Guide for the preparation of infant formula and human milk fortifier premarket submissions

2021

Table of contents

1.0 Introduction

Infant formula is a substitute for human milk that is given to infants typically during the first year of life. Infant formula is sold either as a ready-to-serve liquid, a concentrate that must be diluted with water, or as a powder that is to be mixed with water before feeding infants. For some infants, infant formula is the only source of nutrition received from birth to approximately 6 months of life when other foods are typically introduced. The first 6 months are critical for infants as they undergo rapid growth and development during this period. As such, stringent safeguards must be in place to protect this vulnerable population to ensure that infant formulas are well tolerated, safe to use and promote growth and development. The term infant formula includes preterm infant formula as well as specialty infant formula, such as those which are hypoallergenic or are for inborn errors of metabolism.

Human milk fortifiers are foods whose composition includes at least added vitamin, mineral nutrient or amino acid, that are intended to be added to human milk (breast-milk) to increase its nutritional value. Human milk fortifiers are administered to certain preterm infants or other infants (e.g., infants with low birth weight) when they are medically required to meet particular nutritional requirements. Human milk fortifiers are not nutritionally adequate unless they are added to human milk.

In Canada, infant formulas and human milk fortifiers are regulated under the Food and Drugs Act (FDA) and the Food and Drug Regulations (FDR). Specifically under Division 25 of the FDR, manufacturers must submit a premarket submission prior to selling or advertising any new infant formula or human milk fortifier, or an infant formula or human milk fortifier that has undergone a major change. The premarket submission must contain detailed information on the composition and manufacturing of the infant formula or human milk fortifier and its packaging and labelling, as well as evidence to establish that the new or changed infant formula or human milk fortifier is safe and nutritionally adequate to promote acceptable growth and development in infants for whom it is intended. In cases where only minor changes are made to the existing infant formula or human milk fortifier, a voluntary submission may be considered appropriate.

This guide is intended to assist infant formula or human milk fortifier manufacturers in preparing an infant formula or human milk fortifier premarket submission. Sections 4.6, 4.7 and 4.8 of this guide refers to Health Canada's Good Manufacturing Practices for Infant Formula (referred to as "the GMPs" in this document), which also generally apply to human milk fortifiers, which establish the general requirements for effective control of: ingredients, formulations, processes, facilities and equipment used for the production of all infant formulas and human milk fortifiers to be sold, distributed or marketed in Canada. These requirements apply regardless of whether the infant formula or human milk fortifier is manufactured in Canada or in another country whose manufacturing regulations may differ from those of Canada. The GMPs apply to new or changed infant formulas and human milk fortifiers, and to third party facilities subcontracted to manufacture or package these products.

Upon completion of a premarket review of a new infant formula or human milk fortifier submission, and if Health Canada has no further questions or objections, a letter will be issued for the sale of the infant formula or human milk fortifier in Canada.

All infant formula and human milk fortifier manufacturers are required to be licensed under the Safe Food for Canadians Act (SFCA) and Safe Food for Canadians Regulations (SFCR) to conduct activities including manufacturing, labelling, packaging, exporting, importing or sending infant formula or human milk fortifier across provincial or territorial boundaries. After obtaining your letter from Health Canada, please consult MyCFIA and the What to Consider Before Applying for a Safe Food for Canadians licence to apply for the Safe Food Canadians licence.

2.0 Regulatory Context

2.1 Regulatory definitions

The following term is defined under Section 2 of the FDA:

The following term is defined under Section A.01.010 of the FDR:

The following terms are defined under Section B.25.001 of the FDR:

The following term is defined under Section B.27.001 of the FDR:

2.2 Infant formula and human milk fortifier regulations in Canada

Under Sections B.25.046 and B.25.048 (for infant formula) and under Sections B.25.011 and B.25.015 (for human milk fortifier) of the FDR, manufacturers are required to send a premarket submission prior to selling or advertising any new infant formula, or one that has undergone a major change. The submission must contain detailed information on:

The specific requirements for a new infant formula are provided under Section B.25.046 (2), subsections (a) to (m) of the FDR, and those for an infant formula having undergone a major change can be found under Section B.25.048 (2), subsections (a) to (g), of the FDR. The specific requirements for a new human milk fortifier are provided under Section B.25.011, subsections (a) to (n), of the FDR, and those for a human milk fortifier having undergone a major change can be found under Section B.25.015 (2), subsections (a) to (g), of the FDR.

2.3 When is a premarket submission required?

A premarket submission is required for 1) any new infant formula or human milk fortifier, 2) any infant formula or human milk fortifier that has undergone a major change.

The regulatory requirements specific to infant formulas are found under Sections B.25.046 and B.25.048 and those specific to human milk fortifiers are under Sections B.25.011 and B.25.015 of the FDR.

Manufacturers are strongly encouraged to use the Verification Checklists provided in this document; Appendix 1 for infant formula submissions, and Appendix 2 for human milk fortifier submissions, to ensure all required information is included in the submission package.

Manufacturers are strongly encouraged to request a pre-submission meeting with Health Canada during preparation of a premarket submission for new infant formula or human milk fortifier or when planning a change in formulation, packaging or processing. A pre-submission meeting request should be sent to Health Canada's Food Directorate Submission Management and Information Unit (SMIU) at smiu-ugdi@hc-sc.gc.ca.

2.3.1 New infant formula or human milk fortifier

Manufacturers must provide Health Canada with a premarket submission for a new infant formula or human milk fortifier or when it is, for the first time, manufactured, sold in Canada, or manufactured by a person who manufactures it.

Section B.25.046 (2), subsections (a) to (m) of the FDR specify the regulatory requirements for a new infant formula while Section B.25.011, subsections (a) to (n), specify the regulatory requirements for a new human milk fortifier.

2.3.2 Infant formula or human milk fortifier that has undergone a major change

Manufacturers must notify Health Canada prior to the sale of any infant formula or human milk fortifier that has undergone a major change in ingredient(s), packaging or manufacturing process that could be expected to cause an adverse impact on safety, on nutrient levels or nutrient availability. Examples of major changes for which a premarket submission is needed include:

Section B.25.048 (2), subsections (a) to (g) of the FDR specify the regulatory requirements for an infant formula having undergone a major change, while Section B.25.015 (2), subsections (a) to (g), specify the regulatory requirements for a human milk fortifier having undergone a major change.

Manufacturers who are planning on a change in formulation, packaging or processing should contact Health Canada's Food Directorate SMIU to set up a pre-submission meeting at smiu-ugdi@hc-sc.gc.ca.

2.3.3 New infant food ingredient

A manufacturer of a new ingredient that has never been used in an infant formula or human milk fortifier in Canada should submit either a novel food or new infant food ingredient (NIFI) submission for evaluation. The manufacturer should receive approval of the ingredient as either a novel food or NIFI, before a premarket submission is made for an infant formula or human milk fortifier containing the ingredient. The process is described in Appendix 3, Flow Chart for approval of a novel food or new infant food ingredient.

Novel food

If the ingredient is novel (for example, because it has no history of safe use as a food in Canada), its safety must first be assessed by Health Canada as required under Division 28 of the FDR. The petitioner should consult Health Canada's Guidelines for the Safety Assessment of Novel Foods.

New infant food ingredient (NIFI)

If the new ingredient is not novel for the general population, or if it has been assessed for safety only in the general population, excluding infants, its safety must be evaluated for the infant population. Requirements in support of a NIFI submission are as follows:

  1. Description of the new ingredient, manufacturing process, and product monograph
  2. History of use, including regulatory status in other jurisdictions
  3. Proposed dietary exposure in infants
  4. Nutritional considerations
  5. Toxicology
  6. Bioavailability and function in adults and infants
  7. Physiological efficacy, gastrointestinal effects and safety considerations in the infant population – This may include clinical studies in term or preterm infants depending on the proposed target population and conducted using the specific new ingredient (or a similar ingredient, provided equivalence is demonstrated with the subject of the NIFI submission)
  8. Allergenicity
  9. Chemical considerations, including food additives used, levels of contaminants such as heavy metals
  10. Microbiology

If the new ingredient is not demonstrated to be safe for infants, it will be rejected.

Premarket submission for infant formula or human milk fortifier

If the NIFI or the Novel Food is assessed as safe for infants, petitioners are welcome to proceed with sending a premarket submission for the infant formula or human milk fortifier with the new ingredient, following the guidelines in this document.

3.0 Administrative considerations

3.1 Administrative information

Submissions to Health Canada should meet the requirements below:

Important: All data and information in the submission should be provided in English or French. Material in other languages must be translated into English or French before it can be accepted and considered by Health Canada.

3.2 Cover letter

A cover letter must accompany the petitioner's premarket submission. The letter should be dated and provide complete contact information, including name, title, full address and telephone number for the petitioner and for all parties, including any third parties authorized by the petitioner, to communicate with Health Canada about the submission.

The letter should briefly describe the product and include brand and product name. Reference to any related or previous submission should be mentioned in the cover letter, and should include the submission number, key dates, brand name, etc.

It is common for companies to use the facilities of a separate manufacturer and to assign some of the technical aspects of the submission to qualified personnel at the manufacturing facility. Such arrangements and all relevant contact information should be stated in the cover letter.

3.3 Verification checklists

Verification checklists (Appendices 1 and 2) have been developed to assist petitioners as they assemble their infant formula or human milk fortifier submission. The checklist summarizes administrative and scientific or technical information that is meant to assist both the petitioner in the preparation of a submission as well as the scientific evaluator in verifying that the required information has been submitted. Although not a statutory requirement, it is requested that the completed checklist be sent with the submission and cover letter.

3.4 How to submit

Infant formula, human milk fortifier and NIFI submissions should be sent by email to Health Canada's Food Directorate SMIU at smiu-ugdi@hc-sc.gc.ca.

3.5 Food Directorate's pre-market submission management process for infant formula

Manufacturers are strongly encouraged to refer to The Food Directorate's Pre-Market Submission Management Process for Food Additives, Infant Formulas and Novel Foods for information on pre-submission meetings, administrative verification, scientific assessment of submissions and decisions.

3.5.1 Submission timelines

Health Canada is committed to improving the timeliness of application reviews for infant formulas and human milk fortifiers. Once a complete submission package is received, Health Canada will apply a service standard of 90 days of active review time for the vast majority of infant formulas and human milk fortifiers. Active review time refers to the time Health Canada evaluators spend reviewing the submission. If the package is incomplete or the information received is not sufficient to establish the safety of the product, Health Canada will notify the applicant in writing and may request additional information. The time between Health Canada's request for additional information and the receipt of this information is not considered as active review time.

4.0 Infant formula and human milk fortifier premarket submission requirements

This section describes the specific information required as part of an infant formula or human milk fortifier submission under the FDR.

4.1 Brand and product name

As per Sections B.25.046 (2) (a) and B.25.048 (2) (a) (for infant formula) and Sections B.25.011 (a) and B.25.015 (2) (a) (for human milk fortifier) of the FDR, a premarket submission must specify the Brand and product name under which the infant formula or human milk fortifier will be sold or advertised for sale.

The product name could include characteristics such as:

4.2 Name and address

As per Sections B.25.046 (2) (b), (c) and B.25.048 (2) (b) (for infant formula) and Sections B.25.011 (b), (c) and B.25.015 (2) (b) (for human milk fortifier) of the FDR, a premarket submission must include the name and address of the principal place of business of the manufacturer and the names and addresses of each establishment in which the infant formula or human milk fortifier is to be manufactured.

If any part of the manufacturing of the new infant formula or human milk fortifier is contracted out to a third party company, the name and address of the contractor should also be submitted. Examples include, but are not limited to, bulk ingredients such as base powder, protein mixtures or carbohydrate powders manufactured by a third party company.

4.3 Description of the major change

As per Section B.25.048 (2) (c) (for infant formula) and Section B.25.015 (2) (c) (for human milk fortifier) of the FDR, the description of the proposed major change to an existing infant formula or human milk fortifier must be provided. The description of the major change should be accompanied by a description of any other change (such as, ingredients, processing, packaging) which were necessary to accommodate the major change.

In cases where there is a change in formulation, a table comparing the formulation between the current and the proposed formula should be provided.

4.4 List of all ingredients

As per Section B.25.046 (2) (d) (for infant formula) and Section B.25.011 (d) (for human milk fortifier) of the FDR, the list of all ingredients must be provided with quantitative amounts specified. The bill of materials for a batch of infant formula should be submitted to meet this requirement.

For infant formula, amounts of nutrients should fall within the range provided in Table II in Division 25 of the FDR, where available. For nutrients not listed in Table II, appropriate Codex standards and nutrient ranges from the Life Sciences Research Office Report on the Assessment of Nutrient Requirements for Infant Formulas (LSRO Report, 1998) should be used as guidance.

The nutrient requirements for preterm infants according to the most recent international expert recommendations are summarized in Appendix 4, which is in the form of a template to facilitate manufacturers to compare the nutritional profile of their products against the requirements. The assessment of the preterm infant formula is based on the formula as ready to use, and human milk fortifier is based on the composition of the human milk fortifier when added to preterm human milk (not fortifier alone) according to the directions for use. The levels of nutrients added to a new human milk fortifier or one that has undergone a major change would be reviewed and assessed on a case-by-case basis as part of the pre-market review process.

Any food additives present in the infant formula, human milk fortifier or in the manufacture of an ingredient should be described and their levels of use should be provided as a percentage weight of infant formula or human milk fortifier, as consumed.

4.5 Ingredient specifications

As per Section B.25.046 (2) (e) (for infant formula) and Section B.25.011 (f) (for human milk fortifier) of the FDR, the specifications for nutrient, microbiological, and physical quality for all ingredients and for the new infant formula or human milk fortifier product must be provided in the premarket submission. They are required to allow Health Canada to determine whether a formula meets the Canadian compositional requirements and for the identification of potential microbial, physical, nutritional and chemical hazards, including allergens. The information required includes, but is not limited to, certificates of analysis and supplier raw material specification sheets.

Finished product specifications with minimums and maximums should also be provided for the infant formula or human milk fortifier product, as prepared according to directions for use, with the amounts expressed as per 100 kcal. The infant formula prepared according to directions for use must comply with the provisions in Sections B.25.054, B.25.055 and B.25.056 of the FDR in addition to all other regulatory requirements in Division 25. Specifically, amounts of nutrients declared in the finished product specifications should fall within the permitted minimum and maximum amounts provided for each nutrient in Table II in Division 25 of the FDR or the appropriate standards (refer to Section 4.4 of this guide). The minimum and maximum amounts of nutrients added to a new human milk fortifier or a human milk fortifier that has undergone a major change would be reviewed and assessed on a case-by-case basis as part of the pre-market review process.

A Finished Product Specification template is available for infant formula in Appendix 5.

4.6 Quality control procedures for testing nutrients

As per Section B.25.046 (2) (f) (for infant formula) and Section B.25.011 (g) (for human milk fortifier) of the FDR, manufacturers must provide details of quality control procedures regarding the testing of the ingredients and of the new infant formula or human milk fortifier. This would include providing documentation demonstrating that the manufacturer maintains, or has access to, suitably equipped laboratories to control the production and acceptance of raw ingredients, packaging materials, in-process and finished products. Method and process validation and stability capabilities, may also be required. Refer to Section 3.6 of the GMPs.

As articulated in Sections 3.6, 3.9.2 and 3.10 of the GMPs, manufacturers are required to implement a quality control procedure to test each nutrient in each nutrient premix used during manufacturing, and conduct appropriate in-process and finished product testing of nutrients (prior to product release). The results provided should verify that all nutrients required by the regulations and any nutrient added by the manufacturer are present at the appropriate levels in each batch of the infant formula or human milk fortifier.

Each lot of powdered infant formula and human milk fortifier should meet, at a minimum, the microbiological criteria for powdered infant formula adopted by Health Canada as outlined in Table 1 in Section 3.10 of the GMPs. These recommendations are in accordance with the Code of Hygienic Practice for Powdered Formulae for Infants and Young Children (Codex Alimentarius Commission CAC/RCP 66-2008).

For liquid infant formulas and human milk fortifiers, which are considered low-acid foods packaged in hermetically sealed containers (refer to Section 3.9 of the GMPs and Division 27 of the FDR), Part 4 of the SFCR provides the requirements for each application of the scheduled process to low-acid foods. Specifically, each application of the scheduled process to low-acid canned foods requires a record of the incubation results.

General guidelines on incubation testing can be found in Codex CAC/RCP 23-1979 Code of Hygienic Practice for Low and Acidified Low Acid Canned Foods. Section 3.10 of the GMPs for finished product control of liquid and powdered formula.

4.7 Manufacturing process and quality control procedures

As per Section B.25.046 (2) (g) (for infant formula) and Section B.25.011 (h) (for human milk fortifier) of the FDR, a premarket submission must include details of the manufacturing process and quality control procedures used throughout processing. This means that the information showing effective control of ingredients, formulations, processes, facilities and equipment used in the production of infant formula or human milk fortifier to be sold, distributed or marketed in Canada must be provided. Refer to the GMPs.

The manufacturer must provide the following information for Health Canada's review:

It is the manufacturer's responsibility to notify Health Canada about new manufacturing facilities. Refer to New Manufacturing Facilities for Infant Formula and Human Milk Fortifiers.

4.8 Expiration date and stability data

As per Section B.25.046 (2) (h) (for infant formula) and Section B.25.011 (i) (for human milk fortifier) of the FDR, Section 3.13 of the GMPs provides general requirements on Stability Program and Expiry Date control, which also apply to human milk fortifiers.

The manufacturer must provide the following information to Health Canada:

Appendix 6 provides a template for infant formula stability data. In addition, Section 3.13 of the GMPs provides general requirements on Stability Program and Expiry Date control, which also apply to human milk fortifiers.

4.9 Nutritional adequacy

As per Sections B.25.046 (2) (i) and B.25.048 (2) (d) (for infant formula) and Sections B.25.011 (j) and B.25.015 (2) (d) (for human milk fortifier) of the FDR, the evidence relied on to establish that an infant formula or human milk fortifier is nutritionally adequate to promote acceptable growth and development in infants must be submitted to Health Canada for review, as per paragraph B.25.046 (2) (i), B.25.048 (2) (d), and B.25.011(j), B.25.015 (2) (d) of the FDR respectively.

Refer to the following guidance documents to assist with preparation of studies to support nutritional adequacy:

4.10 Evidence for major changes

As per Section B.25.048 (2) (e) (for infant formula) and Section B.25.015 (2) (e) (for human milk fortifier) of the FDR, a clinical growth and tolerance trial and a Protein Efficiency Ratio (PER) study may be required for infant formula or human milk fortifier that has undergone a major change.

Health Canada encourages petitioners to have a pre-submission meeting with Health Canada on the required regulations, since these vary on a case-by-case basis.

4.11 Packaging

As per Section B.25.046 (2) (j) (for infant formula) and Section B.25.011 (k) (for human milk fortifier) of the FDR, the packaging material used for infant formulas or human milk fortifiers must be approved as food grade, and must comply with Division 23 of the FDR. The manufacturer must provide an issued letter of no objection from the Bureau of Chemical Safety of Health Canada for confirmation of acceptability. The GMPs should be consulted for further information on the manufacturing requirements for packaging infant formula. Additional information on the premarket submission process for food packaging is also available in Health Canada's guidance document on packaging materials.

4.12 Directions for preparation, use and storage

As per Sections B.25.046 (2) (k), B.25.057 (1) (e) and (2) (e) (for infant formula) and Sections B.25.011 (l), B.25.020 (e) and (f) (for human milk fortifier) of the FDR, the directions for the preparation, use and storage of an infant formula or human milk fortifier must be included in the label text provided as part of the premarket submission package, as detailed below.

4.12.1 Directions for preparation and use

The purpose of providing appropriate instructions in the label text is to reduce the risk of foodborne illness in infants. The directions for preparing and using the infant formula or human milk fortifier can include diagrams or pictograms. For powdered infant formula, these instructions should align with Health Canada's guide on preparing and handling powdered infant formula. For powdered infant formulas and human milk fortifiers, refer to Codex Alimentarius Commission in the CXC 66-2008 Code of Hygienic Practice for Powdered Formulae for Infants and Young Children.

The directions for preparation and use for infant formula should include:

For human milk fortifiers, the following safety precautions should be included:

For human milk fortifiers, a statement similar to the following should be included 'Tolerance to enteral feedings should be confirmed by offering small volumes of unfortified human milk. Once enteral feeding is well-established, (product name) can be added to human milk. A chart similar to Table 1 should also be included:

Table1. Human milk fortifier labelling chart for typical amounts for addition to human milk
Additional Calories Desired Human Milk Human Milk Fortifier Approximate Yield

x Calories/ y mL

z mL

Packaging type (e.g., 1 packet)

w mL

Examples

2 Calories/ 30 mL

50 mL

1 packet

55 mL

4 Calories/ 30 mL

25 mL

1 packet

30 mL

4.12.2 Storage

Instructions on how to properly store infant formulas or human milk fortifiers before and after opening the containers/package should include information on temperature, exposure to light or heat and the length of time that the containers can be safely stored. Statements such as 'Do not freeze' or 'keep frozen' and 'Avoid excessive heat' should be included as well, if applicable.

Once prepared, infant formula, or human milk fortifier in human milk, can spoil quickly. Length of time that these can be used after preparation should be included. Possible wording includes: 'Either feed immediately or cover and store in refrigerator at 2-4°C (35-40°F) for no longer than 24 hours. Do not use prepared formula if it is unrefrigerated for more than 1 hour'.

4.13 Label text

As per Sections B.25.046 (2) (l) and B.25.048 (2) (f) (for infant formula) and Sections B.25.011 (m) and B.25.015 (2) (f) (for human milk fortifier) of the FDR, the written text of all labels, including package inserts, to be used in connection with the infant formula or human milk fortifier must be provided to Health Canada as part of the premarket submission.

Sections B.25.057 and B.25.020 of the FDR set out the labelling requirements for infant formula and human milk fortifier, respectively. The formula should also comply with general food labelling regulations. The CFIA's Food Labelling for Industry guidance document should be consulted for more information on general food labelling requirements.

Section B.25.020 (1), (2) and (3) of the FDR lists specific information required for inner and outer human milk fortifier labels:

The written text of all labels, including package inserts, to be used in connection with the infant formula or human milk fortifier must be provided as part of the premarket submission. Electronic copies should be sent to Health Canada's Food Directorate SMIU at smiu-ugdi@hc-sc.gc.ca as soon as they are available after sending in a premarket submission. The electronic copies provided should allow for magnification, such that all text is legible.

Warning statements

Important safety information should be clearly listed under a bolded, all caps warning header, WARNING.

There should be a safety warning about the risks associated with heating and reheating infant formula in the microwave such as, 'Never heat formula in a microwave oven. Serious burns can result.' The label text must include a warning about priority food allergens that may have come into contact with the infant formula or human milk fortifier.

To ensure safety of use for human milk fortifiers, the product label should also include:

Infant formula advisory

It is highly recommended that labelling include the words 'Important Notice' followed by a statement on the superiority of breastfeeding. This direction aligns with the International Code of Marketing of Breast-milk Substitutes, to which Canada is a signatory.

Infant formula indications for use

Some specialty infant formulas are indicated for infants with certain medical conditions. Indications for use identify products that are meant for the dietary management of medical conditions. Examples of appropriate indications for use that have been accepted for infant formula include:

Any proposed new indication for use of an infant formula must be supported by clinical studies performed with the specific infant formula being notified. These specialty formulas and their accompanying indications for use are reviewed by Health Canada during the premarket submission review process.

Lactose free infant formula claims must be accompanied by information on the finished product specification for lactose which should be ≤10 mg/100 kcal. In Canada, all milk-based lactose free infant formulas are labelled with a contraindication statement against the use of these formulas in infants with galactosemia.

Human milk fortifier indications for use

Examples of appropriate indications for use that have been accepted for human milk fortifiers include:

As with specialty formula, any proposed new indication for use must be substantiated by clinical studies performed with the specific human milk fortifier being notified and will be reviewed by Health Canada during the premarket submission review process.

4.14 Signed submission

As per Sections B.25.046 (2) (m) and B.25.048 (2) (g) (for infant formula) and Sections B.25.011 (n) and B.25.15 (2) (g) (for human milk fortifier) of the FDR, the name, title and dated signature of the contact person responsible for the infant formula or human milk fortifier premarket submission must be included.

4.15 Scientific rationale for new human milk fortifier or major change

As per Sections B.25.011 (e) and B.25.15 (2) (c) of the FDR, a rationale for the purpose and use of the new human milk fortifier or one that has undergone a major change must be submitted.

5.0 Foreign reviews

When conducting a premarket review of a new infant formula or human milk fortifier, or a major change, Health Canada could also consider other relevant information, such as information provided to, or obtained from, a foreign regulator, or post-market data from another jurisdiction. While such information is not required under the premarket submission, information from another regulator relating to the approval of an infant formula or human milk fortifier, or a major change, in a foreign jurisdiction may help to streamline Health Canada's review process.

For any questions on the use of information from a foreign regulator or post-market data, manufacturers are encouraged to contact Health Canada at bns-bsn@hc-sc.gc.ca.

6.0 References to breastmilk

The International Code of Marketing of Breast-milk Substitutes (Code), to which Canada is a signatory, outlines labelling principles that promote clear labelling regarding the appropriate use of an infant formula while promoting breastfeeding. Comparing infant formula to breastmilk, including comparisons of the levels of a nutrient in infant formula to the levels of the same nutrient in breastmilk, is contrary to the message embodied in the Code.

Health Canada strongly urges the infant formula industry to support and implement the principles of the Code. In addition, the CFIA's guidance, Labelling requirements for infant foods, infant formula and human milk provides information about acceptable claims and aligns with certain principles set out in the Code. For example, highlighting an ingredient in infant formula as a key component of breastmilk is considered misleading as many components in breastmilk are equally important.

7.0 Glossary and abbreviations

This section provides a glossary of key terms and abbreviations used in this guide.

7.1 Glossary

Batch

A specific quantity of infant formula intended to have uniform character and quality within specified limits, which is produced according to a single manufacturing order and which may constitute the whole or a part of a lot.

Lot

A quantity of infant formula produced under identical conditions, all packages of which bear a lot number that identifies the production during a particular time interval from a particular 'line' or other critical processing unit. It may be defined by a time period (e.g., from sanitation to sanitation) or some other processing measure. It is often associated with a number and enables tracing of the constituent parts or ingredients as well as labour and equipment records involved in the manufacturing of an infant formula. This enables manufacturers and other entities to perform quality control checks, calculate expiration dates, and issue corrections or recall information to subsets of the production output.

Nutritional adequacy

An infant formula is nutritionally adequate if it promotes acceptable growth and development in infants when consumed in accordance with the directions for use. Clinical trial evidence is often used to determine whether a given infant formula is nutritionally adequate.

Premarket submission

The FDR requires that manufacturers notify Health Canada prior to the marketing of any new infant formula or human milk fortifier or of an infant formula or human milk fortifier that has undergone a major change in formulation, manufacturing or packaging. Sections B.25.046 and B.25.048 of the FDR specify the information that must be presented in the premarket submission for infant formula, and for human milk fortifiers in Section B.25.011 and B.25.015.

Premix

A combination of ingredients containing two or more nutrients as specified on the label, which is compounded in a manufacturing operation distinct from the processing of the final product.

Safety

A reasonable certainty of no harm (US Food and Drug Administration, Federal Food, Drug, and Cosmetic Act, Section 409).

7.2 Abbreviations

CFIA
Canadian Food Inspection Agency
FDA
Food and Drugs Act
FDR
Food and Drug Regulations
GMP
Good Manufacturing Practice
HACCP
Hazard Analysis Critical Control Point
HMF
Human Milk Fortifier
IF
Infant Formula
LSRO
Life Sciences Research Office
NIFI
New Infant Food Ingredient
PCP
Preventive Control Plan
PRSL
Potential Renal Solute Load
SFCA
Safe Food for Canadians Act
SFCR
Safe Food for Canadians Regulations
SMIU
Submission Management Information Unit

Appendix 1a. Verification checklist for infant formula submissions – new

Administrative information

Submission content

Yes (√)

Rationale for No

Cover letter provided

Title of the submission indicated

Completed checklist attached

Contact information provided (company name, full postal address, contact name, telephone number, email address)

Electronic version of the submission

If applicable, previous reference submission # and date on letter:

Information required under Part B of the Food and Drug Regulations

New infant formula submission

Yes (√)

Rationale for No

Name under which it will be sold or advertised for sale (FDR B.25.046.2 a)

Name and address of the principal place of business of the manufacturer (FDR B.25.046.2 b)

Names and addresses of each establishment in which it is manufactured (FDR B.25.046.2 c)

List of all ingredients, stated quantitatively (FDR B.25.046.2 d)

Specifications for nutrient, microbiological and physical quality for the ingredients and for the new infant formula (FDR B.25.046.2 e)

Details of quality control procedures respecting the testing of the ingredients and of the new infant formula (FDR B.25.046.2 f)

Details of the manufacturing process and quality control procedures used throughout the process (FDR B.25.046.2 g)

Results of tests carried out to determine the expiration date of the new infant formula (FDR B.25.046.2 h)

Evidence relied on to establish that the new infant formula is nutritionally adequate to promote acceptable growth and development in infants when consumed in accordance with the directions for use (FDR B.25.046.2 i)

Description of the type of packaging to be used (FDR B.25.046.2 j)

Directions for use (FDR B.25.046.2 k)

Written text of all labels (bilingual coloured mock ups are preferred), including package inserts, to be used in connection with the new infant formula (FDR B.25.046.2 l)

Name and title of the person who signed the submission and the date of signature (FDR B.25.046.2 m)

Appendix 1b. Verification checklist for infant formula submissions – major change

Administrative information

Submission content

Yes (√)

Rationale for No

Cover letter provided

Title of the submission indicated

Completed checklist attached

Contact information provided (company name, full postal address, contact name, telephone number, email address)

Electronic version of the submission

Information required under Part B of the Food and Drug Regulations

Submissions related to a major change to an existing infant formula

Yes (√)

Rationale for No

Name under which it will be sold or advertised for sale (FDR B.25.048.2 a)

Name and address of the principal place of business of the manufacturer (FDR B.25.048.2 b)

Description of the major change (FDR B.25.048.2 c)

Evidence relied on to establish that the infant formula is nutritionally adequate to promote acceptable growth and development in infants when consumed in accordance with the directions for use (FDR B.25.048.2 d)

Evidence relied on to establish that the major change has had no adverse effect on the infant formula (FDR B.25.048.2 e)

Written text of all labels, including package inserts, to be used in connection with the new infant formula (bilingual coloured mock ups are preferred) (FDR B.25.048.2 f)

Name and title of the person who signed the submission and the date of signature (FDR B.25.048.2 g)

Appendix 2a. Verification checklist for human milk fortifier submissions – new

Administrative information

Submission content

Yes (√)

Rationale for No

Cover letter provided

Title of the submission indicated

Completed checklist attached

Contact information provided (company name, full postal address, contact name, telephone number, email address)

Electronic version of the submission

If applicable, previous reference submission# and date on letter:

Information required under Part B of the Food and Drug Regulations

New human milk fortifier submission

Yes (√)

Rationale for No

Name under which it will be sold or advertised for sale (FDR B.25.011 a)

Name and address of the principal place of business of the manufacturer (FDR B.25.011 b)

Names and addresses of each establishment in which it is manufactured (FDR B.25.011 c)

List of all ingredients, stated quantitatively (FDR B.25.011 d)

Scientific rationale for the formulation (FDR B.25.011 e)

Specifications for nutrient, microbiological and physical quality for the ingredients and for the new human milk fortifier (FDR B.25.011 f)

Details of quality control procedures respecting the testing of the ingredients and of the new human milk fortifier (FDR B.25.011 g)

Details of the manufacturing process and quality control procedures used throughout the process (FDR B.25.011 h)

Results of tests carried out to determine the expiration date of the new human milk fortifier (FDR B.25.011 i)

Evidence relied on to establish that the new human milk fortifier is nutritionally adequate to promote acceptable growth and development in infants when consumed in accordance with the directions for use (FDR B.25.011 j)

Description of the type of packaging to be used (FDR B.25.011 k)

Directions for use (FDR B.25.011 l)

Written text of all labels (bilingual coloured mock ups are preferred), including package inserts, to be used in connection with the new human milk fortifier (FDR B.25.011 m)

Name and title of the person who signed the submission and the date of signature (FDR B.25.011 n)

Appendix 2b. Verification checklist for human milk fortifier submissions – major change

Administrative information

Submission content

Yes (√)

Rationale for No

Cover letter provided

Title of the submission indicated

Completed checklist attached

Contact information provided (company name, full postal address, contact name, telephone number, email address)

Electronic version of the submission

Information required under Part B of the Food and Drug Regulations

Submissions related to a major change to an existing human milk fortifier

Yes (√)

Rationale for No

Name under which it will be sold or advertised for sale (FDR B.25.015.2 a)

Name and address of the principal place of business of the manufacturer (FDR B.25.015.2 b)

Description of the major change (FDR B.25.015.2 c)

Evidence relied on to establish that the human milk fortifier is nutritionally adequate to promote acceptable growth and development in infants when consumed in accordance with the directions for use (FDR B.25.015.2 d)

Evidence relied on to establish that the major change has had no adverse effect on the human milk fortifier (FDR B.25.015.2 e)

Written text of all labels, including package inserts, to be used in connection with the new human milk fortifier (bilingual coloured mock ups are preferred) (FDR B.25.015.2 f)

Name and title of the person who signed the submission and the date of signature (FDR B.25.015.2 g)

Appendix 3. Flow chart for approval of a novel food or new infant food ingredient (NIFI)

Figure 1. Title
Figure 1. Text version below.
Figure 1 - Text description

PENDING

Reference 1 For information on the requirements for a novel food submission, consult Health Canada's Guidelines for the Safety Assessment of Novel Foods.
Reference 2 For information on the requirements for a NIFI submission, see Section 2.3.3 of this guide.
Reference 3 An unfavourable decision would result in closure of the submission. A new submission would be required.
Reference 4 For further information on clinical testing, consult Health Canada’s Growth and Tolerance Clinical Trial Protocol - Healthy Term Newborn Infants

Appendix 4. Nutrient requirement template for preterm infant formula or fortifier with human milk (as fed) per 100 kcal

NOTE: Single value indicates a minimum recommendation. Value in a square bracket has been reported as the calculated value in respective citation.

  1. MACRONUTRIENTS
Nutrient FDR requirements International expert recommendations Nutritional profile Specification
Name Unit ESPGHAN (2010)Reference 1 Tsang, et. al. (2005)Reference 2 >1000 g BW LSRO (2002)Reference 3 WHOReference 4 >1000 g BW (stabilization to term)Footnote a Koletzko, et.al. (2014)Reference 5 Min Max

Protein

g

1.8 – 4

3.2 – 4.1Footnote b

2.6 – 3.8

2.5 – 3.6

[2.5 – 3.0]

3.2 – 4.1

Fat

g

3.3 – 6

4.4 – 6.0

4.1 – 6.5

4.4 – 5.7

[3.8 – 5.7]

4.4 – 6.0

- LA

g

0.5

0.350 – 1.400

0.462 – 1.309

[0.350 – 1.425]Footnote c

NS

0.350 – 1.400

- ALA

g

NS

0.050

NS

(1 – 4 E% per kg/day)

0.077 – 0.228

(1.75 – 4% of total fatty acids)

NS

0.050

- LA:ALA

-

NS

5 – 15

5 – 15

6 – 16

NS

NS

- ARA

g

NS

0.016 – 0.039

0.022

[0 – 0.034] Footnote d

NS

0.032 – 0.041

- DHA

g

NS

0.011 – 0.027

0.016

[0 – 0.020]Footnote e

NS

0.050 – 0.055

Carbohydrate

g

NS

10.5 – 12

5.4 – 15.5

9.6 – 12.5

[6.3 – 12.9]

10.5 – 12

  1. VITAMINS AND MINERALS
Nutrient FDR requirements International expert recommendations Nutritional profile Specification
Name Unit ESPGHAN (2010)Reference 1 Tsang, et. al. (2005)Reference 2 >1000 g BW LSRO (2002)Reference 3 WHOReference 4 >1000 g BW (stabilization to term)Footnote a Koletzko, et.al. (2014)Reference 5 Min Max

Vitamin A

IU

250 – 500

1200 – 2467

538 – 1364

680 – 1267

583 – 1250

1217 – 3333

mcg RE

--

[360 – 740]

[162 – 410]

[204 – 380]

[175 – 375]

[365 – 1000]

Vitamin D

IU

40 – 100

800 – 1000Footnote f per day

115 – 364

75 – 270

[400 – 800]Footnote f per day

100 – 350 from milk only

Vitamin E

IU

0.6

[3.0 – 15]

4.6 – 10.9

[3.0 – 12]

[5.0 – 10.0]

[3.0 – 15]

mg α-TE

--

2 – 10

[3.1 – 7.3]

2 – 8 Footnote g

[3.4 – 6.7]

2 – 10

Vitamin K

mcg

8

4 – 25

6.2 – 9.1

4 – 25

[6.7 – 8.3]

4 – 25

Vitamin C

mg

8

10 – 42

13.8 – 21.8

8.3 – 37

[5 – 8]

18 – 50

Thiamine

mcg

40

125 – 275

138 – 218

30 – 250

[33 – 42]

127 – 273

Riboflavin

mcg

60

180 – 365

192 – 327

80 – 620

[300 – 383]

181 – 364

Vitamin B6

mcg

35

41 – 273

115 – 191

30 – 250

[15]Footnote h

45 – 273

Vitamin B12

mcg

0.15

0.08 – 0.7

0.23 – 0.27

0.08 – 0.7

[0.15]Footnote f

0.09 – 0.73

Niacin

mcg

250

345 – 5000

2800 – 4400

550 – 5000

[720]

900 – 5000

Pantothenic acid

mcg

300

300 – 1900

900 – 1500

300 – 1900

[667 – 1083]

450 – 1900

Folic acid

mcg

4

32 – 90

19 – 45

30 – 45

[50]Footnote f

32 – 91

Biotin

mcg

2

1.5 – 15

2.8 – 5.5

1.0 – 37

[1.3]

1.5 – 15

Choline

mg

12

7 – 50

11.1 – 25.5

7 – 23

NS

7.3 – 50

Inositol

mg

NS

4 – 48

25 – 74

4 – 44

NS

4 – 48

Taurine

mg

NS

NS

3.5 – 8.2

5 – 12

NS

NS

Carnitine

mg

NS

NS

2.2 – 2.6

2 – 5.9

NS

NS

Calcium (Ca)

mg

50

110 – 130

77 – 200

123 – 185

[134 – 200]

109 – 182

Phosphorus (P)

mg

25

55 – 80

46 – 127

82 – 109

[65 – 98]

55 – 127

Ca:P

--

1.2 – 2

NS

NS

1.7 – 2.0:1

NS

NS

Magnesium

mg

6

7.5 – 13.6

NS

6.8 – 17

[4.1 – 8.1]

7.5 – 13.6

Sodium

mg

20 – 60

63 – 105

53 – 105

39 – 63

[48 – 77]

63 – 105

Potassium

mg

80 – 200

60 – 120

60 – 106

60 – 160

[81 – 114]

71 – 177

Chloride

mg

55 – 150

95 – 161

82 – 226

60 – 160

[74 – 118]

95 – 161

Iron

mg

0.15

1.8 – 2.7

1.538 – 3.636

1.7 – 3.0

[1.7 – 2.5]

1.8 – 2.7

Zinc

mg

0.5

1.0 – 1.8

0.769 – 2.727

1.1 – 1.5

[0.42 – 0.67]

1.3 – 2.3

Copper

mcg

60

90 – 120

92 – 136

100 – 250

[58 – 101]

90 – 210

Manganese

mcg

5

6.3 – 25

0.5 – 6.8

6.3 – 25

[0.5 – 0.9]

0.9 – 13.6

Iodine

mcg

5

10 – 50

7.7 – 54.5

6 – 35

[26 – 53]

9 – 50

Selenium

mcg

NS

4.5 – 9

1.0 – 4.1

1.8 – 5.0

[2.6 – 3.9]

4.5 – 9

Chromium

mcg

NS

0.027 – 1.12

0.08 – 2.05

NS

0.04 – 0.08

0.027 – 2.045

Molybdenum

mcg

NS

0.27 – 4.5

0.23 – 0.27

NS

0.16 – 0.32

0.27 – 4.5

Fluoride

mcg

NS

1.4 – 55

NS

0 – 25

NS

1.4 – 55

  1. NUCLEOTIDES
Nutrient FDR requirements International expert recommendations Nutritional profile Specification
Name Unit ESPGHAN (2010)Reference 1 Tsang, et. al. (2005)Reference 2 >1000 g BW LSRO (2002)Reference 3 WHOReference 4 >1000 g BW (stabilization to term)Footnote a Koletzko, et.al. (2014)Reference 5 Min Max

Total Nucleotides

mg

NS

NS

NS

NS

NS

NS

AMP

mg

NS

NS

0.27 – 0.73

NS

NS

NS

CMP

mg

NS

NS

1.6 – 3.7

NS

NS

NS

GMP

mg

NS

NS

0.03 – 0.54

NS

NS

NS

UMP

mg

NS

NS

0.69 – 0.9

NS

NS

NS

Abbreviations

ALA
Alpha-linolenic acid
AMP
Adenosine monophosphate
ARA
Arachidonic acid
BW
Body weight
Ca:P
Calcium to phosphorous ratio
CMP
Cytosine monophosphate
DHA
Docosahexaenoic acid
g
gram
GMP
Guanosine monophosphate
LA
Linoleic acid
LSRO
Life Sciences Research Office
Max
Maximum
mcg
microgram
mg
milligram
Min
Minimum
NS
None specified
PUFA
Polyunsaturated fatty acids
RE
Retinol equivalents
TE
Tocopherol equivalents
UMP
Uridine monophosphate
WHO
World Health Organization.

References

Reference 1

Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr. 2010:50. 85-91.

Return to reference 1 referrer

Reference 2

Tsang RC, Uauy R, Koletzko B, Zlotkin S. Nutrition of the preterm infant, Scientific basic and practical guidelines. Cincinnati, OH: Digital Educational Publishing Inc. 2005.

Return to reference 2 referrer

Reference 3

Klein CJ. Nutrient requirements for preterm infant formulas. J Nutr 2002;132:1395S-577S.

Return to reference 3 referrer

Reference 4

Tudehope D. et al. Nutritional Needs of the Micropreterm Infant March 2013, Volume 162, Issue 3, Supplement, Pages S72–S80

Return to reference 4 referrer

Reference 5

Koletzko B, Poindexter B, Uauy R. Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. Karger, 2014:99-120

Return to reference 5 referrer

Footnotes

Footnote a

Calculated based on the average of the maximum and minimum energy recommendations for the indicated population; 120 kcal/kg/d for stabilization to term.

Return to footnote a referrer

Footnote b

3.6 – 4.1 g / 100 kcal for infants < 1 kg BW; 3.2 – 3.6 g/100 kcal for infants 1 - 1.8 kg BW

Return to footnote b referrer

Footnote c

Total fatty acids: 8% (minimum) and 25% (maximum)

Return to footnote c referrer

Footnote d

A minimum recommendation for ARA was not established. Maximum: 0.6% of total fatty acids with the further stipulation that the ARA:DHA is within the range of 1.5-2.0 : 1

Return to footnote d referrer

Footnote e

A minimum recommendation for DHA was not established. Maximum: 0.35% of total fatty acids with the further stipulation that the ARA:DHA is within the range of 1.5-2.0 : 1

Return to footnote e referrer

Footnote f

Recommendation given per day, independent of body weight and energy intake

Return to footnote f referrer

Footnote g

The ratio of vitamin E to PUFA (mg α-TE per g PUFA) should exceed 1.5 (mg α-TE/g PUFA)

Return to footnote g referrer

Footnote h

Recommendation per gram protein fed

Return to footnote h referrer

Appendix 5. Suggested template for finished product specification data, infant formula

Nutrients (unit) Label Claim Release Limits FDR (1990) LSRO 1998 Codex Stan 72-1981
per 100 ml per 100 kcal Min per 100 kcal Min % label claim Max per 100 kcal Max % label claim MIN per 100 kcal MAX per 100 kcal MIN per 100 kcal MAX per 100 kcal MIN per 100 kcal MAX per 100 kcal
Energy (kcal)

---

---

63

71

60

70

Protein (g)

1.8

4

1.7

3.4

1.8

3

Total carbohydrate (g)

---

---

9

13

9

14

Total Fat (g)

3.3

6

4.4

6.4

4.4

6

Linoleic acid (LA) (mg. % fat)

500

---

350

2240

300

1400*

Alpha-linolenic acid (ALA) (mg, % fat)

---

---

77

256

50

---

Arachidonic acid (ARA) (mg/100kcal)

---

---

---

---

---

---

Docosahexaenoic acid (DHA) (mg, % fat)

---

---

---

---

---

0.5%*

Carnitine (mg)

---

---

1.2

2

1.2

---

Taurine (mg)

---

---

0

12

---

12

Nucleotides (mg)

---

---

0

16

---

---

Choline (mg)

12

---

7

30

7

50*

Inositol (mg)

---

---

4

40

4

40*

Vitamin A (IU)

250

500

200

500

200

600

Vitamin D (IU)

40

100

40

100

40

100

Vitamin E (IU)

0.6

---

0.7

7.5

0.7

5*

Vitamin K (mcg)

8

---

1

25

4

27*

Vitamin B1 - Thiamin (mcg)

40

---

30

200

60

300*

Vitamin B2 - Riboflavin (mcg)

60

---

80

300

80

500*

Vitamin B3 - Niacin (mcg)

250

---

550

2000

300

1500*

Vitamin B5 - Pantothenic acid (mcg)

300

---

300

1200

400

2000*

Vitamin B6 - Pyridoxin (mcg)

35

---

30

130

35

175*

Vitamin B12 - Cobalamin (mcg)

0.15

---

0.08

0.7

0.1

1.5*

Folic acid (mcg)

4

---

11

40

10

50*

Biotin (mcg)

2

---

1

15

1.5

10*

Vitamin C (mg)

8

---

6

15

10

70*

Calcium (mg)

50

---

50

140

50

140*

Phosphorus (mg)

25

---

20

70

25

100*

Magnesium (mg)

6

---

4

17

5

15*

Iron (mg)

0.15

---

0.2

1.65

0.45

---

Zinc (mg)

0.5

---

0.4

1

0.5

1.5*

Manganese (mcg)

5

---

1

100

1

100*

Copper (mcg)

60

---

60

160

35

120*

Iodine (mcg)

5

---

8

35

10

60*

Sodium (mg)

20

60

25

50

20

60

Potassium (mg)

80

200

60

160

60

180

Chloride (mg)

55

150

50

160

50

160

Selenium (mcg)

---

---

1.5

5

1

9*

Ratio LA:ALA

---

---

6

16

5

15

Ratio Calcium:Phosphorus

1.2

2

1.1

2

1

2

Ratio Vitamin B6:Protein (mcg/g)

15

---

---

---

---

---

Ratio alpha-tocopherol:linoleic acid (IU/g)

0.6

---

---

---

---

---

*GUL, Guidance Upper Level

Appendix 6. Suggested template for stability data, infant formula

PRODUCT NAME:

Research or Commercial Batch:

Temperature:

Other product name (if applicable):

Batch Number:

Proposed Shelf Life:

Packaging Type:

0 month (initial time point)

X month (middle time point)

X month (final time point)

Label Claim Data Points Data Points Data Points
Nutrients (unit) per 100 ml per 100 kcal per 100 kcal AVERAGE % Label Claim per 100 kcal AVERAGE % Label Claim per 100 kcal AVERAGE % Label Claim per 100 kcal AVERAGE % Label Claim per 100 kcal AVERAGE % Label Claim per 100 kcal AVERAGE % Label Claim

Energy (kcal)

Protein (g)

Total carbohydrate (g)

Total Fat (g)

Linoleic acid (LA) (mg, % fat)

Alpha-linolenic acid (ALA) (mg, % fat)

Arachidonic acid (ARA) (mg)

Docosahexaenoic acid (DHA) (mg, % fat)

Carnitine (mg)

Taurine (mg)

Nucleotides (mg)

Choline (mg)

Inositol (mg)

Vitamin A (IU)

Vitamin D (IU)

Vitamin E (IU)

Vitamin K (mcg)

Vitamin B1 - Thiamin (mcg)

Vitamin B2 - Riboflavin (mcg)

Vitamin B3 - Niacin (mcg)

Vitamin B5 - Pantothenic acid (mcg)

Vitamin B6 - Pyridoxin (mcg)

Vitamin B12 - Cobalamin (mcg)

Folic acid (mcg)

Biotin (mcg)

Vitamin C (mg)

Calcium (mg)

Phosphorus (mg)

Magnesium (mg)

Iron (mg)

Zinc (mg)

Manganese (mcg)

Copper (mcg)

Iodine (mcg)

Sodium (mg)

Potassium (mg)

Chloride (mg)

Selenium (mcg)

Page details

Date modified: