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Authorities and Procedures for Licensing Veterinary Biological Products in the United States
ADVANCESIN VETERINARYMEDICINE,VOL.41
Authorities and Procedures for Licensing Veterinary Biological Products in the United States DAVID A. ESPESETH AND THOMAS J. MYERS U.S. Department of Agriculture, Animal and Plant Health Inspection Service, Veterinary Services, Center for Veterinary Biologics, Riverdale, Maryland 20782 I. II. III. IV.
V. VI. VII. VIII. IX. X.
Introduction Organization Licensing Procedures for Conventional Vaccines and Bacterins Licensing Procedures for Nonconventional Products A. Recombinant Products B. Immunomodulators Conditional Licenses Licenses for F u r t h e r Manufacture Sublicensing Exemptions to Licensure Autogenous Products Summary Reference
I. I n t r o d u c t i o n
In the United States, veterinary biological products are regulated in accordance with the Virus Serum Toxin (VST) Act of 1913, as amended in 1985 (21 United States Code 151-159). The VST Act makes it unlawful to: 1. Prepare, sell, or ship any worthless, contaminated, dangerous, or harmful veterinary biological product in or from the United States. 2. Prepare, sell, or ship any veterinary biological product in or from 585
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the United States, unless it is prepared in a licensed establishment in compliance with U.S. Department of Agriculture regulations. The regulations developed to administer this Act are published in Title 9, Code of Federal Regulations (9 CFR), Parts 101-118 (January 1, 1996). The regulations define veterinary biological products to be: all viruses, serums, toxins, and analogous products of natural or synthetic origin, such as diagnostics, antitoxins, vaccines, live microorganisms, killed microorganisms, and the antigenic or immunizing components of microorganisms intended for use in the diagnosis, treatment, or prevention of diseases of animals (9 CFR 101.2).
For a biologics producer to demonstrate that a product is not worthless, contaminated, dangerous, or harmful, the producer must demonstrate that the product is pure, safe, potent, and efficacious [9 CFR 102.3(b)].
II. Organization
Within the USDA, the VST Act is administered by the Animal and Plant Health Inspection Service (APHIS), Veterinary Services, Center for Veterinary Biologics (CVB). Three primary units within CVB are responsible for the licensing, inspection, and testing functions of the Veterinary Biologics program:
1. Center for Veterinary Biologics--Licensing and Policy Development (CVB-LPD) in Riverdale, Maryland, is responsible for prelicensing activities, such as the review of license applications and the development and publication of licensing requirements and program policies. 2. Center for Veterinary Biologics-Inspection and Compliance (CVBIC) in Ames, Iowa, is responsible for postlicensing activities, such as inspection of establishments, release of product serials (lots) for marketing, receiving consumer complaints, and coordinating investigations of suspected violations of the VST Act. 3. Center for Veterinary Biologics-Laboratory (CVB-L) in Ames, Iowa, is responsible for conducting confirmatory tests on Master Seeds, Master Cells, and product serials (both prelicense and postlicense), and for developing new test methods, references, and reagents used in such tests. Further information concerning CVB and the Veterinary Biologics Program (including regulations, memorandums, and notices) can be
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obtained from the CVB home page on the Internet at http:// www.aphis.usda.gov/vs/cvb/index.html.
III. Licensing P r o c e d u r e s for Conventional Vaccines and Bacterins
Two types of licenses are required in order to produce and market a veterinary biological product in the United States (9 CFR 102.2)" 1. A United States Veterinary Biologics Establishment License. 2. A United States Veterinary Biological Product License. Procedures for the issuance of establishment and product licenses in the United States are designed to define and document what is being licensed and who will be responsible for the production and distribution of the product that is authorized. These procedures are also intended to ensure the purity, safety, potency, and efficacy of each product and the accuracy of labeling. To obtain a United States Veterinary Biologics Establishment License, an application (APHIS form 2001) must be filed with APHIS identifying the name and address of the applicant and any subsidiaries or divisions that will be doing business under the license. The application also identifies the person responsible for the license, including corporate officers for corporations. The following information must be submitted in support of an application for an establishment license (9 CFR 102.3): 1. An application for a U.S. Veterinary Biological Product License. 2. A copy of the articles of incorporation if the applicant or subsidiaries are incorporated. 3. Plot plans and blueprints of the facilities to be licensed and a legend that provides a brief description of the activities performed and equipment located in each room, including decontamination procedures and other precautions against cross-contamination. 4. A certificate from the appropriate water pollution control agency indicating that the establishment is in compliance with applicable water quality control standards. 5. A short resume describing the training and experience of those employees at the establishment who will be responsible for essential steps in production, testing, and initial distribution of product. Prior to issuing an establishment license, CVB-IC personnel conduct a prelicensing inspection of the facilities. Inspectors review the ade-
588
DAVID A. ESPESETH AND THOMAS J. MYERS
quacy of record-keeping systems designed to document each step in production. Inspectors also review the construction and operation of the establishment to validate that they are as represented on the blueprints and legends and to ensure that conditions are acceptable for production of the veterinary biological product intended to be licensed. Laboratory practices are observed to ensure that facilities are being operated at an acceptable standard. CVB-IC personnel train a person at the establishment to collect and submit valid samples from each serial (lot) of product for testing at CVB-L. Quality control testing and other compliance requirements are also reviewed at this time. The report of the prelicensing inspection is forwarded to CVB-LPD for consideration in the licensing process. If the establishment is found satisfactory in all regards, the establishment license is issued with the first product license [9 CFR 102.4, (a), (b)]. An application for a United States Veterinary Biological Product License (APHIS Form 2003) and the following information and data must be submitted during the licensing process for a new veterinary biological product [9CFR 102.3, (b) & 102.5]:
1. An Outline of Production: The Outline of Production is the detailed protocol for manufacturing and testing the product. The outline includes information on each microorganism (Master Seed) found in the product; the methods for culturing and harvesting the microorganisms; a stepwise description of the preparation of the product; and a description of the purity, safety, and potency tests conducted on the product (9 CFR 114.8 & 114.9). 2. Purity data: The production of a pure and uniform product is based on the Master Seed concept (9 CFR 113.8), in which a stock of a specifically identified microorganism is the source of all seed materials for production. In most cases, the final product must not be more than five serial passages from the Master Seed. The Master Seed, Master Cell Stock, primary cells, ingredients of animal origin, and final product must be tested for viral, bacterial, mycoplasmal, and fungal contamination. Eggs used in the production of biological products must be derived from specific-pathogen-free flocks. The purity and identity of Master Seeds and Master Cells are confirmed by testing conducted at CVB-L (9 CFR 113.25-113.32, 113.34, 113.36, 113.37, 113.42, 113.43, 113.46, 113.47, 113.51-113.53, 113.55, & Veterinary Biologics Memorandum No. 800.65 and 800.88). 3. Laboratory safety data: Safety testing may include a combination of various studies. Live virus vaccines are typically evaluated in the host animal using the product at a 10 • dose, while killed products are usually evaluated at a 1x dose. The vaccinated animals should be
LICENSING OF VETERINARYBIOLOGICALPRODUCTS
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evaluated both for systemic and local reactions. Live products must be characterized to determine if they have the ability to shed from the host and be transmitted to contact animals. Reversion-to-virulence (backpassage) studies are required to provide information on the genetic stability of live attenuated vaccines. Adjuvants for products used in food-producing animals must be approved by the USDA Food Safety Inspection Service (9 CFR 113.33, 113.38-113.41, 113.44, 113.45 & Veterinary Biologics [General Licensing Considerations] No. 800.201). 4. Efficacy data: Product efficacy must be demonstrated by statistically valid host animal vaccination and challenge studies. The vaccination must be conducted using an experimental product containing the minimum level of antigen prepared from the highest allowable passage level from the Master Seed, as defined in the Outline of Production. The precise challenge method and the criteria for determining protection vary with the immunizing agent. Sufficient data must be collected to validate each label claim; that is, each recommended route or method of administration, each recommended species or age of animal to be vaccinated, and any claims for degree or duration of protection must be supported (9 CFR 113.64-113.455 & Veterinary Biologics [General Licensing Considerations] No. 800.200). 5. Potency data: Potency tests are designed to measure the relative strength of a product. Data must be submitted to demonstrate that a proposed potency test is correlated with the host animal efficacy study. Potency tests are then conducted on each serial (lot) of product prior to release for marketing. For release of live vaccines, virus titrations or bacterial counts are used. For killed viral or bacterial products, potency tests may be conducted in laboratory or host animals (e.g., challenge or serology), or with quantitative in vitro methods (9 CFR 113.64113.455). 6. Field safety data: Field safety studies are designed to detect unexpected reactions (local lesions, morbidity, mortality, etc.) that may not have been observed during the development of the product. The tests are done on the host animal, at a variety of geographic locations, using large numbers of susceptible animals that the vaccine producer does not own. The test animals should represent all the ages and husbandry practices for which the product is indicated. A request to conduct a field safety trial must be reviewed and approved both by APHIS and by authorities in the cooperating States (9 CFR 103.3). 7. Three prelicensing serials: Licensees are required to produce and test three consecutive serials (lots) of final product in their licensed establishment in accordance with the approved Outline of Production. Samples of these serials are tested at CVB-L to confirm the purity,
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DAVID A. ESPESETH AND THOMAS J. MYERS
safety, and potency test results submitted by the producer. These serials are also used by the producer to conduct the field safety studies. Upon satisfactory completion of all requirements, including review and acceptance of labels and circulars, a U.S. Veterinary Biological Product License may be issued.
IV. Licensing Procedures for Nonconventional Products A. RECOMBINANT PRODUCTS
Master Seed viruses or bacteria developed through genetic recombination techniques present unique licensing considerations. These products must meet the same standards of purity, safety, potency, and efficacy required of conventional products. Additionally, the licensee must conduct studies to evaluate any potential effects on the h u m a n environment that could result from release of a live recombinant microorganism. This would include studies to: 1. Biochemically characterize the recombinant microorganism. 2. Evaluate its genetic stability (both in vitro and in vivo). 3. Examine for any changes in the tissue tropism or virulence of the microorganism in the host. 4. Assess its potential to shed from the host and spread to target and nontarget host species. 5. Evaluate its ability to persist in the environment. 6. Examine its potential to undergo recombination with similar field strains of the microorganism. The data from these studies are used by APHIS to conduct a risk analysis and to prepare an Environmental Assessment, in accordance with the National Environmental Policy Act (NEPA), prior to release of the product for field testing or licensure. The NEPA procedures also require public notification, through the Federal Register, of any recombinant microorganism release action to be taken by APHIS. B. IMMUNOMODULATORS
Products designed to enhance or suppress host immune responses are also licensed by APHIS. To be licensed, however, the product must meet the definition of a veterinary biological product and carry a claim for the prevention or treatment of a specific veterinary disease. Because of the unique nature of these products, specific standard requirements are not in place for licensing this product category. Neverthe-
LICENSING OF VETERINARY BIOLOGICAL PRODUCTS
591
less, the licensee must demonstrate the purity, safety, potency, and efficacy (as defined by the product claim) of the product prior to licensure. Clinical efficacy trials may be employed in place of typical vaccination-challenge trials to evaluate such products if an acceptable laboratory challenge model cannot be developed.
V. Conditional Licenses
APHIS may issue a conditional license in order to meet an emergency condition, limited market, local situation, or other special circumstance (9 CFR 102.6). Such a license may be approved under an expedited procedure, provided the product is shown to be pure and safe, and to have a reasonable expectation of efficacy. This process allows APHIS to:
1. Respond to emergency disease outbreaks. 2. License products for minor species and other limited market situations where the cost of establishing full efficacy before marketing would prohibit the development of needed products. 3. License needed products when host animal efficacy has been established, but difficulty in the development of a fully satisfactory potency test would result in undue delay in the issuance of a regular license. Conditional licenses are issued for a period of I year. Before reissuance, the licenses must demonstrate acceptable progress toward completion of host animal efficacy and/or potency tests. Labels for conditionally licensed products must bear a statement that the product is under conditional license and that potency and efficacy studies are in progress. Conditional licenses are not issued for any product already marketed under a regular license by another manufacturer.
VI. Licenses for Further Manufacture
Licensing products for further manufacture has permitted split manufacturing procedures, where two or more licensed establishments work together to produce a product. These are regular licenses for products that are only permitted to be shipped from one licensed establishment to another licensed establishment or for export. This procedure permits one company to obtain a license for further manufacture to prepare a product to a certain stage of production and ship it to a second company. The second company finishes the product and re-
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DAVID A. ESPESETH AND THOMAS J. MYERS
leases it under a regular license. Licensing in this manner has permitted the industry to take the best advantage of its production capacity and to expand company product lines without extensive development costs [9 CFR 114.3 (d) & Veterinary Services Memorandum No. 800.61]. VII. Sublicensing Sublicensing of a licensed product from one company to another is also permitted. In this process the company that has a license for the product contracts to transfer to a second company the data, technology, and materials necessary to produce the product. The Outline of Production must be transferred along with Master Seed and Master Cell Stock. The receiving company must repeat purity testing of the Master Seed and Master Cell Stock and do an immunogenicity test in a reduced number of animals to confirm previous data. Additional field safety studies are not required. This process has been useful in the transfer of products and technology from one company to another (Veterinary Services Memorandum 800.58).
VIII. Exemptions to Licensure Biological products may be produced and used in the absence of federal establishment and product licenses only under the following three circumstances" 1. Products used by USDA, or under USDA supervision, in a USDA disease control program (9 CFR 106). 2. Products prepared under state license, issued by a state program considered by APHIS to be equivalent to the federal program (9 CFR 107.2). Such products are limited to distribution only within the licensing state. (Currently, only California has such a program.) 3. Products prepared by a person for use in animals owned by that person or by a veterinarian for use under a veterinarian-clientpatient relationship (9 CFR 107.1).
IX. Autogenous Products Microorganisms isolated from diseased animals by a veterinarian or appropriate specialist may be submitted to a licensed establishment
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for preparation of an autogenous vaccine or bacterin (9 CFR 113.113). Such products carry the following restrictions: 1. They must carry a warning statement what the potency and efficacy of autogenous biologics have not been established. 2. They may only be used by or under the direction of a veterinarian or approved specialist. 3. Unless specifically exempted by APHIS, they may only be used in the herd or flock of origin. Groups of animals under the same ownership but at different locations are considered separate herds or flocks. 4. Unless specifically exempted by APHIS, production seed viruses or bacteria for autogenous products may not be older than 15 months from the date of isolation, or 12 months from the date of harvest of the first serial (lot) of product prepared from the seed, whichever comes first. 5. The expiration date for a serial of an autogenous product may not exceed 18 months from the date of harvest.
X. Summary The licensing procedures reviewed above provide a framework for the production of pure, safe, potent, and efficacious veterinary biological products. The licensing, inspection, and testing activities of the Veterinary Biologics program provide the oversight necessary to ensure the continued availability of high-quality veterinary biological products in the United States. REFERENCE Anonymous (1993). Autogenous biologics guidelines issued by AVMA. J. Am. Vet. Med. Assoc. 203, 175-176.
Authorities and Procedures for Licensing Veterinary Biological Products in the United States DAVID A. ESPESETH AND THOMAS J. MYERS U.S. Department of Agriculture, Animal and Plant Health Inspection Service, Veterinary Services, Center for Veterinary Biologics, Riverdale, Maryland 20782 I. II. III. IV.
V. VI. VII. VIII. IX. X.
Introduction Organization Licensing Procedures for Conventional Vaccines and Bacterins Licensing Procedures for Nonconventional Products A. Recombinant Products B. Immunomodulators Conditional Licenses Licenses for F u r t h e r Manufacture Sublicensing Exemptions to Licensure Autogenous Products Summary Reference
I. I n t r o d u c t i o n
In the United States, veterinary biological products are regulated in accordance with the Virus Serum Toxin (VST) Act of 1913, as amended in 1985 (21 United States Code 151-159). The VST Act makes it unlawful to: 1. Prepare, sell, or ship any worthless, contaminated, dangerous, or harmful veterinary biological product in or from the United States. 2. Prepare, sell, or ship any veterinary biological product in or from 585
586
DAVID A. ESPESETH AND THOMAS J. MYERS
the United States, unless it is prepared in a licensed establishment in compliance with U.S. Department of Agriculture regulations. The regulations developed to administer this Act are published in Title 9, Code of Federal Regulations (9 CFR), Parts 101-118 (January 1, 1996). The regulations define veterinary biological products to be: all viruses, serums, toxins, and analogous products of natural or synthetic origin, such as diagnostics, antitoxins, vaccines, live microorganisms, killed microorganisms, and the antigenic or immunizing components of microorganisms intended for use in the diagnosis, treatment, or prevention of diseases of animals (9 CFR 101.2).
For a biologics producer to demonstrate that a product is not worthless, contaminated, dangerous, or harmful, the producer must demonstrate that the product is pure, safe, potent, and efficacious [9 CFR 102.3(b)].
II. Organization
Within the USDA, the VST Act is administered by the Animal and Plant Health Inspection Service (APHIS), Veterinary Services, Center for Veterinary Biologics (CVB). Three primary units within CVB are responsible for the licensing, inspection, and testing functions of the Veterinary Biologics program:
1. Center for Veterinary Biologics--Licensing and Policy Development (CVB-LPD) in Riverdale, Maryland, is responsible for prelicensing activities, such as the review of license applications and the development and publication of licensing requirements and program policies. 2. Center for Veterinary Biologics-Inspection and Compliance (CVBIC) in Ames, Iowa, is responsible for postlicensing activities, such as inspection of establishments, release of product serials (lots) for marketing, receiving consumer complaints, and coordinating investigations of suspected violations of the VST Act. 3. Center for Veterinary Biologics-Laboratory (CVB-L) in Ames, Iowa, is responsible for conducting confirmatory tests on Master Seeds, Master Cells, and product serials (both prelicense and postlicense), and for developing new test methods, references, and reagents used in such tests. Further information concerning CVB and the Veterinary Biologics Program (including regulations, memorandums, and notices) can be
LICENSING OF VETERINARYBIOLOGICALPRODUCTS
587
obtained from the CVB home page on the Internet at http:// www.aphis.usda.gov/vs/cvb/index.html.
III. Licensing P r o c e d u r e s for Conventional Vaccines and Bacterins
Two types of licenses are required in order to produce and market a veterinary biological product in the United States (9 CFR 102.2)" 1. A United States Veterinary Biologics Establishment License. 2. A United States Veterinary Biological Product License. Procedures for the issuance of establishment and product licenses in the United States are designed to define and document what is being licensed and who will be responsible for the production and distribution of the product that is authorized. These procedures are also intended to ensure the purity, safety, potency, and efficacy of each product and the accuracy of labeling. To obtain a United States Veterinary Biologics Establishment License, an application (APHIS form 2001) must be filed with APHIS identifying the name and address of the applicant and any subsidiaries or divisions that will be doing business under the license. The application also identifies the person responsible for the license, including corporate officers for corporations. The following information must be submitted in support of an application for an establishment license (9 CFR 102.3): 1. An application for a U.S. Veterinary Biological Product License. 2. A copy of the articles of incorporation if the applicant or subsidiaries are incorporated. 3. Plot plans and blueprints of the facilities to be licensed and a legend that provides a brief description of the activities performed and equipment located in each room, including decontamination procedures and other precautions against cross-contamination. 4. A certificate from the appropriate water pollution control agency indicating that the establishment is in compliance with applicable water quality control standards. 5. A short resume describing the training and experience of those employees at the establishment who will be responsible for essential steps in production, testing, and initial distribution of product. Prior to issuing an establishment license, CVB-IC personnel conduct a prelicensing inspection of the facilities. Inspectors review the ade-
588
DAVID A. ESPESETH AND THOMAS J. MYERS
quacy of record-keeping systems designed to document each step in production. Inspectors also review the construction and operation of the establishment to validate that they are as represented on the blueprints and legends and to ensure that conditions are acceptable for production of the veterinary biological product intended to be licensed. Laboratory practices are observed to ensure that facilities are being operated at an acceptable standard. CVB-IC personnel train a person at the establishment to collect and submit valid samples from each serial (lot) of product for testing at CVB-L. Quality control testing and other compliance requirements are also reviewed at this time. The report of the prelicensing inspection is forwarded to CVB-LPD for consideration in the licensing process. If the establishment is found satisfactory in all regards, the establishment license is issued with the first product license [9 CFR 102.4, (a), (b)]. An application for a United States Veterinary Biological Product License (APHIS Form 2003) and the following information and data must be submitted during the licensing process for a new veterinary biological product [9CFR 102.3, (b) & 102.5]:
1. An Outline of Production: The Outline of Production is the detailed protocol for manufacturing and testing the product. The outline includes information on each microorganism (Master Seed) found in the product; the methods for culturing and harvesting the microorganisms; a stepwise description of the preparation of the product; and a description of the purity, safety, and potency tests conducted on the product (9 CFR 114.8 & 114.9). 2. Purity data: The production of a pure and uniform product is based on the Master Seed concept (9 CFR 113.8), in which a stock of a specifically identified microorganism is the source of all seed materials for production. In most cases, the final product must not be more than five serial passages from the Master Seed. The Master Seed, Master Cell Stock, primary cells, ingredients of animal origin, and final product must be tested for viral, bacterial, mycoplasmal, and fungal contamination. Eggs used in the production of biological products must be derived from specific-pathogen-free flocks. The purity and identity of Master Seeds and Master Cells are confirmed by testing conducted at CVB-L (9 CFR 113.25-113.32, 113.34, 113.36, 113.37, 113.42, 113.43, 113.46, 113.47, 113.51-113.53, 113.55, & Veterinary Biologics Memorandum No. 800.65 and 800.88). 3. Laboratory safety data: Safety testing may include a combination of various studies. Live virus vaccines are typically evaluated in the host animal using the product at a 10 • dose, while killed products are usually evaluated at a 1x dose. The vaccinated animals should be
LICENSING OF VETERINARYBIOLOGICALPRODUCTS
589
evaluated both for systemic and local reactions. Live products must be characterized to determine if they have the ability to shed from the host and be transmitted to contact animals. Reversion-to-virulence (backpassage) studies are required to provide information on the genetic stability of live attenuated vaccines. Adjuvants for products used in food-producing animals must be approved by the USDA Food Safety Inspection Service (9 CFR 113.33, 113.38-113.41, 113.44, 113.45 & Veterinary Biologics [General Licensing Considerations] No. 800.201). 4. Efficacy data: Product efficacy must be demonstrated by statistically valid host animal vaccination and challenge studies. The vaccination must be conducted using an experimental product containing the minimum level of antigen prepared from the highest allowable passage level from the Master Seed, as defined in the Outline of Production. The precise challenge method and the criteria for determining protection vary with the immunizing agent. Sufficient data must be collected to validate each label claim; that is, each recommended route or method of administration, each recommended species or age of animal to be vaccinated, and any claims for degree or duration of protection must be supported (9 CFR 113.64-113.455 & Veterinary Biologics [General Licensing Considerations] No. 800.200). 5. Potency data: Potency tests are designed to measure the relative strength of a product. Data must be submitted to demonstrate that a proposed potency test is correlated with the host animal efficacy study. Potency tests are then conducted on each serial (lot) of product prior to release for marketing. For release of live vaccines, virus titrations or bacterial counts are used. For killed viral or bacterial products, potency tests may be conducted in laboratory or host animals (e.g., challenge or serology), or with quantitative in vitro methods (9 CFR 113.64113.455). 6. Field safety data: Field safety studies are designed to detect unexpected reactions (local lesions, morbidity, mortality, etc.) that may not have been observed during the development of the product. The tests are done on the host animal, at a variety of geographic locations, using large numbers of susceptible animals that the vaccine producer does not own. The test animals should represent all the ages and husbandry practices for which the product is indicated. A request to conduct a field safety trial must be reviewed and approved both by APHIS and by authorities in the cooperating States (9 CFR 103.3). 7. Three prelicensing serials: Licensees are required to produce and test three consecutive serials (lots) of final product in their licensed establishment in accordance with the approved Outline of Production. Samples of these serials are tested at CVB-L to confirm the purity,
590
DAVID A. ESPESETH AND THOMAS J. MYERS
safety, and potency test results submitted by the producer. These serials are also used by the producer to conduct the field safety studies. Upon satisfactory completion of all requirements, including review and acceptance of labels and circulars, a U.S. Veterinary Biological Product License may be issued.
IV. Licensing Procedures for Nonconventional Products A. RECOMBINANT PRODUCTS
Master Seed viruses or bacteria developed through genetic recombination techniques present unique licensing considerations. These products must meet the same standards of purity, safety, potency, and efficacy required of conventional products. Additionally, the licensee must conduct studies to evaluate any potential effects on the h u m a n environment that could result from release of a live recombinant microorganism. This would include studies to: 1. Biochemically characterize the recombinant microorganism. 2. Evaluate its genetic stability (both in vitro and in vivo). 3. Examine for any changes in the tissue tropism or virulence of the microorganism in the host. 4. Assess its potential to shed from the host and spread to target and nontarget host species. 5. Evaluate its ability to persist in the environment. 6. Examine its potential to undergo recombination with similar field strains of the microorganism. The data from these studies are used by APHIS to conduct a risk analysis and to prepare an Environmental Assessment, in accordance with the National Environmental Policy Act (NEPA), prior to release of the product for field testing or licensure. The NEPA procedures also require public notification, through the Federal Register, of any recombinant microorganism release action to be taken by APHIS. B. IMMUNOMODULATORS
Products designed to enhance or suppress host immune responses are also licensed by APHIS. To be licensed, however, the product must meet the definition of a veterinary biological product and carry a claim for the prevention or treatment of a specific veterinary disease. Because of the unique nature of these products, specific standard requirements are not in place for licensing this product category. Neverthe-
LICENSING OF VETERINARY BIOLOGICAL PRODUCTS
591
less, the licensee must demonstrate the purity, safety, potency, and efficacy (as defined by the product claim) of the product prior to licensure. Clinical efficacy trials may be employed in place of typical vaccination-challenge trials to evaluate such products if an acceptable laboratory challenge model cannot be developed.
V. Conditional Licenses
APHIS may issue a conditional license in order to meet an emergency condition, limited market, local situation, or other special circumstance (9 CFR 102.6). Such a license may be approved under an expedited procedure, provided the product is shown to be pure and safe, and to have a reasonable expectation of efficacy. This process allows APHIS to:
1. Respond to emergency disease outbreaks. 2. License products for minor species and other limited market situations where the cost of establishing full efficacy before marketing would prohibit the development of needed products. 3. License needed products when host animal efficacy has been established, but difficulty in the development of a fully satisfactory potency test would result in undue delay in the issuance of a regular license. Conditional licenses are issued for a period of I year. Before reissuance, the licenses must demonstrate acceptable progress toward completion of host animal efficacy and/or potency tests. Labels for conditionally licensed products must bear a statement that the product is under conditional license and that potency and efficacy studies are in progress. Conditional licenses are not issued for any product already marketed under a regular license by another manufacturer.
VI. Licenses for Further Manufacture
Licensing products for further manufacture has permitted split manufacturing procedures, where two or more licensed establishments work together to produce a product. These are regular licenses for products that are only permitted to be shipped from one licensed establishment to another licensed establishment or for export. This procedure permits one company to obtain a license for further manufacture to prepare a product to a certain stage of production and ship it to a second company. The second company finishes the product and re-
592
DAVID A. ESPESETH AND THOMAS J. MYERS
leases it under a regular license. Licensing in this manner has permitted the industry to take the best advantage of its production capacity and to expand company product lines without extensive development costs [9 CFR 114.3 (d) & Veterinary Services Memorandum No. 800.61]. VII. Sublicensing Sublicensing of a licensed product from one company to another is also permitted. In this process the company that has a license for the product contracts to transfer to a second company the data, technology, and materials necessary to produce the product. The Outline of Production must be transferred along with Master Seed and Master Cell Stock. The receiving company must repeat purity testing of the Master Seed and Master Cell Stock and do an immunogenicity test in a reduced number of animals to confirm previous data. Additional field safety studies are not required. This process has been useful in the transfer of products and technology from one company to another (Veterinary Services Memorandum 800.58).
VIII. Exemptions to Licensure Biological products may be produced and used in the absence of federal establishment and product licenses only under the following three circumstances" 1. Products used by USDA, or under USDA supervision, in a USDA disease control program (9 CFR 106). 2. Products prepared under state license, issued by a state program considered by APHIS to be equivalent to the federal program (9 CFR 107.2). Such products are limited to distribution only within the licensing state. (Currently, only California has such a program.) 3. Products prepared by a person for use in animals owned by that person or by a veterinarian for use under a veterinarian-clientpatient relationship (9 CFR 107.1).
IX. Autogenous Products Microorganisms isolated from diseased animals by a veterinarian or appropriate specialist may be submitted to a licensed establishment
LICENSING OF VETERINARY BIOLOGICAL PRODUCTS
593
for preparation of an autogenous vaccine or bacterin (9 CFR 113.113). Such products carry the following restrictions: 1. They must carry a warning statement what the potency and efficacy of autogenous biologics have not been established. 2. They may only be used by or under the direction of a veterinarian or approved specialist. 3. Unless specifically exempted by APHIS, they may only be used in the herd or flock of origin. Groups of animals under the same ownership but at different locations are considered separate herds or flocks. 4. Unless specifically exempted by APHIS, production seed viruses or bacteria for autogenous products may not be older than 15 months from the date of isolation, or 12 months from the date of harvest of the first serial (lot) of product prepared from the seed, whichever comes first. 5. The expiration date for a serial of an autogenous product may not exceed 18 months from the date of harvest.
X. Summary The licensing procedures reviewed above provide a framework for the production of pure, safe, potent, and efficacious veterinary biological products. The licensing, inspection, and testing activities of the Veterinary Biologics program provide the oversight necessary to ensure the continued availability of high-quality veterinary biological products in the United States. REFERENCE Anonymous (1993). Autogenous biologics guidelines issued by AVMA. J. Am. Vet. Med. Assoc. 203, 175-176.