Chapter 3 – Specific Registration Information by Feed Type – Section 3.23 Yeast Cell Wall Products

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Issued: 2009-11-03

Registration Requirements for Yeast Cell Wall Products

The Animal Feed Division has recently established a regulatory definition for the single ingredient feed named "yeast cell wall". This ingredient is intended to be a source of mannan-oligosaccharides (MOS), mannans and/or beta-glucans. It is described as follows:

#8.76 Yeast cell wall - is the product resulting from the extraction and purification of the structural components of the yeast cell wall from a fermentation conducted in accordance with good manufacturing practices. This fermentation is conducted for the production of beta-glucans, mannans and mannan-oligosaccharides using a non-pathogenic strain of the microorganism Saccharomyces cerevisiae, which does not contain a novel trait. It shall be labelled with one or both of the following statements: "This product is free of antimicrobial activity and is not a source of viable microbial cells"; or « Ce produit est exempté d'activité anti-microbienne et n'est pas une source de cellules microbiennes vivantes. » It shall also be labelled with guarantees for minimum beta-glucans and mannans and/or mannan oligo-saccharides and maximum moisture.

The placement of this single ingredient feed in Part II of Schedule IV of the Feeds Regulations will require registrants to claim the presence of mannan-oligosaccharides, mannans and/or beta-glucans from the cell wall of the yeast Saccharomyces cerevisiae. As this ingredient is listed in Part II of Schedule IV, each source will have to be registered with one or more feed-related claims (i.e., efficacy in support of a feed-related purpose or claim will be required at the time of registration) prior to import, manufacture or sale in Canada. This approach is consistent with that taken for viable microbial products registered by the Animal Feed Division.

The purpose of this section is to provide applicants with the necessary information and requirements to submit an acceptable application for registration of a yeast cell wall product to the Animal Feed Division. It is strongly recommended that the technical and scientific criteria outlined below are carefully reviewed before an application is submitted.

Administrative Requirements

Standard registration requirements, including a completed and signed application for registration form (CFIA/ACIA 0009); application fee as per Chapter 1, "Application for Feed Registration and Ingredient Approval" (please use the Category 2 application code 3255, New Ingredient listed in Part II of Schedule IV); five copies of the proposed product label; a copy of the product formulation (e.g., percentage composition); an accompanying cover letter; signing authority/Canadian agent (if applicable); and additional information as described below. Please note that additional fees may be required at a later date if a full safety assessment is required.

Note that the cover letter should explain the purpose of the application for registration, including what the intended livestock species are, how the yeast cell wall source is to be used (i.e., fed on a gram/head/day basis, inclusion rate in complete feeds, etc.), the desired product claims, what type of documentation/information has been included with the application, etc.

Labelling

1. The proposed label must reflect the purpose of the product (i.e., as a source of yeast cell wall for use in livestock feeds) in addition to meeting the standards, packaging and labelling requirements of the Feeds Act and Regulations.
2. The product label must also be labelled as per the regulatory definition for the ingredient and bear all relevant guarantees and have the necessary labelling statement (i.e., "This product is free of antimicrobial activity and is not a source of viable microbial cells").
3. Additionally, it will be necessary to add feed-related claim statements to the product label. Acceptable feed claims include: improved growth, improved weight gain or feed efficiency, etc.
4. Drug-related claims, or claims that are therapeutic in nature, are not permitted to appear on yeast cell wall product labels that are destined for use in livestock feeds. Examples of unacceptable product claims include: improved immune status or function, reduction in the incidence of disease or diarrhea, improved health status, improved gut health, ability to modify gut microflora.
5. Directions for use are to be stated on the product label, and must be reflective of the inclusion rates of the yeast cell wall product used in the efficacy data/scientific studies submitted with the application for registration.

Product Description and Supporting Information

1. A detailed description of the manufacturing process used to produce the yeast cell wall product is to be provided with the application for registration. Information such as detailed written descriptions, flow charts, time/temperature specifications for particular steps in the production process, quality control measures, a list of all starting materials/reagents/chemicals/processing aids, etc., are to be provided as well.
2. If applicable, the complete product formula (formulation/percentage composition) listing the amount of each ingredient, which must be identified as per the generic names listed in Schedules IV and V of the Feed Regulations, must be provided. Note that registration numbers for Part II ingredients, mixed feeds and other registered products must be included in the formula.

   Note that feeds may not contain ingredients that are not listed in either Schedules IV or V of the Feeds Regulations. If the applicant wishes to use a currently unapproved feed ingredient as part of the product formulation, it is necessary to submit an application for registration to have the ingredient approved for use in livestock feeds in Canada prior to submitting the application package for the yeast cell wall product in question. Information concerning the application process for new feed ingredients can be found in Section 2.3 "Single Ingredient Feed Evaluation Requirements". Note that the application for registration for the yeast cell wall product cannot be reviewed unless all of the ingredients used in the product formulation are approved and listed in either Schedules IV or V of the Feeds Regulations.

3. Original, signed Certificates of Analysis from three different and recent lots of the yeast cell wall product, which support the label guarantees for the active compound(s) (e.g., beta-glucans, mannans).
4. The complete and detailed description of each analytical methodology used to support the label guarantee(s). These methods will be used to determine the levels of the active compound(s) in the yeast cell wall product. Note that if guarantees for multiple yeast cell wall components (i.e., beta-glucans and/or mannans and/or mannan-oligosaccharides) are made on the label, methodologies must be submitted to support each label guarantee.

   Please consult Section 6.2 "Good Laboratory Practices Protocol for Feed Ingredient Approvals" and Section 6.3 "Guidelines for the Evaluation of Methods to Determine the Activity of Enzyme Ingredients Used in Animal Feeds" for additional information concerning our technical requirements for analytical methods for livestock feeds and feed ingredients.

5. Stability (i.e., shelf life) data must also accompany the application for registration, as an expiry date and lot number must appear on the product label. In order to satisfy this requirement, original, signed Certificates of Analysis substantiating the guaranteed shelf life on the label (i.e., on the date of manufacture and at the expiry date) for a minimum of three different lots of the product are required. The certificates of analysis for beta-glucan, mannan and/or mannan-oligosaccharide content at the date of manufacture and at the expiry date must be for the same lot of product. The storage conditions used for the shelf life study should reflect the storage conditions suggested on the label.
6. A 500 g product sample is also required and must be included with the application package. This sample will be used to verify analytical methodologies and label guarantees. A certificate of analysis stating the lot number and date of production for beta-glucan, mannan and/or mannan-oligosaccharide content must accompany the product sample.
7. A minimum of three efficacy studies for each target livestock species is required to support the feed-related claim statements as they appear on the product label. Please note that efficacy data is required whenever feed claims are made for a particular product. For additional information concerning our requirements for efficacy data and scientific studies, please refer to Section 2.2 "Registration Requirements for Specialty Products".

   To summarize, acceptable efficacy data will have to meet the following criteria:

   • experiments must be performed using the target livestock species
   • experiments must be conducted using the yeast cell wall product for which the application for registration is being submitted
   • studies must be carried out by qualified personnel
   • suitable experimental methods (e.g., experimental design, sampling protocol(s), endpoint measurement determination, etc.) must be used in the studies
   • studies must be designed to facilitate the statistical analysis and the data must be analysed by appropriate statistical methods
   • studies must be conducted under conditions similar to those that may be expected to occur in Canada
   • scientific investigations show that the product, when used as directed, results in a significant improvement in one or more nutritional or feed-related claims for the yeast cell wall product in question
   • studies show a significant difference (P<0.05) between the control and treatment groups
   • where the directions for use indicate a range of inclusion rates, the testing protocol must evaluate the entire range of inclusion rates
   • where the results of these studies have not been published in a peer-reviewed journal, copies of the complete raw data sets and complete printouts of statistical analysis will be required for our review

   Examples of unacceptable types of efficacy data include, but are not limited to: incomplete or poorly designed scientific studies, studies that produce non-significant treatment results, scientific data generated from studies using a yeast cell wall product other than the product that is being submitted for registration, conference presentations (e.g., PowerPoint presentations), research summaries, abstracts, magazine articles, promotional publications, and testimonials.

Safety Information

1. As outlined in Section 2.3 "Single Ingredient Feed Evaluation Requirements" and Section 2.4 "Generic Data Requirements for Safety Evaluations of Single Ingredients", scientific investigations supporting product safety may be required, and will be requested on a case-by-case basis. These investigations may include, but are not limited to: chemical analyses and/or harmful residues and/or toxicological evaluation and/or animal feeding studies and/or tissue residue analysis. The scientific studies presented in support of product safety must be:
   1. carried out by qualified research personnel
   2. carried out using suitable/recognized scientific methods and protocols
   3. designed to facilitate statistical analysis (i.e., using a suitable statistical model, proper sampling protocol and sufficient sample size)
   4. analysed using appropriate statistical methods
2. Suitable methodologies for the detection of significant amounts of any ingredient, compound, substance, or organism intentionally incorporated into the feed or occurring as a contaminant must also be provided.
3. If the strain of Saccharomyces cerevisiae used in the production of the yeast cell wall product is considered to be novel (i.e., is derived from a strain that has a novel trait), then a novel feed assessment would be considered. Please consult Section 2.7 "Guidelines for the Assessment of Novel Feeds: Microbial Sources", for additional information.

Temporary Registrations

A temporary registration may be only be granted for yeast cell wall products for which all the basic registration requirements have been met, but for which the substantiating technical and/or scientific information submitted in support of the application for registration is partially lacking or incomplete. Additionally, note that a temporary registration cannot be granted to a product that has not satisfied the regulatory requirements as they pertain to product safety, as stated in Section 9 (5) of the Feeds Regulations.

Examples of why a yeast cell wall product may be granted a temporary registration include, but are not limited to:

• fewer than three acceptable scientific studies per livestock species were submitted
• laboratory methods require additional substantiating technical data
• shelf life data is incomplete

Products bearing a temporary registration number on the label will be identified by the letter "T" in front of the registration number. Note that for products given temporary registrations, no claims will be allowed on product labels, as the desired claims and/or label guarantees have not yet been substantiated by the applicant. Products that have no efficacy data or accompanying analytical method are not acceptable for temporary registration status.

With regards to the livestock species that are to be indicated on the labels of yeast cell wall sources that have been granted temporary registrations, note that only the species for which efficacy data has been submitted and that tends to support acceptable feed-related claims will be permitted to appear on product labels.

The issuance of temporary registrations is considered an interim measure which allows companies to adequately comply with the conditions of their temporary registration, as outlined in their approval letter. Only one temporary registration will be granted per product and the maximum duration for a temporary registration will be three (3) years.

With regards to the submission of applications for permanent registration status (which must be submitted by the end of the temporary registration period) for yeast cell wall products, be aware that if the product has not been proven to be efficacious and the desired product claims have not been supported by acceptable scientific data by the end of the temporary period, and/or if other registration criteria have not been met as outlined in the approval letter granting temporary registration status to the yeast cell wall product in question, the temporary registration will not be renewed and the product will not be considered for full registration. Hence, the current temporary registration will expire, thereby making the product in question non-compliant with Section 3 of the Feeds Act.

Requirements for Renewal of Registration for Yeast Cell Wall Products

As with all registered feeds, yeast cell wall products that have been granted permanent registration status are registered for a three-year period, renewable by March 31 of the third year after the registration date. All applications for registration renewal must be accompanied by a signed and completed application form; the appropriate fee; the complete product formulation (if applicable); and five copies of the product label, as per Chapter 1 "Application for Feed Registration and Ingredient Approval". Additional information may be requested if safety and/or efficacy concerns emerge between the time of registration and the renewal due date.

Note that changes made to the formulation of registered yeast cell wall products are considered to be significant changes to the registration, and require the submission of a signed and completed application form, a copy of the updated formula, and revised product labels, as well as the applicable registration fee (see Chapter 1 for details). Yeast cell wall products submitted at the time of renewal with a change in formulation will necessitate payment of the fee for the evaluation of the new formulation in addition to the renewal fees.

Requirements for Amendments (Significant Change) to Yeast Cell Wall Product Registrations

Applications for significant change will be evaluated on a case-by-case basis. Changes including, but not limited to, the following product characteristics require the submission of efficacy and/or safety data (which meet the criteria previously outlined) as part of the application for registration amendment:

• changes to the label guarantees for beta-glucan, mannan and/or mannan-oligosaccharide content
• changes to the product formulation that affect the efficacy and/or beta-glucan, mannan and/or mannan-oligosaccharide content of the product (e.g., addition/removal of carrier ingredients, addition/removal of a pellet binder, etc.)
• changes to the manufacturing process that may change the nature of the product or contribute to the introduction of chemicals (either as contaminants or additives), or changes to starting materials, processing aids, etc. used in the manufacturing process
• changes to the analytical method(s) used to determine beta-glucan, mannan and/or mannan-oligosaccharide content in the product in question
• changes to, or the addition of, label claims
• the addition of livestock species to the product label (i.e., in cases where a yeast cell wall product is only approved for use in certain species)
• modifications to the directions for use
• changes to the duration of the shelf life of the product

Please refer to Chapter 1 for additional information regarding significant changes to product registrations. The application fees for these types of changes are the same as those for a new application for registration for a Category 2 product.

Formulation changes involving ingredients that are not considered to be active ingredients or a significant source of nutrients (e.g., flavours, carriers) will be evaluated on a case-by-case basis and may or may not require the submission of efficacy and/or safety data. However, it is recommended that the Animal Feed Division be contacted ahead of time in order to determine what type of information and documentation will be required for submission with the proposed application for registration amendment.

Requirements for Registration for Mixed Feeds Claiming the Presence of Yeast Cell Wall, Mannans, Mannan-oligosaccharides and/or Beta-glucans

Mixed feeds (i.e., a feed comprised of two or more single ingredient feeds) claiming the presence of the ingredient yeast cell wall and/or mannans, mannan-oligosacchrides and/or beta-glucans on the product label (e.g., in the brand name, product name, guaranteed analysis) are subject to registration under the Feeds Act and Regulations, as they do not meet exemption from registration criteria.

As each yeast cell wall source must be registered with one or more feed-related claims, these claims must also appear on the product labels for mixed feeds indicating they are a source of mannans, MOS and/or beta-glucans. Additionally, as each source of the ingredient yeast cell wall must be registered with one or more species-specific feed-related claims, the inclusion rate of each yeast cell wall source in the mixed feed's product formulation, as well as the directions for use stated on the product label, must reflect the directions for use indicated on the approved label(s) for the yeast cell wall source(s) used in manufacture of the mixed feed.

Applications for registration for this type of mixed feed are considered Category 1 applications for registration (code 3254). The following documentation is to be included with each submission:

• a signed and completed application form
• a cover letter explaining the purpose of the application for registration
• a copy of the list of ingredients and detailed product formulation, including the registration number(s) of the yeast cell wall source(s) used in the formula
• five copies of the proposed product label
• label guarantee(s) for mannans, mannan-oligosaccharides and/or beta-glucans derived from the yeast cell wall sources used in the mixed feed's product formulation
• relevant label claims originating from the yeast cell wall source(s) used in the mixed feed
• directions for use for the mixed feed that are based upon the registered yeast cell wall source(s) used in the product formulation

Standard mixed feeds (i.e., complete feeds, supplements, etc.) using registered yeast cell wall sources in their product formulations that do not make a claim for the presence of this single ingredient feed, mannans, mannan-oligosaccharides and/or beta-glucans do not require registration, provided they meet all other exemption from registration criteria, as outlined in the Feeds Regulations. Please note that all imported mixed feeds must be registered, as per Section 3 of the Feeds Act.

Note that mixed feeds claiming to be a source of mannans, MOS and/or beta-glucans may only use registered yeast cell wall sources in their product formulations. Applications for mixed feeds containing unregistered yeast cell wall sources will not be accepted for registration and will be screened out and returned to the applicant.

Requirements for Renewal of Registration for Mixed Feeds Claiming the Presence of Yeast Cell Wall, Mannans, Mannan-oligosaccharides and/or Beta-glucans

The following information is to be submitted with each application for registration renewal:

• cover letter explaining the purpose of the application
• a signed and completed application form, accompanied by the proper renewal fee
• five copies of the product label
• a copy of the current product formula, if applicable
• any additional information, documentation, scientific data, etc. that is required to be submitted with application for registration renewal

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Registration Checklist for Yeast Cell Wall Products

Administrative Registration Requirements
Completed application package per Chapter 1

Proposed Label
Brand name (optional)
Product name reflecting purpose of the product and the intended species
Product claim statement (e.g., improves the weight gain in grower pigs)
Guaranteed analysis for beta-glucan, mannan and/or mannan-oligosaccharide content
Complete list of ingredients by generic name as listed in Schedule IV or V of the Feeds Regulations, including registration numbers for any Part II ingredients or mixed feeds, as required
Directions for use to permit safe and effective use of the feed
Caution and/or warning statements (if applicable)
Feed processing instructions (e.g., do not pellet) (if applicable)
Name and address of registrant
Net weight (metric measure)
Date of manufacture
Expiration date
Registration number (to be added)

Product Composition
Formulation/percentage composition listing amount of each ingredient by generic name as listed in Schedule IV or V of the Feeds Regulations including registration numbers for Part II ingredients or mixed feeds
Formulation/Ingredients - verify that the levels of ingredients do not exceed maximums per Schedules IV and V
The registration number of each yeast cell wall source used in the mixed feed (if applicable)

Scientific Studies
A minimum of 3 scientific studies per target species to support the intended purpose(s)
Experiments performed using the target livestock species
Efficacy studies conducted using the yeast cell wall product that is being submitted for registration
Studies carried out by qualified personnel
Suitable experimental methods used in the studies
Studies designed to facilitate statistical analysis
Data analysed by the appropriate statistical methods
Studies conducted under conditions similar to those that may be expected to occur in Canada
Scientific investigations show that the product, when used as directed, results in a significant improvement in one or more of the proposed feed-related claims for the product
Studies show a significant difference (P<0.05) between the control and treatment groups
Where the directions for use indicate a range of inclusion rates, the testing protocol has evaluated each one of the inclusion rates used in the scientific studies
Where results of these studies have not been published in a refereed journal, copies of the raw data and printouts of the statistical analysis are required for our review.

Laboratory Methods
Original, signed copies of Certificates of Analysis for a minimum of three different and recent lots of product supporting the label guarantees for beta-glucan, mannan and/or mannan-oligosaccharide levels
Complete and detailed laboratory methodologies to analyse (determine) beta-glucan, mannan and/or mannan-oligosaccharide content

Expiry Date
Expiry date appears on the product label
Original, signed Certificates of Analysis substantiating the guaranteed shelf life as stated on the label (i.e., the date of manufacture and at the expiry date) for a minimum of three different and recent lots of product have been included with the application

Safety Review (as required)
Complete and detailed description of the manufacturing process (including flow charts, written descriptions, etc.) has been provided
Toxicity data has been included with the application, if applicable or required

Sample
A 500 g sample and accompanying Certificate of Analysis for beta-glucan, mannan and/or manna-oligosaccharide content, which also states the lot number and date of production, have been included with the application for registration

Note: Further information may be required after a review of the preliminary submission.

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