RG-1 Regulatory Guidance:
Chapter 3 – Guidance on data requirements for feed approval and registration
3.31 Registration requirements for gut modifier products

• Background
• Regulatory status
• Approval and registration process steps for gut modifier – ingredients versus products
• Identification of the gut modifier ingredient(s)
• Registration of a gut modifier specialty product with claims

Background

Gut modifiers as livestock feed are products that, once fed, have a mode of action in the gastrointestinal (GI) tract of an animal.  They achieve this by acting on the feed itself while in the gut or by modifying the GI environment to provide a benefit to the animal or the environment as may be linked to a nutritional effect.

The gut modifier category can encompass a variety of feed ingredients, including new feed ingredients and new purposes for existing approved ingredients^Footnote 8. These ingredient types (sub-categories) may include, but are not limited to:

• viable microbial strains
• prebiotics
• postbiotics
• enzymes
• organic acids
• essential oils

Note that gut modifier products may be regulated as a veterinary drug or a feed depending on a number of criteria as described in the Guidance document on classification of veterinary drugs and livestock feeds. The document provides guidance, criteria and examples to help clarify the regulatory differences between veterinary drugs and feeds, and assists in determining the appropriate regulatory oversight for a product destined for oral use in livestock species.

Gut modifier products that directly target the reduction of  pathogens or aid in the treatment or mitigation of disease in the animal are considered to be veterinary drugs.

Regulatory status

The gut modifier category can be applied to ingredients (single ingredient feeds) or mixed feeds (specialty feeds). Approved ingredients must be categorized as a gut modifier.  As specialty products do not meet the exemption from registration criteria, as outlined in Section 5(2) of the Feeds Regulations, these must be registered by the Canadian Food Inspection Agency (CFIA) before their manufacture, sale or import in Canada.

The following section clarifies the overall process for approval of an ingredient as a gut modifier ingredient and the registration of a gut modifier specialty product.

Approval and registration process steps for gut modifier – ingredients versus products

Step 1 – Categorization of a gut modifier ingredient

A gut modifier ingredient is an active ingredient (for example, thymol) or source of an active ingredient (Yucca schidigera pulp powder) that, when fed, exhibits a mode of action in or on the gastrointestinal tract. Once an ingredient is approved as a gut modifier, it will be listed in Schedule IV indicating its approval as an ingredient for use as a component in a gut modifier product.

Note: a claim is not needed at the ingredient categorization step; however, an applicant may provide data to support a claim on the ingredient itself, as discussed below.

Step 2 – Registration of a gut modifier product with claims

Gut modifier products may be a single ingredient feed from the gut modifier category or a mixed feed containing 1 or more gut modifying ingredients (that is, as actives) and other non-active ingredients. 

Note that in some situations, an active ingredient from the gut modifier category may also be considered for registration as a single ingredient feed, as described below.

If an ingredient is to be used as a gut modifier product on its own, a company must supply data to support the gut modifier mode of action (as indicated in step 1) with a claim(s) for the ingredient alone. This ingredient could then be added to a mixed feed as a gut modifier on its own merit. In effect, this blends step 1 and step 2. The ingredient must meet the specifications as listed in the ingredient description and be used according to the approved directions for use (for example, rates of incorporation for the species/classes of livestock). This ingredient would receive a registration number.

For either situation,  a gut modifier product must be registered with claims supported by data demonstrating either:

• typical production/performance effects
• gut modifying effects, or
• a mixture of both

Note: 2 distinct applications can be submitted at the same time for step 1 and 2.

Identification of the gut modifier ingredient(s)

A gut modifier product must contain 1 or more identified active ingredient(s) that have been classified as gut modifier ingredients in Schedule IV.

The ingredient(s) that is (are) providing the gut modifier effect in a product must be identified as the active ingredient(s). There are 3 pathways for having an ingredient identified as a gut modifier.

1. If the ingredient is already listed in Schedule IV in the gut modifier sub-class, there is no need to request any further action. The ingredient must meet the specifications as listed in the ingredient description, be used according to any listed directions and meet all labelling requirements.
2. If the ingredient is an approved ingredient but not identified as a gut modifier in Schedule IV, a request to add a gut modifier purpose, with data to support a gut modifier mode of action, is required. If the intended use rate for gut modification exceeds a limit existing for the ingredient or is for a different species, safety data is required to modify the maximum levels and species/classes.
3. If the ingredient is not listed in Schedule IV or V, the ingredient is considered to be an unapproved ingredient, and a request for approval with a separate application is required. A safety assessment will be required along with information to support the gut modifier mode of action. The submission should follow the established route of submitting an application as per RG-1, Chapter 2 - 2.3 Single ingredient feed evaluation requirements.

A minimum of 1 study to demonstrate a gut modification effect must be provided for the ingredient from in-house research or scientific literature. Research should demonstrate that a mode of action is in the gut.

Studies may be either in vitro and/or in vivo. Some endpoints, such as gut integrity and microbiome, may be better supported with in vivo studies. In vitro studies are useful for providing data for mechanistic data with consideration of the species, feeding rates, and duration of feeding.

The studies do not have to be from an applicant's proprietary product; however, each study must clearly link to the ingredient which is the subject of the submission. Where published peer-reviewed studies are provided to support an application, bridging information must be provided to show the relevance of published studies to the application under review. The identity of the active gut modifier ingredient(s) in the studies should be demonstrated as being relevant to the submitted ingredient(s). Guidance may be found in the RG-1 Chapter 2.8 Guidance on bridging an application to data from publicly available literature and previously approved feed applications.

Note that data to support a specific claim is not necessary to have an ingredient approved and classified as a gut modifier in Schedule IV. The ingredient may only be used as a "component of a gut modifier" specialty product that will require registration with supported claims as described below.

Registration of a gut modifier specialty product with claims

This section is divided into the following 3 parts:

• Part 1 – Registration requirements for new gut modifier products
• Part 2 – Amendments to registrations of gut modifiers
• Part 3 – Renewal of registrations of gut modifiers

It is recommended that the data requirements outlined below be carefully reviewed and followed prior to submitting an application for feed registration to the CFIA.

After reviewing all documents, if specific questions on requirements remain, please contact the CFIA by email at: cfia.afp-paa.acia@inspection.gc.ca.

Part 1: Registration requirements for new gut modifiers

1.1 Administrative requirements

• Submit the application package for registration or approval as per section1.3.1 My CFIA online livestock feed applications of RG-1 Chapter 1
• For each application, data must be submitted with your application via My CFIA
  • Upload the following supporting documents in My CFIA at the appropriate section during the application process

If you are unable to sign up for My CFIA, refer to how to apply by mail.

1.2 Labelling

Proposed labels for gut modifiers must include the following, in addition to standard labelling requirements listed in RG-1, Chapter 4.1 – Labelling and guarantees - Labelling of livestock feed:

• product name
• the feed name on the label can include "gut modifier"
• complete list of ingredients
• a minimum guarantee for each of the active ingredients in the gut modifier product
• target livestock species and feed type
• directions for use and applicable use rates in line with the proposed claims on the label of the gut modifier
• proposed claim for the gut modification or effects in the gut and/or for animal performance (for example, may improve growth rate in pigs) when used or fed as directed
• date of manufacture
• shelf life
• recommended storage conditions to maintain activity until the expiration date

1.3 Product identification and description

1.3.1 General information

• short description  explaining the purpose of the product for registration
• identification of the gut modifier active ingredient(s) in the product (see Identification of the gut modifier ingredient(s) above) summary of documentation/information included with the application
• supportive information about approvals in other jurisdictions may be provided
• directions for use
• target livestock feeds
• proposed product claim(s)
• proposed shelf-life
• detailed product formulation and a complete list of ingredients identified by generic name as listed in the Schedules of the Feeds Regulations, and registration number for ingredients listed in Part II of the Schedules, or mixed feeds
• if the product is, or contains, an unapproved ingredient, additional information as per RG-1, Chapter 2 - 2.3 Single ingredient feed evaluation requirements

1.3.2 Analytical information

• certificates of analysis from 3 different and recent lots of the product to support claims, labelled guaranteed analysis and shelf-life stability
• analytical methodology used to substantiate the label guarantee(s) (if an accredited method is used, providing the reference name of the method will be acceptable)
• product sample or samples may be required to verify analytical methodologies and/or label guarantees
  • Samples will be requested on a case-by-case basis

Further guidance may be found in RG 6.4 – Guidance of the acceptability and preparation of certificates of analysis for livestock feed applications  and the International Cooperation for Convergence of Technical Requirements for the Assessment of Feed Ingredients (ICCF) Guidance on Stability testing of Feed Ingredients, Guidance on Stability testing of feed ingredients.

1.4 Requirements in support of product claims and other information

General criteria for acceptable scientific studies are outlined in RG-1, Chapter 2.2 - Registration requirements for specialty products

1.4.1 Studies in support of claims for gut modifier products

Gut modifier products are specialty feeds that must have claims and require registration. They may be a single ingredient feed from the gut modifier category or a mixed feed containing one or more gut modifying ingredients (that is, active and non-active ingredients). Claims are applied in either situation. Data to be submitted must support claims when the product is used or fed as directed on the label. Studies should be based on the final product(s) for which registration is sought.

Where the results of these studies have not been published in a peer-reviewed journal, raw data and statistical analyses must be submitted in their entirety for review.

A minimum of 3 studies are required to demonstrate the product's efficacy for each effect when fed as directed per the target livestock species and may include the production class if the claim necessitates that specification. Due to the potential for very different claims associated with gut modifier products, it is not possible to prescribe one specific set of requirements to support this category.

1.4.1.1 Studies for production and performance based claims

As gut modifier products are known to exhibit variable results in vivo, it will be necessary to submit 3 studies per species and production class. In this case, general production and performance claims may be supported by a combination of more than one endpoint exhibiting beneficial results per study. Beneficial effects can include improved growth, feed intake, weight gain or feed efficiency. More detail on flexibilities to the number and types of production performance studies is outlined in the RG-1 Chapter 2.9 Data flexibility for production performance endpoints and associated claims.

Note that the number of independent in vivo efficacy studies required depends on the number of target species/categories for which the application is made and the claims to be supported. Extrapolation of efficacy data from certain species to other physiologically related species is possible as, in principle, data can be extrapolated between physiologically similar species. The degree to which species are physiologically related is judged predominantly in terms of gastrointestinal function. Similarities in metabolism may also be considered. The interspecies extrapolation, however, can be applied only in case the animals are kept for the same purpose, that is, meat production or reproduction (including milk or egg production), the mode of action can reasonably be presumed to be the same between species and the effects claimed are the same. More detail on flexibilities to the number and types of production performance studies is outlined in the RG-1 Chapter 2.9 Data flexibility for production performance endpoints and associated claims.

1.4.1.2 Studies to support gut modification based claims

A minimum of 3 studies per species and production class are required to support a desired gut modification based claim. Studies must include at least one in vivo study and may also include in vitro studies. If an outcome is strongly correlated, such as, for example, an organic acid response in the microvilli, the number of required studies may be reduced if supported by a scientific rationale.

In some cases, in vitro models with robust data sets that have been repeatedly shown to have validity in vivo could be considered in support of claims.

Some considerations for studies include:

• Validated in vitro models could support the reduction of in vivo requirements
• In vitro models should be published and peer-reviewed
• Meta-analysis studies could be useful for these types of modes of action, but more details will be needed when using them to replace a distinct study

Depending on the mode of action and claim, it is clear that certain extrapolations across species may be made to reduce the number of trials in cases where a supported scientific rationale is provided.

While extrapolations from ruminant to ruminant or monogastric to monogastric animals could be indicated, extrapolations from ruminants to monogastric species may not be. Extrapolation from monogastrics to classes of ruminant livestock during the pre-rumination period may be considered. An example would be a gut modification effect that increases the surface area of microvilli in small intestine models.

In most cases, dosages would need to be species-specific and will depend on body weight, age, feed intake, etc. This is especially true for ruminants when trying to compare feeding rates from g per head per day (g/h/d) to kg/tonne of feed. In other words, this would not be different than for traditional performance/production type claims.

Treatments in vitro should be relevant to feed inclusion rates and species. In vitro studies could be considered; however, it may be difficult to extrapolate an in vitro treatment to an as-fed dosage or inclusion rate as would be indicated on the label.

1.4.2 Product stability and shelf life

For certain gut modifier product types, it will be necessary to support product stability and shelf life as stated on the product label. Typically, products which are protein-based can degrade when exposed to environmental conditions; these include enzymes, microbial strains, fermentation products, extracts and oils, and chelated products. It will be important to identify the active ingredient(s) and determine if one of the ingredient types listed above applies. The stability of these actives should be assessed accordingly.

The ICCF Guidance on stability testing of feed ingredients provides very detailed guidance on studies; however, the following are the minimal requirements to demonstrate maintenance of the claim over the specified shelf life.

Accelerated stability studies may be acceptable. Details are provided in a VICH guidance document as discussed here Stability: Stability testing of new veterinary drug substances (revision) (PDF)

1.4.2.1 Product stability in pelleted feeds

Likewise, a consideration that those actives identified above are not impacted following heat treatment during pelleting should be given. Pelleting studies must reflect the conditions recommended on the label.

1.5 Requirements in support of product safety

In cases where approved ingredients are already listed in the Schedules of the Feed Regulations, safety may have already been substantiated for the ingredient itself during the original approval process and may not require the submission of new safety studies to support the new purpose as a gut modifier.  If, however, the ingredient is a new ingredient, or its use has changed based on inclusion rates, duration of feeding, or species, a safety assessment will be required with the submission of data as outlined in:

• RG-1, Chapter 2 - Data requirements for single ingredient approval and feed registration
  • 2.4 Generic data requirements for safety evaluations of single ingredients
  • 2.5 Data requirements for product safety evaluations: Explanatory notes
  • 2.7 Guidelines for the assessment of novel feeds: microbial sources
• RG-1, Chapter 3.22 – Viable microbials and yeasts

Part 2: Amendments to registrations of gut modifiers

Registrants wishing to make a change to the formula or label of a registered product must submit an application package for an amendment to registration or approval as per section 1.3.1 My CFIA online livestock feed applications of RG-1 Chapter 1.

Data requirements for the changes are dependent on the type of changes being requested. Refer to the data requirements for that type of feed. Submit the documents in support of the changes with your application via My CFIA. Upload the supporting documents in My CFIA at the appropriate section during the application process.

Each change made to an existing registration must be detailed in the box Requested changes on the last application page review and submit.

Part 3: Renewal of registrations of gut modifiers

You must submit an application package before the expiry date for renewal to registration or approval as per section 1.3.1 My CFIA online livestock feed applications of RG-1 Chapter 1.

If your registration has specific requirements for renewal, the CFIA will let you know what information you'll need to submit at the time of renewal.

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