RG-1 Regulatory Guidance:
Chapter 3 – Guidance on data requirements for feed approval and registration
3.6 Enzyme supplements and mixed feeds containing registered enzyme supplements

Background

An enzyme is a substance that acts as a catalyst in living organisms that regulates the rate at which chemical reactions proceed without being altered in the process. Every enzyme has a specific function, and in many cases an array of enzymes is required to complete a reaction for different nutrients. The most commonly used feed enzymes are the hydrolases which include for example, amylase, cellulose, lipase, mannanase, pectinase, phytase, protease, and xylanase.

Enzyme supplements may be added to livestock feeds to catalyse feed degradability thereby improving digestibility. They can be added to a feed immediately before consumption, or added during processing (for example, as a forage or grain treatment) to enhance the stability and digestibility of the stored/ensiled feed.

Enzyme supplements may be regulated as a drug or a feed depending on a number of factors as per the Guidance Document on Classification of Veterinary Drugs and Livestock Feeds. That document provides guidance and criteria to help clarify the regulatory differences between drugs and feeds, and assists in determining the appropriate regulatory oversight for a product destined for use in livestock species.

There are 3 types of fermentation products which can have enzyme activity, as described below:

• Fermentation product, complete or crude
  The enzymes as well as the entire medium are recovered, complete with other metabolites and fermentation substances. There is no separation step in the processing. This includes the solids and solubles associated with the fermentation (for example, Aspergillus niger fermentation product).
• Fermentation solubles product
  This consists of only the soluble portion of the fermentation product, from which the solids have been separated (for example, Aspergillus niger fermentation solubles).
• Fermentation extract
  This is a purified enzyme source resulting from further extracting and purifying the solubles (for example, Aspergillus niger fermentation extract).

Regulatory status

Products marketed for their enzyme activity in livestock feeds are considered to be enzyme supplements, and are subject to registration by the Animal Feed Division (AFD) of the Canadian Food Inspection Agency (CFIA) prior to importation, manufacture or sale in Canada. Ingredients currently approved as sources of enzyme activity in livestock feeds are listed in the "Fermentation Products" category (5.4) of Class 5, Protein Feeds in Schedule IV of the Feeds Regulations. Enzymes added to feeds must be in the form of non-viable fermentation by-products. Further information on viable microbial products is available in the RG1-Chapter 3 Section 3.22.

Before submitting an application to register an enzyme supplement, all ingredients, including the fermentation products making up the enzyme supplement, must be approved and listed in Schedule IV of the Feeds Regulations. If any ingredient of an enzyme supplement, including a fermentation product, is not found in Schedule IV, an application for that ingredient is required. The application for the enzyme supplement should only be submitted once all ingredients in the enzyme supplement are approved.

When the enzyme source is derived from a novel microorganism, a safety assessment will be conducted according to the document entitled Guidelines for the Safety Assessment of Novel Feeds: Microbial Products (RG-1, Section 2.7). The data requirements for submitting an application can be found in Section 2.7.

This document is divided into 3 parts as follows:

• Part 1 - Registration requirements for enzyme supplements, mixed feeds containing enzyme supplements or dilutions of enzyme supplements
• Part 2 - Amendments to registrations of enzyme supplements, diluted enzyme supplements and mixed feeds claiming the presence of enzyme supplements
• Part 3 - Renewal of registrations for enzyme supplements, diluted enzyme supplements and mixed feeds claiming the presence of enzyme supplements

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

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

Part 1: Registration requirements for enzyme supplements, mixed feeds containing enzyme supplements or dilutions of enzyme supplements

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 the attached checklist.

Registration requirements for enzyme supplements

1.2 Labelling

Proposed labels for enzyme supplements must include the following, in addition to standard labelling requirements listed in RG-1, Chapter 4.1 – Labelling of Livestock Feed:

• the product name, that reflects the purpose of the product and the intended species
• a complete list of ingredients
• a nutritional claim statement (if applicable)
• a guarantee for the enzyme activity or activities, and the enzyme unit definition^Footnote 1, with details of the enzyme assay conditions^Footnote 2
• directions for use to permit safe and effective use of the feed
• recommended storage conditions in order to maintain activity until the expiration date
• expiry date (stated as the number of months from date of manufacture)
• a cautionary and/or warning statement, if applicable

1.2.1 Safe handling of enzyme feeds

Microbial products (including fermentation products) have the potential to cause dermal and respiratory irritation and/or sensitization. Applicants are therefore required to include the following statement on all enzyme supplement labels:

• "This product may cause dermal and respiratory irritation and/or sensitivity. Appropriate protective equipment must be worn during handling."

Alternatively, applicants may choose to provide scientific rationale as to why this statement does not apply to their product and is therefore not necessary. For example, the applicant may provide the results of dermal/respiratory sensitization/irritation studies in support of the product.

1.3 Product identification and description

1.3.1 General Information

• cover letter explaining the purpose of the product for registration
• summary of documentation/information included with the application
• background supportive information pertaining to approvals in other jurisdictions
• directions for use
• target livestock feeds.
• proposed product claim(s)
• proposed shelf-life
• detailed product formulation and complete list of ingredients identified by generic name as listed in Schedule IV or V of the Feeds Regulations, and registration number for ingredients listed in Schedule IV, Part II, or mixed feeds.
• brief manufacturing process of the enzyme supplement to demonstrate that the product meets the description of the approved ingredient definition as listed in Schedule IV.
• if the product is an unapproved single ingredient, additional information as per RG-1, Chapter 2 - 2.3 Single Ingredient Feed Evaluation Requirements

1.3.2 Analytical method

A laboratory method is required. The methodology must be effective in verifying the enzyme activity guarantees for both enzyme supplements, and finished feeds or complete feeds, as per the Feeds Regulations (Section 2(1)).

The proposed label guarantees must be supported by certificates of analysis from 3 different and recent lots of product which describe the usefulness of the enzyme supplements.

Where an AOAC method is being used, the applicant need only reference the AOAC method on the certificate of analysis of each guarantee.

Where a proprietary method of analysis is used, the applicant must submit a copy of their method for assessment with the feed application. The proposed method(s) will be reviewed and tested individually, according to the protocol described in Chapter 6 section 6.3 Guidelines for the Evaluation of Methods to Determine the Activity of Enzyme Ingredients Used in Animal Feed. Product sample or samples may be requested by the AFD on a case–by-case basis to verify analytical methodologies and/or label guarantees. The sample must come from a recent lot (within the last 12 months) and the amount supplied must be sufficient for the enzyme activity to be determined 20 times using the method (minimum 50 grams).

The AFD will contact the applicant directly if a product sample must be sent to the CFIA lab. The applicant will be provided with a reference number used to complete Appendix I "Laboratory Sample Submission Form - PDF (864 kb)" in order to submit their samples to the CFIA lab.

Only the sample(s) along with the completed Appendix I "Laboratory Sample Submission Form - PDF (864 kb)" are to be submitted directly to the CFIA Laboratory, at the following address:

Ottawa Laboratory (Carling)
Feed Bioanalysis and Microscopy Section
Building 22, Central Experimental Farm
960 Carling Ave.
Ottawa ON
K1A 0C6

All other documentation must be submitted to the AFD, which will forward the appropriate copies to the CFIA Laboratory.

1.4 Requirements in support of product claims and other information

The 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

1.4.1.1 Nutritional claim(s)

Applicants may have nutritional claims for enzyme supplements; these may appear on labels. However, nutritional claims are not mandatory for any enzyme supplements, including any source of approved phytase.

Scientific data in support of a nutritional purpose is not required for enzymes recognized in peer-reviewed publications to enhance feed digestibility or nutrient availability (for example, β-mannanase, β-glucanase, xylanase, galactomannanase , ɑ-amylase, cellulase, phytase, carbohydrase).

When performance claims (for example, improvement of feed efficiency, improvement of daily weight gain, improvement in milk, meat, egg or wool production) are made, valid scientific studies must be presented in support of each label claim, as described in RG-1, Chapter 2.2 - Registration Requirements for Specialty Products.

1.4.1.2 Phytase claims

The claim:

• "Phytase improves the availability of phytin-bound phosphorus in cereal and oil-seeds based diets for swine and poultry"

is acceptable for all approved sources of phytase, and may appear on the label. This does not require efficacy data, as long as the minimum inclusion rate is equivalent to 500 U/kg (units of phytase per kg of complete swine or poultry feed). This rate of use is based on the industry history of use, and is acceptable for products for which AOAC method #2000.12 9(4.10.06) has been used to measure the enzyme activity. The unit definition for the AOAC method is "One phytase unit is defined as that quantity of enzyme that will liberate 1 micromole of inorganic ortho-phosphate per minute under conditions of the assay".

1.4.2 Product Stability and Shelf Life

To support product stability and the shelf life as stated on a product label, it will be necessary to:

• demonstrate maintenance of the enzyme activity over the specified shelf life
• submit certificates of analysis for the active ingredient(s) or substance(s) to substantiate the guaranteed shelf life (In other words, at the date of manufacture and the expiry date)
  • a minimum of 3 different lots of the product.
  • certificates of analysis for the level/concentration of the active ingredient(s) or substance at the date of manufacture and at the expiry date must be for the same lot of product
  • storage conditions used in the shelf life study must reflect the recommended storage conditions as stated on the product label

1.4.3 Product stability in pelleted feeds

If the directions for use indicate that the enzyme supplement can be used in feeds undergoing commercial feed processing (for example, premix, supplement, mineral), analysis will be required to support that the enzyme(s) retains an effective level of activity during processing, and stability under typical storage conditions. The data to support the addition of the enzyme supplement to the various feed types could be provided by the original applicant, or by subsequent applicants choosing to add the enzyme supplement to their product.

Where data showing the stability of an enzyme supplement to pelleting conditions is not provided, one of the following statements must be added to the label:

• "Do not pellet" or
• "Apply post-pelleting" or
• "Pelleting this product may significantly reduce enzyme activity".

1.5 Registration requirements for mixed feeds containing enzyme supplements or dilutions of enzyme supplements considered mixed feed.

Mixed feeds containing registered enzyme supplements are exempt from registration, if the following conditions are met:

• the mixed feed is manufactured in Canada and;
• the presence of the enzyme products is not highlighted on the label, other than the brand name and registration number in the list of ingredients;
• the feed meets all other criteria for exemption from registration under the Feeds Regulations

Mixed feeds with labels that highlight the presence of registered enzyme supplements or enzyme activity must also be registered. In addition to the administrative requirements as per the RG 1 Chapter 1 and applications fees for an efficacy review Category 2 (new feed), the following information will be required with the feed application:

• the product formulation, to verify the guarantee for enzyme activity, and verify that the amount of enzyme supplement supplied is not less than that approved (per the embedded registered enzyme supplement label)
• 3 copies of the proposed label, with:
  • the complete list of ingredients, including the name and registration number for the approved enzyme supplement or
  • the name and registration number of the approved enzyme supplement, in conjunction with the standard ingredient statement "The list of ingredients used in this feed may be obtained from the registrant or manufacturer of the feed."
  • guarantee(s) for enzyme activity expressed as per the parent product, as well as nutrient guarantees applicable for the type of mixed feed in question. (Note: enzyme unit definition is required on the label for mixed feeds)
  • the approved nutritional claim for the registered enzyme supplement (if applicable)
  • feed processing claims, on supplement and premix labels only, as per the registered enzyme supplement label
  • expiry dates and storage conditions, on supplement and premix labels only, as per the registered enzyme supplement label if applicable (for example, pelleting statements)

Mixed feeds, as private label products, that highlight the presence of enzyme supplements or enzyme activity must be registered. For more information about registration of private label products, consult Chapter 2 Section 2.2 of RG-1. For this type of feed application, provide administrative requirements as per the RG 1 Chapter 1 and application fees for Category 1 Standard Feeds; submission Code 3254.

1.5.1 Product Stability

If the registered enzyme supplement is diluted using a different carrier (from granular to liquid form) than the parent product, supporting data (for example, method of analysis, stability data, certificates of analysis) as described in the document may be required.

1.5.2 Studies in support of claims

If label claims are being made for mixed feeds containing enzymes for which no claims have been previously approved, the registrant must submit efficacy data in support of those claims.

Part 2: Amendments to registrations of enzyme supplements, diluted enzyme supplements and mixed feeds claiming the presence of enzyme supplements

Registrants wishing to make a change to the formula or label of a registered product must submit an amendment for a (significant change/re-registration) to the AFD (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.

Proposed significant changes may include, but are not limited to, changes to any of the following:

• brand or product name
• product claim statement(s)
• enzyme guarantee(s)
• shelf life
• heat stability/pelleting statement
• directions for use including addition of new target species
• formulation and list of ingredients on the label
• manufacturing process (not applicable to diluted enzyme supplements)
• methodology (not applicable to diluted enzyme supplements)

Data requirements for significant changes to enzyme supplements will be dependent on the changes being requested and would be evaluated on a case-by-case basis. In general, any proposed change that will affect product efficacy will also require supplemental or new efficacy data. Examples include: a proposed change or revision of the laboratory method; a change in the directions for use; or a change in heat stability (pelleting) conditions. 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 for enzyme supplements, diluted enzyme supplements and mixed feeds claiming the presence of enzyme supplements

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 information is found in the attached checklist.

In addition to typical renewal requirements, a signed statement from the registrant is required confirming that no changes have been made to the manufacturing process for the product since the last registration. A signed cover letter from the registrant should confirm that the laboratory method approved by the CFIA, and used to verify the label guarantees for enzyme activity, has not changed nor been revised by the company since the last registration of the product.

Printable checklist - PDF (241 kb)

Submission checklist for enzyme supplements and mixed feeds containing registered enzyme supplements

The completed checklist, for enzyme supplements and mixed feeds containing registered enzyme supplements 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.

Submissions received without a completed checklist will be returned.

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

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