AQUACULTURE DRUGS FDA PROSPECTIVE

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AQUACULTURE DRUGSFDA PROSPECTIVE

• Barbara Montwill
• FDA/CFSAN
• Office of Seafood
• Shrimp School 2005
• University of Florida

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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)

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Aquaculture

• Aquaculture 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

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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

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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

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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

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Aquaculture Drugs

• As defined by the Federal Food, Drug
• And 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

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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

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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)

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Aquaculture Drugs

• New 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

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Aquaculture Drugs

• Drugs are approved
• dosage
• route of administration
• species
• limitation of use/ indication for use
• frequency

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Aquaculture Drugs

• Any 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)

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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 cant be harmful residues

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Aquaculture Drugs

• Drugs banned for extra-label use in food
• animals
• 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.

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Aquaculture DrugsApproved

• Current Drugs Approved for
• Aquaculture in USA (Total 6)
• Chorionic gonadotropin (HCG)
• Formalin
• Oxytetracycline
• Sulfadimethoxine-ormetoprim
• Sulfamerazine
• Tricaine methanesulfonate (MS-222)

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Aquaculture DrugsApproved

• Drugs approved for use in shrimp in
• the U.S.
• Formalin (control external protozoan parasites)
• Some drug use under an Investigational New Animal
  Drug (INAD)

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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

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Aquaculture DrugsLow Regulatory Priority

• Acetic Acid
• Calcium Chloride
• Calcium Oxide
• Carbon Dioxide Gas
• Fullers 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

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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)

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Aquaculture Drugs

• Details information on the approved products
  available at CVMs Website
• www.fda.gov/cvm

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FDA testing program
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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

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FDA testing program

• Shrimp
• Chloramphenicol
• Nitrofurans
• Fluoroquinolones
• Oxytetracycline
• Quinolones Qxolinic Acid and Flumequine
• Catfish
• Fluoroquinolones
• Malachite green
• Quinolones Oxolinic Acid and Flumequine

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FDA testing program

• Salmon
• Quinolones Flumequine
• Ivermectin
• Oxolinic Acid
• Malachite green
• Crab
• Chloramphenicol

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FDA testing program

• Seafood products tested
• Domestic
• Import

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FDA testing program

• Countries sampled based on where
• product is imported from
• Shrimp
• Brazil
• Ecuador
• Indonesia
• Thailand
• Vietnam
• China
• India

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FDA testing programChloramphenicol

• Chloramphenicol has never been approved for use
  in food producing animals
• Causes aplastic anemia in humans
• Adverse reactions not dose dependent and safe
  level of exposure had not been determined
• Oral solution withdrawn because of documented
  history of misuse in food animals

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FDA testing programNitrofurans

• Nitrofurans (except topical applications) were
  banned for use in food animals in 1991.
• Considered carcinogen
• Recently have banning topical uses for food
  animals due to residues concerns

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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)

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FDA testing program

• FDA determination of violation is
• based on drug residues findings with approved
  regulatory method
• Determinative Method
• Confirmatory Method

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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 CFSANs Website
• www.cfsan.fda.gov/seafood1.html

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REQUIRMENTS FOR IMPORTED PRODUCTS
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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.

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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

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Importer Verification Written Verification
Procedures

• Obtaining the processors 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 processors
  facilities

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Importer Verification Written Verification
Procedures

• Maintaining the processors 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

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Detention Procedures for Imported Products
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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

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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

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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

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Detention requirements for individual shipments

• Individual 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

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Detention requirements removal from DWPE

• Firms, 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

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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

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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

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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

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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
• Importers 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

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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 entrys compliance
  with applicable laws and regulations.

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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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Shrimp School Raffle Time
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