[Author’s Note: USDA Center for Veterinary Biologics (CVB) Senior Biologics Specialist Kendall Graber discussed how the USDA manages compliance to the Title 9 regulations for animal biologics at the virtual International GMP Conference in March. Part I provided background on USDA’s authorities in this area while Part II provided a comparison of GMPs in 21 CFR and requirements in 9 CFR—the similarities, and differences—and CVB’s compliance program. Part III below covers a review of expectations outlined in VS Memos 800.206, 800.91, and 800.51 and discussion of key 9 CFR sections and what is looked for on inspection to comply with each.]

Documentation is Ubiquitous

One of the ways CVB manages compliance is through onsite inspections. Veterinary Services memorandum 800.91 defines 14 categories of inspection (Figure 1). Inspectors can inspect the entire premises of the establishment, all buildings, all biological products, all materials and equipment, the methods used, and any record pertaining to production, testing, storage, disposition, sale, or distribution of veterinary biologics products.

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Graber provided an overview of CVB’s processes for several of the expectations (as discussed in Part II) that are comparable to GMPs. “But before I do, you may notice that documentation is not one of the categories. This is not because it is not important. Rather, it is because it is integral to every category. 9 CFR 116, records and reports, covers these requirements.”

9 CFR 116.1 requires detailed reports of all information necessary for a complete accounting of activities. It requires contemporaneous record-keeping, recording of when actions took place, and sufficient details of the events throughout the entire process. The records must be legible and indelible, must be detailed enough to provide an understanding of what happened, and must be verified by a second individual.

The 14 Inspection Categories

Next, the CVB biologics specialist presented the key categories that are described in VS memo 800.91 and the related 9 CFR requirements that are commonly reviewed on inspection (Figure 1). He explained that he was not presenting a complete list of references or procedures.

Figure 3 Fourteen Categories of Inspection
FIGURE 1 | Fourteen Categories of Inspection

The examples Graber provided are listed with the 9 CFR reference and section topic in bold followed by more detail on the expectations and what CVB looks for on inspection related to that regulation. The test was taken directly from his verbal comments.

9 CFR 114.7: Personnel working in areas where products are manufactured and tested should receive training and periodic retraining specific to their duties and the products manufactured.

“On inspection we observe operations to determine if employees appear to be adequately trained and supervised, demonstrating competence in good laboratory techniques and preparation of veterinary biologics products. We also review training records for selected individuals.”

9 CFR 102.4: Facilities and Equipment states that an inspection shall be made to determine whether the condition, equipment, facilities, and the like, and the methods used to prepare biologic products are in conformity with the requirements in the regulations.

“On inspection, we will review the facilities and equipment to ensure they match what is recorded on the filed facility documents. We will verify that the condition of the facilities and the equipment assure consistency, and to assure that the products accomplish the purpose for which they are intended. We also ensure other operations where live biological agents are handled, including organisms used within quality control, are appropriate, contained, and separated as required.”

Outline of Production

In the process of product licensure, a firm must provide an “outline of production” detailing how the product is prepared. CVB must have an outline of production on file for each licensed biological product.

Preparation of a biological product in a licensed establishment must be done in accordance with the outline of production, which must be prepared as proscribed in 9 CFR 114.9. It is the agreement between the firm and the CVB on how the product will be produced.

The outline of production contains six sections and is further described in VS memo 800.206. Standardization of the outline ensures consistent placement of key information used in regulating veterinary biologics.

Outlines are to be written in a manner that ensures consistent production and testing methods. It should have enough detail to ensure consistent manufacture of all serials (Figure 2).

Figure 4 Outline of Production
FIGURE 2 | Outline of Production

Production, Packaging and Labeling, Distribution, GPV, Deviations

9 CFR 102.5: Production requires that products are prepared as described in the outline of production.

“On inspection, we observe production procedures in progress for compliance with the outline of production. We verify their records are complete and that each critical step is listed in the outline of production.

We view records of production for accountability and identification by tracing serials and production lots from raw materials to filling. We determine if the manufacturer’s record keeping system provides for unique identification, tracking, and recording of each ingredient, and if safeguards are in place to prevent errors in the preparation of the product.

If record-keeping deficiencies are found, we determine if they apply only to that serial or if there are consistent deficiencies for that product, group of products, or all products. We will select serials and determine if they have been prepared according to the version of the outline of production in effect when the lot was presented to CVB for market release.”

9 CFR 112.1: Packaging and Labeling states that only approved labels should be used and must be used correctly.

“On inspection, we review the methods used to ensure the correct label with the correct serial number and expiration date are used for each label and packaging event.

We want to ensure that the firm maintains accountability for all labels printed for use on licensed product. Licensees or permitees are prohibited from marketing a serial or product until they receive notification from APHIS of the disposition authorized to market release or shipment of that serial.

Licensees or permitees are prohibited from marketing a serial or product until they receive notification from APHIS of the disposition authorizing the market release or shipment of that serial.”

9 CFR 116.2: Distribution requires firms to maintain detailed disposition records.

“On inspection, we will evaluate the firm’s inventory control prior to release and during distribution, and we will evaluate if the product has been distributed prior to approval for release.

We will review distribution records for accuracy and adequacy for inventory control and determine if the firm can carry out a total stock scale recall down to the user level should it become necessary. We will also determine if cooler space is adequate for licensed product at the normal level of production, and confirm the storage temperature is maintained within the acceptable temperature limits.”

VS Memo 800.91: Miscellaneous. “Under this category, we review the firm’s pharmacovigilance program. We will review the firm’s adverse event reports and evaluate the investigations and actions taken. We also ensure that final product samplers are adequately trained and authorized, as well as verifying storage locations and storage conditions of APHIS reserve samples.”

VS Memo 800.210: Manufacturing Deviations. “We review investigation procedures for process deviations and quality effects including procedures for root cause analysis as described in VS memoranda.

On inspection, we will review the reports to determine if the investigation procedure was followed, and review evaluation of effectiveness of the corrective and preventive actions. We will also verify that products found unsatisfactory have been destroyed and properly reported; determine if there was an investigation as to why the product was found unsatisfactory for marketing; and if any corrective or preventive actions were taken.”

Animal Origin Materials and Species Requirements

Another parallel between 9 CFR and 21 CFR Graber mentioned previously was material supply requirements. One of the ways to ensure quality is through production standards such as the control of starting materials.

9 CFR 113.50: Ingredients of biological products requires all ingredients to meet accepted standards of purity and quality.

 9 CFR 113.53: Ingredients of Animal Origin lays out the requirements for ingredients of animal origin. Specifically, items not subjected to heat sterilization or other approved sterilization methods must be tested for extraneous agents by acceptable methods.

This testing serves as one of the mechanisms in the control of adventitious agents. The accepted test methods are described in 9 CFR 113. The general testing requirements for animal origin raw materials are:

  • 9 CFR 113.26, .27, and .28 which show methods for testing for bacteria, fungi, and mycoplasma
  • 9 CFR 113.46, which describes methods for testing for cytopathic and hemadsorbing agents
  • 9 CFR 113.47 describes fluorescent antibody testing for specific virus depending upon the source species of the material

9 CFR 113.47 defines specific diseases to be tested for based on the source of the materials. The regulation lays out specific requirements for testing of diseases which may be present in the animals from which the materials were derived. Some examples are bovine, caprine, and ovine cells tested for Bluetongue virus, and porcine origin for porcine parvovirus. This provides an additional level of protection based on the risks posed by each species.

9 CFR 113.47 also defines specific diseases to be tested for regardless of the species source of the materials. All animal origin raw materials shall be tested for bovine viral diarrhea virus, reovirus, and rabies virus. Testing is performed on a cell line of the same species of origin as the ingredient, and any evidence of cytopathic effect produces an unsatisfactory result.

Master seed testing is performed on a cell line of the species for which the vaccine is recommended. While some species barriers may exist, infectious agents can and do cross species and pose a risk to susceptible hosts.

In addition to testing requirements, VS memorandum 800.51 defines sourcing requirements for ingredients of animal origin. Specifically, animal origin raw materials are to be sourced from the United States, or countries considered free, low risk, or not infected with foreign animal diseases of concern, and with negligible or controlled risk of bovine spongiform encephalopathy according to APHIS animal disease status designations. The animal disease status can be found on the USDA website.

[Editor’s Note: Part IV, the final part of this four-part series, will examine CVB’s international activities.]

[Related: Animal health manufacturers are invited to try out Redica Systems for free. Click here to gain limited access to the platform.]

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