Author’s Note: The following is the conclusion of a four-part series covering a presentation by USDA Center for Veterinary Biologics (CVB) Senior Biologics Specialist Kendall Graber at the International GMP Conference held virtually in March 2021. Part IV covers CVB’s role in product testing and release, and market release of serials, international harmonization efforts, and CVB’s work with international partners such as VICH and CAMEVET.

Part I provided background on CVB while Part II compared GMPs in 21 CFR and requirements in 9 CFR and Part III offered an in-depth look at expectations under 9 CFR.

CVB Aims to Protect the U.S. Herd

One of the primary goals of CVB is protection of the U.S. herd. In addition to performing the inspection and licensing functions discussed earlier in this series, CVB closely monitors the quality of vaccines used in the United States by performing random and release testing on vaccine production lots, called “serials.” In addition, it monitors herd health in other countries, restricts importation of animal origin materials from countries where serious disease issues are taking place, and participates in international harmonization efforts.

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VS memorandum 800.51 lists five foreign animal diseases of specific concern. They are:

  • Foot and mouth disease
  • African swine fever
  • Classical swine fever
  • Highly pathogenic avian influenza
  • Newcastle disease

No ingredients of mammalian origin may be sourced from a country if foot and mouth disease, African swine fever, or classical swine fever is present in any region of the country.

If an outbreak of any of these diseases occurs in countries providing ingredients of animal origin, the CVB must be consulted for an assessment of the risk. A risk assessment, including an analysis of the risk of contamination to licensed biologics, must be submitted to the CVB for review to justify using an ingredient of animal origin from a country that has a foreign animal disease of concern. This determination does not abrogate any other import requirements—all national import and export services restrictions still apply.

In addition to testing of starting materials, the CVB also requires final product testing prior to market release. Section five of each outline of production (see Part III) must indicate the stages of preparation of the biological product in which the samples are collected.

Marketing Serials Requires CVB Approval

The outline of production discussed in depth in Part 3 must reference all applicable standard requirements. These are described in 9 CFR 113. The outline must also describe all additional tests, in detail, and state the minimum requirement for each satisfactory test. And finally, each product must be tested as described in the outline.

9 CFR 116.7 requires detailed records of all tests conducted on each serial and subserial to be maintained by the licensee. It also states that summaries of the tests shall be prepared and submitted to the CVB using APHIS form 2008 or an acceptable equivalent prior to the release of the serial or sub-serial.

“I should also mention that while on inspection we review laboratory records for testing performed, especially testing required by the outline of production,” Graber said. “These include selected tests for raw materials and other ingredients, bulk lots, serials, seeds, cell stocks, and diluents.”

Licensees or permittees are prohibited from marketing a serial of licensed product until they have received notification from CVB of the disposition authorizing the market release or shipment of the serial. If there are enough samples to conduct potency testing, those are submitted to the CVB along with the APHIS form 2008 documenting satisfactory test results.

A portion of the samples is stored, allowing CVB to maintain a repository of all serials released to the market. Both submissions are required for a serial to be considered eligible for release. Serials may be tested by the CVB laboratory, but not all serials are tested by the CVB. The selection may be random or based on risk, and the serial may be tested for more than one release parameter.

In addition to testing of starting materials, the CVB also requires final product testing prior to market release

If a serial is selected for testing, that serial is not eligible for release until the testing is complete, the results are validated, and the data is entered into the CVB database. The APHIS form 2008 with test information is reviewed for compliance to the outline of production. The disposition of the serial is evaluated and recorded on the form.

The form may be audited back if it is incomplete or if additional information is required for evaluation. When the form 2008 is processed, the laboratory test report is sent back to the firm as part of the information.

In addition to inspections and review of serials prior to release, CVB performs other post-licensing activities. Compliance activities include product surveillance through pharmacovigilance, stability monitoring by testing selected products prior to expiration, and investigations when compliance issues are reported.

“We also exercise some regulatory flexibility, such as evaluating requests for extension of dating on a case-by-case basis,” Graber explained. “And we evaluate requests to reprocess product which may not have met one of the parameters of the outline of production, as well as requests for changes in production processes or facilities.”

Requests for GMP Certification

Graber addressed how his agency responds to requests from foreign countries for GMP certification prior to allowing import of a product from the U.S. (Figure 1).

Figure 5 Facilitation of U.S. Exports
FIGURE I | Facilitation of U.S. Exports

“When requested,” he explained, “we provide documentation that a firm is authorized to manufacture, package, and sell veterinary medicinal products in the United States using the principles of good manufacturing as required of the Virus-Serum-Toxin Act and regulations pursuant to that act.”

CVB also provides documentation that specific products are manufactured in accordance with the principles and practices of good manufacturing, as required by the Virus-Serum-Toxin Act and regulations and standards pursuant to the act. “We have also recently implemented a certificate of inspection similar to the GMP certificates issued by other regulatory bodies after onsite inspections,” the CVB official said.

In addition to inspections and review of serials prior to release, CVB performs other post-licensing activities

When exported to other countries, products from the United States are subjected to many international standards. Some of the more recognizable are the ISO standards and those of the World Organization for Animal Health (also known as “Office International des Epizooties” (OIE), which issues manuals and standards. CVB provides comments to the OIE and is engaged in the creation of OIE documents.

The CVB also serves as a reference laboratory for rabies vaccines. “While structured differently, over 80% of the text of the GMP regulations is identical to ISO 9001,” Graber pointed out.

International Harmonization Efforts Underway

There has been some movement towards international harmonization of quality standards for veterinary biologics. These focus on the international standards for quality, including technical harmonization of processes and recognition of equivalents.

“Harmonization is a benefit since the individual requirements can result in duplicate and redundant testing,” Graber explained. “The CVB works with several groups involved with harmonization, such as the International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products, or VICH, the Canada-U.S. Trade Agreement, and the Committee for the Americas for Veterinary Medicine (CAMEVET).”

VICH was established in 1996 and is under the auspices of the OIE. It is a tripartite arrangement formally involving the EU, Japan, and the United States. Australia, New Zealand, Canada, and South Africa also participate.

VICH provides a basis for wider international harmonization of registration requirements. The working groups within the VICH include those focused on biologics quality, biologics stability, good clinical practice, pharmacovigilance, and target animal safety.

Canada and the United States have a history of cooperation and communication, due in part to the similarity of their programs. Some of the goals that have been established are mutual recognition of serial release testing and laboratory activities, as well as mutual recognition of inspection and licensing requirements and the coordinated review of applications and information exchange.

Currently, CVB exchanges information based on manufacturer approval and posts French Canadian translations of labeling material on its website.

CAMEVET was established in 2000. It includes representatives from the OIE and the Americas, regulatory entities, and the veterinary industry. It functions to support the international harmonization of registration norms and control of veterinary medicines.

“We are committing to harmonization and continued participation in international meetings and exchanging reference materials and information,” Graber stressed. “It is critical to maintain a transparent process for risk assessment-based international marketing of biologics. And although they are not stated as GMP, the 9 CFR standards are recognized worldwide.”

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