks environmental impact

Chemicals in Aquaculture Purpose and use

Sediment and water management Enhancement of aquatic productivity Feed formulation Manipulation and enhancement of

reproduction Growth promotion Health management Improvement of survival rates Transport of live organisms

Chemicals in Aquaculture Benefits (if carried out properly):

control of infection disease prophylactic measure against infections growth and productivity promoters

Concerns (over use or misuse): residue in edible portion developing bacterial resistance human health implications environmental implications

Pesticides Register and regulated by EPA

Federal Insecticide, Fugicide and Rodenticide Act (FIFRA)

Title 40 of the Code of Federal Regulations (CFR)

Use and condition specified on label

Aquaculture DrugsAs defined by the Federal Food, DrugAnd Cosmetic Act (FFDCA) a drug is:

articles recognized in the official United States Pharmacopeia

articles intended to use in diagnosis, cure, mitigation, treatment, or prevention of disease

articles intended to affect the structure or function of the body of man or animal

articles intended to be a component of above

Aquaculture Drugs

Intended use of a compound determines if a compound is a drug.

Antibiotics are drugs: they treat or mitigate disease or affect structure or function

Aquaculture Drugs ALL aquaculture drugs whether for direct

medication or for addition to feed must be approved for use in the US

As mandated by the Federal Food, Drug and Cosmetic Act, a new animal drug may not be sold in interstate commerce unless it is the subject of a New Animal Drug Application (NADA).

Use of unapproved drugs or misuse is a violation, product is adulterated under 21 U.S.C. Section 342 (a)(1) and Section 342 (a)(2)(C)

Aquaculture DrugsNew Animal Drug must be: Effective for the intended use Safe for the target animal Safe for human food (no harmful

residues) determine if the drug has potential to cause

adverse effects (e.g. cancer) determine a tolerance/ safety level

Safe for environment Safe for users

Aquaculture DrugsDrugs are approved: dosage route of administration species limitation of use/ indication for use frequency

Aquaculture DrugsAny deviation from the label is considered:

Extra-label use prohibited except under the provisions

of Animal Drug Use Clarification Act (AMDUCA), Title 21 Code of Federal Regulations Part 530 (21CFR530)

Aquaculture Drugs Only by a licensed veterinarian or under

his/her supervision The animal must be very sick or will die

w/out treatment The veterinary must be familiar w/ the

producers animals No new animal drug is approved for this

illness For food animals there can’t be harmful

residues

Aquaculture DrugsDrugs banned for extra-label use in foodanimals: Chloramphenicol; Clenbuterol; Diethylstilbestrol (DES); Dimetridazole; Ipronidazole (and other

nitroimidazoles); Furazolidone, Nitrofurazone (and other

nitrofurans) Sulfonamide drugs in lactating dairy cattle

(except approved use of sulfadimethoxine, sulfabromomethazine, and sulfaethoxypyridazine);

Fluoroquinolones; Glycopeptides.

Aquaculture DrugsApproved

Current Drugs Approved for Current Drugs Approved for

Aquaculture in USA (Total 6)Aquaculture in USA (Total 6)

Chorionic gonadotropin (HCG) Formalin Oxytetracycline Sulfadimethoxine-ormetoprim Sulfamerazine Tricaine methanesulfonate (MS-222)

Aquaculture DrugsApproved

Drugs approved for use in shrimp in Drugs approved for use in shrimp in

the U.S.:the U.S.:

Formalin (control external protozoan parasites)

Some drug use under an Investigational New Animal Drug (INAD)

Aquaculture Drugs FDA do not object use of drugs

determined to be new animal drugs of low regulatory priority if the following conditions are met: The substances are used for prescribed

indications, levels The substances used according to GMPs The substances are appropriate grade for use

in food animals There is not likely to be adverse effect on the

environment

Aquaculture DrugsLow Regulatory Priority

Acetic Acid Calcium Chloride Calcium Oxide Carbon Dioxide Gas Fuller’s Earth Garlic (whole form) Hydrogen Peroxide Ice Magnesium Sulfate

Onion (whole form) Papain Potassium Chloride Povidone Iodine Sodium Bicarbonate Sodium Chloride Sodium Sulfite Thiamine

Hydrochloride Urea and Tannic Acid

Aquaculture Drugs Classification of these substances as

new animal drugs of low regulatory priority are based on current knowledge and should not be considered as an approval

nor an affirmation of their safety and effectiveness

does not exempt facilities from complying with other environmental requirements (e.g. with National Discharge Elimination System requirements)

Aquaculture Drugs Details information on the approved

products available at CVM’s Website:

www.fda.gov/cvm

FDA testing program

FDA testing program Unapproved drugs

administered to aquaculture fish pose a potential human health hazard.

These substances may be carcinogenic, allergenic and/or may cause antibiotic resistance in man

?

FDA testing program Shrimp

Chloramphenicol Nitrofurans Fluoroquinolones Oxytetracycline Quinolones: Qxolinic Acid and Flumequine

Catfish Fluoroquinolones Malachite green Quinolones: Oxolinic Acid and Flumequine

FDA testing program Salmon

Quinolones: Flumequine Ivermectin Oxolinic Acid Malachite green

Crab Chloramphenicol

FDA testing program Seafood products tested

Domestic Import

FDA testing programCountries sampled based on where product is imported from:

Shrimp Brazil Ecuador Indonesia Thailand Vietnam China India

FDA testing programChloramphenicol

Chloramphenicol has never been Chloramphenicol has never been approved for use in food producing approved for use in food producing animals animals

Causes aplastic anemia in humansCauses aplastic anemia in humans

Adverse reactions not dose dependent Adverse reactions not dose dependent and safe level of exposure had not and safe level of exposure had not been determinedbeen determined

Oral solution withdrawn because of Oral solution withdrawn because of documented history of misuse in food documented history of misuse in food animalsanimals

FDA testing programNitrofurans

Nitrofurans (except topical Nitrofurans (except topical applications) were banned for use in applications) were banned for use in food animals in 1991. food animals in 1991.

Considered carcinogen Considered carcinogen Recently have banning topical uses for Recently have banning topical uses for

food animals due to residues concernsfood animals due to residues concerns

FDA testing program Because tested compounds are not

approved, presence of any residues is a violation

Only limitation is sensitivity of the analytical method, a limit of detection (LOD)

FDA testing programFDA determination of violation is

based on drug residues findings with approved regulatory method

Determinative Method Confirmatory Method

FDA testing programAnalytical methods

Analytical methods recommended by FDA

Chloramphenicol: Determiantion of Chloramphenicol Residues

in Shrimp and Crab Tissues by Electrospray Triple Quadrupole LC/MS/MS

LC/MS/MS Analysis of Chloramphenicol in Shrimp

Nitrofurans: Determination of Nitrofurans Metabolites in

Shrimp using LC/MS/MS Both methods are available at CFSAN’s

Website:www.cfsan.fda.gov/seafood1.html

REQUIRMENTS FOR IMPORTED PRODUCTS

Imported Products (21 CFR Part 123.12)

HACCP for all imported fish and fishery products

Under the US FDA Seafood HACCP regulation, aquaculture processors will be expected to reject fish from producers who use drugs illegally.

Importer Verification: Written Verification Procedures

Product specifications to ensure that the product is not injurious to health and not processed under insanitary conditions, and

Affirmative steps

Importer Verification: Written Verification Procedures

Obtaining the processor’s HACCP plan and sanitation records for the lot being entered

Obtaining either a continuing or lot-by-lot certification of proper drug usage

Regularly inspecting the foreign processor’s facilities

Importer Verification: Written Verification Procedures Maintaining the processor’s HACCP

plan and written guarantee that the product is processed in accordance with the U.S. requirements

Periodically end-product testing and written guarantee that the product is processed in accordance with the U.S. requirements

Detention Procedures for Imported Products

Types of detention DETENTION OF AN INDIVIDUAL ENTRY

- Stopping a shipment of an individual entry (due to sample collection or physical examination)

DETENTION WITHOUT PHYSICAL EXAMINATION (DWPE)- Stopping a shipment without collection of

a physical examination by FDA

Procedures for detention of individual entry

Appear violative after initial review of entry or exam

FDA samples and analyzes lot Lot released if no violation found Non-violation does not affect future shipment

Violative product not allowed entry

Procedures for Detention without Physical Examination (DWPE)

Detention based on past violative history (individual processors, countries or geographical area)

Import Alerts has been issued that may cover one or more firms or country

Detention requirements for individual shipmentsIndividual shipments may be released from detention if: The importer submit to FDA an Application for

Authorization to Reconditioning Each shipment is sampled and analyzed Analysis performed by a competent private

laboratory Lab results reported to FDA for review If not violative the shipment is released

Detention requirements –removal from DWPEFirms, countries or products may be removed from DWPE if: Minimum 5 consecutive non-violative

shipments in a 6 month period (can be multiple ports) FDA must be assured that firms are compliant

over a reasonable period to remove from DWPE At least one shipment audited by FDA to

ensure analytical validity Shipments are individual, routine,

commercial entries and represent separate production operations

Detention requirements –removal from DWPE

FDA may request additional documentation to ensure compliance with other provisions of U.S. laws and regulations

FDA may require an establishment inspection

Firms or countries must request removal in writing after 5 non-violative shipments in a 6 month period

Private Laboratories Private labs are employed for two

purposes: Testing of detained imports under FDA review Manufacturer/processor testing for quality

control, HACCP purposes FDA ORA Laboratory Manual provides

a guidance for private laboratories(section 7) This guidance applies only to laboratories

performing testing of product under DWPE

Private Laboratories FDA does not have authority to regulate a

private laboratory, but has legal authority over regulated import products tested and can based its decision on analysis performed by private laboratory

Good relationship is necessary FDA has option to audit Laboratory must be:

Credible Competent Uses standards Uniform Recognized current methods Practices quality assurance and quality control activities

Private Laboratories Submission to FDA Submit the private laboratory complete analytical

package to the servicing Laboratory for the Compliance Branch of your local FDA office.

A complete analytical package should include: Importer’s Certification Notice of FDA Action Form with Commercial Invoice Collection and Analysis Reports Analytical Results Summary Sheet Private Laboratory Certification Analytical Worksheet: including method reference,

validation of the method, instrumentation and operating parameters, all computer printouts, information on blank/fortification samples, certification of standard purity, quality controls applied and all other information necessary to determine the technical validity of the analysis

Private laboratories The Private Laboratory Guidance is

available through the FDA website:

www.fda.gov/ora/science_ref/lm/vol3/section/07.pdf

NOTE: While the guidance is written in reference to private laboratory, it is really the importer that is responsible for the entry’s compliance with applicable laws and regulations.

Private laboratories

FDA does not accept results of testing of product not under DWPE for the purpose of speeding entry reviews

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