Proposed guidance on registration requirements for gut modifier products

On this page

• 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
• Submission checklist for gut modifiers feed application

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 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 1. These ingredient types (sub-categories) may include, but are not limited to, viable microbial strains, prebiotics, enzymes, organic acids, and 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 aid in pathogen reduction or treatment or mitigation of diseases in the animal are considered to be veterinary drugs.

Regulatory status

Gut modifier products regulated as feeds do not meet the exemption from registration criteria, as outlined in Section 5(2) of the Feeds Regulations. Gut modifier products are considered specialty products and must be approved and registered by the Canadian Food Inspection Agency (CFIA) before the manufacture, sale or import in Canada.

The gut modifier category can be applied to ingredients (single ingredient feeds) or mixed feeds (specialty feeds). The following section clarifies the overall process for approval of an ingredient as a gut modifier ingredient and the subsequent registration of a gut modifier product.

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

Step 1 – Classification 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 classification 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 specialty product with claims

Gut modifier products are specialty feeds that may be a single ingredient feed from the gut modifier category or a mixed feed containing one or more gut modifying ingredients (that is, as actives and other non-active ingredients.) Claims must be applied in either situation.

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.

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: Step 1 and step 2 can be part of the same submission and do not need to be done in 2 distinct steps/applications.

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 ingredients identified as gut modifiers.

• If the ingredient(s) are 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.
• 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.
• 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 from in-house research or scientific literature. Research should demonstrate that a mode of action is in the gut and that it is relevant for a gut modification action.

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). Bridging information to the applicability to livestock species, feeding rates, and feeding duration may be required. 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.

Examples of acceptable gut modifier modes of action (not exhaustive)

Improving gut integrity:

• increase microvilli length
• tight gap junctions
• increased production of intestinal mucus
• reduce low-level chronic gut inflammation

Modifying the gut environment:

• fatty acid production in the gut
• pH changes in the gut
• facilitate absorption of nutrients

Changes to the microbiome:

• indirect benefits to the gut microbiome after a physiological event such as castration, vaccination, heat stress or weaning

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 modifier products

1.1 Administrative requirements

General administrative information regarding the procedures for application for feed registration can be found in Regulatory Guidance: RG-1, Chapter 1 – Administrative requirements for pre-market assessment and product registration of livestock feed.

Specific information is found in Submission checklist for gut modifiers feed application

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 (for example, 12 months from the date of manufacture when stored under appropriate conditions)
• recommended storage conditions to maintain activity until the expiration date

1.3 Product identification and description

1.3.1 General information

• cover letter 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)) 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 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-1, Chapter 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

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 forspecialty 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 1 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 1 specific set of requirements to support this category.

A gut modifier product is registered with claims supported by data demonstrating:

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

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 1 endpoint exhibiting beneficial results per study. Beneficial effects can include improved growth, feed intake, weight gain or feed efficiency.

Examples of typical beneficial production/performance endpoints include:

• increased feed efficiency or feed conversion ratio
• increased feed intake or dry matter intake
• increased growth or average daily gain
• increased egg production
• increased milk production
• increase in the number of weaned piglets

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. One may extrapolate available efficacy data from certain species to other physiologically related similar species. This can include comparing species in terms of their gastrointestinal function and their metabolism. Comparing interspecies effects, can be applied only in cases where the animals are kept for the same purpose. In other words, the mode of action can reasonably be presumed to be the same, between species for meat production effects or for reproduction effects (including milk or egg production).

1.4.1.2 Studies to support gut modification based claims

Studies supporting gut modification based claims can include both in vitro and/or in vivo studies. Three studies are required to support a desired claim; a minimum of one in vivo study must be included. If an outcome is strongly correlated, such as, for example an organic acid response in the microvilli, the number of studies may be lowered.

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:

• Good in vitro models exist and 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

Gut modification based claims can include the following examples. This is not an exhaustive list:

• improving rumen development (calves)
• stabilizing rumen pH
• increasing the surface area of intestinal microvilli for improved nutrient absorption
• increased villi height and ratio villi height /crypt depth
• replenishing intestinal flora after a physiological event
• digestibility enhancers
• odor control and methane reduction potential

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, such as, for example, ruminant to ruminant or monogastric to monogastric animals. Crossing from ruminants to monogastric species is, however, not indicated. The pre-ruminant to mono-gastric comparison could also be considered for certain endpoints.

For example, for the gut modification by increasing the surface area of microvilli, comparisons across small intestine models from non-ruminant species versus ruminant species could apply.

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 the 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 on the minimal requirements to demonstrate maintenance of the claim over the specified shelf life.

Accelerated stability studies may be acceptable. Details are provided in the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH) guidance document Stability: Stability Testing of New Veterinary Drug Substances (Revision) – PDF (257 kb)

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 yeast

Part 2: Amendments to registrations of a gut modifier

Registrants wishing to make a change to the formula or label of a registered product must submit an Application for Feed Approval or Registration (significant change/re-registration) to the CFIA (Category 2 submission). General administrative information regarding application procedures for amendments to feed registrations can be found in RG-1 - Chapter 1 - administrative requirements for pre-market assessment and product registration of livestock feed.

Significant changes for gut modifiers may include, but are not limited to, changes to:

• label guarantees
• product formulation, including active ingredients
• manufacturing process
• label claims
• directions for use and/or application rates
• shelf life of the product
• ingredient stability (heat or pelleting stability)

Data requirements for significant changes are dependent on the type of changes being requested and would be evaluated on a case-by-case basis. For more information on data requirements for amendments to registrations, refer to RG-1, Chapter 2.2 Registration requirements for specialty products

Part 3: Renewal of registrations of a gut modifier

General administrative information regarding the application procedures for renewals of feed registrations can be found in RG-1, Chapter 1 Administrative requirements for pre-market assessment and product registration of livestock feed.

Specific requirements to accompany an application for renewal of a gut modifier registration include:

• a copy of the current product formulation
• a copy of the product label
• original and signed certificates of analysis for the active ingredient(s) for 3 different and recent production lots of the final product
  • The analytical methodology used and limit of detection/limit of quantification must be noted
• original and signed certificates of analysis for three different and recent production lots of the final product for known contaminants applicable to the product type
  • The analytical methodology used and the limit of detection/quantification must be noted
• a signed statement that the manufacturing process and all raw materials, processing aids, carriers, catalysts, anti-oxidants, etc., have not changed since the original approval

Please note that additional information may be requested during renewal if safety or efficacy questions emerge after the original registration.

Changes made to the formulation or product label (for example, active ingredients, claims, purpose, directions for use, target livestock species feeds, etc.) are considered to be significant changes to existing registrations. An application for renewal with a significant change would be required.

If there is a change to the product at renewal, use this checklist to describe the changes as applicable.

Submission checklist for gut modifiers feed application

The completed checklist, for gut modifiers feed submissions, must be included with each application for feed registration. Indicate the submission page number corresponding to each item in the checklist; if the item does not apply, a written justification must still be provided.

Gut modifier 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).

Submissions received without a completed checklist will be returned.

With your submission package, you must include the following information (mandatory).

In case of 2 or 3 above, a minimum of 1 study from in-house research or the scientific literature to demonstrate a gut modification effect of the ingredient must be provided. Address all design considerations as listed under Identification of the gut modifier ingredient(s).

In case of 3 above, the submission should follow the established route of submitting an application as per RG-1, Chapter 2 - 2.3 Single ingredient feed evaluation requirements.

Registration requirements for new gut modifiers

• Administrative requirements
• Labelling
• Product identification and description
• Requirements in support of product claims and other information
• Data requirements in support of product safety
• Amendments to registrations of a gut modifier
• Renewals of feed registration

Administrative requirements

General administrative information regarding the procedures for application for feed registration can be found in regulatory guidance: RG-1, Chapter 1 – Administrative requirements for pre-market assessment and product registration of livestock feed.

Labelling

Product identification and description

Requirements in support of product claims and other information

Data requirements in support of product safety

Amendments to registrations of a gut modifier

Renewals of feed registration