EVIDENCE FOR QUALITY OF FINISHED
NATURAL HEALTH PRODUCTS
Natural Health Products Directorate
June 2007
Version 2
鈥淥ur mission is to help the people of Canada maintain and improve their
health, while respecting individual choices and circumstances.鈥?
Health Canada
鈥淥ur role is to ensure that Canadians have ready access to natural health
products that are safe, effective and of high quality while respecting freedom
of choice and philosophical and cultural diversity.鈥?
Natural Health Products Directorate
脡galement offert en fran莽ais sous le titre:
Preuves attestant de la qualit茅 des produits de sant茅
naturels finis
This publication is also available electronically at the
following address: www.healthcanada.gc.ca/nhp
漏 Her Majesty the Queen in Right of Canada, represented
by the Minister of Health, 2007.
Cat. H164-40/2007E-PDF
ISBN 978-0-662-46390-0
Contact the Natural Health Products Directorate
Natural Health Products Directorate
Health Canada
2936 Baseline Rd., Tower A
Ottawa, Ontario
K1A 0K9
www.healthcanada.gc.ca/nhp
Telephone: 1-888-774-5555
Fax: (613) 948-6810
Email: NHPD_DPSN@hc-sc.gc.ca
FOREWORD
Guidance documents are meant to provide assistance to industry and health care
professionals on how to comply with the policies and governing statutes and
regulations. They also serve to provide review and compliance guidance to staff,
thereby ensuring that mandates are implemented in a fair, consistent and effective
manner.
Guidance documents are administrative instruments not having force of law and, as
such, allow for flexibility in approach. Alternate approaches to the principles and
practices described in this document may be acceptable provided they are supported
by adequate scientific justification. Alternate approaches should be discussed in
advance with the relevant program area to avoid the possible finding that applicable
statutory or regulatory requirements have not been met.
As a corollary to the above, it is equally important to note that Health Canada reserves
the right to request information or material, or define conditions not specifically
described in this guidance, in order to allow the Department to adequately assess the
safety, efficacy or quality of a health product. Health Canada is committed to ensuring
that such requests are justifiable and that decisions are clearly documented.
This document should be read in conjunction with the relevant sections of other
applicable guidance documents.
Evidence for Quality of Finished Natural Health Products 1
TABLE OF CONTENTS
TABLE OF CONTENTS.................................................................................................. 2
SECTION 1. INTRODUCTION ....................................................................................... 4
1.1 Purpose ............................................................................................................ 4
1.2 Background....................................................................................................... 4
1.3 Scope................................................................................................................ 4
1.4 General Overview ............................................................................................. 5
1.4.1 Compendial Applications ............................................................................... 7
1.4.2 Non-Compendial Applications ....................................................................... 7
1.4.3 Acceptable Pharmacopeia............................................................................. 8
SECTION 2. GENERAL QUALITY REQUIREMENTS .................................................. 9
2.1 Characterization................................................................................................ 9
2.1.2 Identification Tests ........................................................................................ 9
2.1.2.2 Specifications for Medicinal Ingredients ...................................................... 11
2.2 Standardized Products.................................................................................... 11
2.2.1 Standardized Extracts ................................................................................. 11
2.3 Manufacturing Requirements .......................................................................... 13
2.3.1 Raw Material Manufacturing Information ..................................................... 13
2.3.1.1 Standardized Products ................................................................................ 13
2.3.1.2 Other Extracts ............................................................................................. 14
2.3.1.3 Isolates and Synthetic Duplicates................................................................ 14
2.3.1.4 Enzymes...................................................................................................... 15
2.3.1.5 Probiotics..................................................................................................... 15
2.3.2 Proprietary Information Concerning the Manufacturing Process ................. 16
2.3.3 Finished Product Manufacturing Information ............................................... 16
2.4 Finished Product Specifications Requirements............................................... 17
2.4.1 Analytical Methods ...................................................................................... 17
2.4.2 Identity Testing on the Finished Product ..................................................... 17
2.4.3 Purity ........................................................................................................... 18
2.4.3.1 Microbial Contaminants ............................................................................... 19
2.4.3.2 Chemical Contaminants .............................................................................. 19
2.4.3.3 Additional Tests........................................................................................... 22
2.5 Quantity .......................................................................................................... 24
2.5.1 Quantification by Assay ............................................................................... 24
2.5.2 Quantification by Input................................................................................. 24
2.6 Stability Testing............................................................................................... 26
SECTION 3. SPECIFIC TESTS AND CRITERIA FOR FINISHED PRODUCTS ......... 28
Evidence for Quality of Finished Natural Health Products 2
3.1 Disintegration .................................................................................................. 28
3.2 Dissolution ..................................................................................................... 28
3.3 Uniformity of Dosage Units ............................................................................ 29
3.4 Sterilization .................................................................................................... 29
3.5 Antimicrobial Effectiveness Testing ............................................................... 30
SECTION 4. HOMEOPATHIC MEDICINES................................................................. 31
4.1 Definition of a Homeopathic Medicine............................................................. 31
4.2 Overview of Quality Specifications for Homeopathic Medicines...................... 31
4.2.1 Manufacturing.............................................................................................. 31
4.2.2 Specifications .............................................................................................. 32
4.2.2.1 Identification ................................................................................................... 32
4.2.2.2 Purity.............................................................................................................. 32
4.2.2.2.1 Microbial Contaminants............................................................................... 32
4.2.2.3 Nosodes ...................................................................................................... 32
4.2.2.4 Chemical Contaminants ................................................................................. 33
SECTION 5. REFERENCES......................................................................................... 34
5.1 Health Canada documents ............................................................................. 34
5.2 Related documents ......................................................................................... 34
APPENDIX 1. GLOSSARY.......................................................................................... 36
APPENDIX 2. SCHEDULE 1 OF THE NATURAL HEALTH PRODUCTS
REGULATIONS ............................................................................................................ 40
APPENDIX 3. QUALITY REQUIREMENTS OF MEDICINAL INGREDIENTS USED IN
HOMEOPATHIC MEDICINE......................................................................................... 41
APPENDIX 4. ACCEPTABLE LIMITS FOR MICROBIAL AND CHEMICAL
CONTAMINANTS ......................................................................................................... 42
APPENDIX 5. CALCULATIONS.................................................................................. 44
APPENDIX 6. LIST OF ACCEPTABLE DOSAGE FORMS ........................................ 45
APPENDIX 7. FINISHED NATURAL HEALTH PRODUCT SPECIFICATION
TEMPLATE................................................................................................................... 46
APPENDIX 8. PHYSICAL TESTS REQUIRED FOR DIFFERENT DOSAGE FORMS 49
Evidence for Quality of Finished Natural Health Products 3
SECTION 1. INTRODUCTION
1.1 Purpose
This guidance document is intended to provide applicants (manufacturers, packagers,
labellers, importers, distributors) with the details necessary to comply with the Natural
Health Products Regulations (the Regulations) at the time of submitting the product
licence application (PLA) with respect to the manufacture and quality requirements of
natural health products (NHPs).
1.2 Background
Based on valuable feedback received from stakeholders during various information
sessions, and experience gained by reviewing PLAs by scientific reviewers/assessment
officers and submission coordinators at the Natural Health Products Directorate
(NHPD), the Evidence for Quality of Finished Natural Health Products Guidance
Document has been revised.
1.3 Scope
The procedures outlined in this document apply to the quality assessment of all types of
pre-market submissions of NHPs that fall under the purview of the Regulations. This
document should be read in conjunction with other NHPD guidance documents such as
the Product Licensing Guidance Document, Good Manufacturing Practices Guidance
Document, Evidence for Safety and Efficacy of Finished Natural Health Products
Guidance Document and Evidence for Homeopathic Medicines Guidance Document to
ensure the product requirements are comprehensively applied and documented in a
product licence application. Further, reference has also been made to a number of
national and international standards, such as the United States Pharmacopoeia (USP),
European Pharmacopoeia (Ph. Eur.), and Therapeutic Goods Administration of
Australia (TGA) where it is recommended that these standards be applied.
This document is intended for use by applicants, as well as by scientific
reviewers/assessment officers and submission coordinators within NHPD and other
stakeholders.
The NHPs available in Canada can be broadly classified into:
鈥? Single ingredient products; and
鈥? Multi-ingredient products.
The general quality requirements are outlined in Section 2 of this document. Specific
quality requirements of products containing particular items from Schedule 1 of the
Regulations have also been included where they differ from the general requirements.
Evidence for Quality of Finished Natural Health Products 4
A multi-ingredient product is defined as a finished product containing more than one
item from Schedule 1 of the Regulations (Appendix 2).
Section 3 of this document outlines specific test requirements for the finished natural
health product in various dosage forms.
Section 4 of this guidance document outlines the quality requirements for homeopathic
medicines.
1.4 General Overview
The regulatory requirements for the quality of the finished NHPs are set out in Sections
5 (License Application), 44 (Specifications), 98 (Medicinal Ingredient Representations)
and 103 (Tablet Disintegration Times) of the Regulations.
PART 1
PRODUCT LICENCES
Licence Application
Section 5
An application for a product licence shall be submitted to the Minister and shall contain the following
information and documents:
(i) a copy of the specifications to which the natural health product will comply
PART 3
GOOD MANUFACTURING PRACTICES
Specifications
Section 44
(1) Every natural health product available for sale shall comply with the specifications submitted in
respect of that natural health product under paragraph 5(i) and with every change to those specifications
made by the product licence holder.
(2) The specifications shall contain the following information:
a. detailed information respecting the purity of the natural health product, including statements
indicating its purity tolerances;
b. for each medicinal ingredient contained in the natural health product, detailed information
respecting its quantity per dosage unit and its identity, including statements indicating its quantity
and identity tolerances;
c. if a representation relating to the potency of a medicinal ingredient is to be shown on a label of
the natural health product, detailed information respecting the potency of the medicinal
ingredients, including statements indicating its potency tolerances; and
d. a description of the methods used for testing or examining the natural health product.
(3) The specifications and every change to those specifications shall be approved by a quality assurance
person.
Evidence for Quality of Finished Natural Health Products 5
PART 5
GENERAL
Medicinal Ingredient Representations
Section 98
Section C. 01.012 of the Food and Drug Regulations applies in respect of natural health products.
C. 01.012. A manufacturer who makes representations on a label of a drug in oral dosage form, or in any
advertisement, with respect to the site, rate or extent of release to the body of a medicinal ingredient of
the drug, or the availability to the body of a medicinal ingredient of the drug shall
(a) before making the representations, conduct such investigations, using an acceptable method, as may
be necessary to demonstrate that the site, rate or extent of release to the body of the medicinal ingredient
of the drug and the availability to the body of the medicinal ingredient of the drug, correspond to the
representations; and
(b) on request submit the record of such investigations to the Director.
PART 5
GENERAL
Tablet Disintegration Times
Section 103
Subsection C. 01.015(1) and paragraphs C. 01.015(2) (d) to (f) of the Food and Drug Regulations apply
in respect of natural health products.
C. 01.015. (1) Subject to subsection (2), no person shall sell for human use a drug in the form of a tablet
that is intended to be swallowed whole unless, when tested by the official method DO-25, Determination
of the Disintegration Time of Tablets, dated July 5, 1989,
(a) in the case of an uncoated tablet, the tablet disintegrates in not more than 45 minutes;
(b) in the case of a plain coated tablet, the tablet disintegrates in not more than 60 minutes; and
(c) in the case where the label of the drug indicates that the tablet carries an enteric coating or a coating
designed to serve a purpose similar to that of an enteric coating, the tablet does not disintegrate when
exposed for 60 minutes to simulated gastric fluid, but when it is subsequently exposed for a continuous
period to simulated intestinal fluid the tablet disintegrates in not more than 60 minutes.
(2) Subsection (1) does not apply in respect of a drug in the form of a tablet where
(d) the drug is labelled as complying with a standard contained in a publication referred to in Schedule B
to the Act;
(e) the drug has been demonstrated by an acceptable method to be available to the body; or
(f) representations regarding the drug are made on its label, or in any advertisement, with respect to the
site, rate or extent of release to the body of a medicinal ingredient of that drug, or the availability to the
body of a medicinal ingredient of that drug.
Evidence for Quality of Finished Natural Health Products 6
All NHPs that are to be sold in Canada need a product specification. The technical
specifications submitted along with the product license application should include:
鈥? tests for identity, microbial and chemical purity, quantity and potency, if applicable;
鈥? test methods for identity, microbial and chemical purity, quantity and potency; and
鈥? tolerance limits for microbial and chemical purity, quantity and potency.
Applicants should ensure that products are tested against the product specification
requirements prior to release of the product for sale. If a claim is made on the label of a
product for pharmacopoeial standard (e.g., USP grade), then applicants should strictly
meet all requirements of relevant monographs including those requirements described
in the general chapters, as stipulated in the specified pharmacopoeia.
The two basic streams of product licence applications are:
1.4.1 Compendial Applications
When a reference is made to NHPD monographs in the applications, applicants are not
required to fill out the Quality Summary Report. Additional details in this regard are
available in the guidance document Compendium of Monographs. In essence,
applicants attest to meeting the relevant finished product specifications, as listed in the
Compendium of Monographs.
1.4.2 Non-Compendial Applications
Applicants can also attest to meeting the relevant monographs and all other applicable
requirements from one of the acceptable pharmacopeia listed below. Where there are
pharmacopeial monographs for active ingredients only and the pharmacopeia do not
contain monographs for the finished product in the dosage form which is being applied
for, the applicant should attest to meeting the relevant finished product specifications in
the NHPD Compendium of Monographs. In this case, the applicant should provide a
signed attestation that includes a complete description of the monographs to which they
comply. In these cases, applicants do not need to fill out the Quality Summary Report
(QSR).
In all other cases, applicants should complete the Quality Summary Report.
Applications may also be submitted in ICH Common Technical Document (CTD) format.
If an applicant proposes finished product specifications that are outside the minimum
requirements outlined in this guidance document, the applicant will be required to
provide the proposed specifications, rationale for not meeting NHPD requirements and
submit to NHPD additional scientific data to support the rationale. For instance, when an
applicant proposes to use a different analytical method other than the one outlined in
this guidance document, or proposes a tolerance limit exceeding the one described,
proper justification is required and a risk-benefit analysis must also be provided. For any
Evidence for Quality of Finished Natural Health Products 7
new method used, the applicant should provide a detailed description of the methods, or
a reference to the method if published.
NHPD will then assess the data provided by the applicant to determine whether the
information is relevant and sufficient to support the quality of the NHP.
1.4.3 Acceptable Pharmacopeia
The following pharmacopoeias are currently considered acceptable by NHPD:
United States Pharmacopeia (USP)
British Pharmacopoeia (BP)
European Pharmacopoeia (Ph. Eur.)
It is expected that if a monograph is published in one of these pharmacopoeia, the
minimum specifications used for testing of the medicinal ingredient and finished
products will be in accordance with the published monograph. The most recent version
of the pharmacopoeia should be used in all cases.
Evidence for Quality of Finished Natural Health Products 8
SECTION 2. GENERAL QUALITY REQUIREMENTS
In order to ensure quality of the finished products, manufacturers of NHPs should
specify and implement quality requirements at every stage of manufacture of the raw
material and finished product.
The quality requirements outlined in this chapter are general criteria for finished
products containing NHPs, and additional product-specific requirements for items 1-8 of
Schedule 1 of the Regulations (Appendix 2). Homeopathic product requirements,
where unique, are detailed in Section 5.
In general, the guidelines encompass a list of tests, acceptance criteria, limits and
ranges for the parameters prescribed that must be provided in finished product
specifications, thus setting out the quality criteria for acceptance of NHPs for their
intended use.
2.1 Characterization
Standardized plant extracts, all isolates of natural origin as well as their synthetic
duplicates require characterization. For standardized extracts which use novel
chemical(s) as marker compounds or bio-active compounds for standardization,
characterization of the marker chemical may be required.
Characterization should include the chemical name and Chemical Abstract Service
(CAS) Registry number. Additional details such as spectroscopic methods used to
characterize the compound (e.g., Nuclear Magnetic Resonance (NMR), Infra-red
spectroscopy (IR), Raman, Mass Spectroscopy) may be required.
2.1.2 Identification Tests
Complete testing for identification purposes is usually performed at the raw material
stage to identify the medicinal ingredient using physical and/or chemical identification
tests.
Under section 44(2) (d) of the Regulations, the finished product specifications shall
contain a description of the methods used for testing or examining the natural health
product containing medicinal ingredients which are substances defined in Schedule 1
(see Appendix 2).
In the case of a medicinal ingredient where the constituents responsible for the
biological activity are unknown or a chromatographic fingerprint cannot be established,
or because of the complex nature of the finished product, it is sufficient to provide
physical identity tests at the raw material stage.
Where possible, the medicinal ingredient should be identified by spectroscopic and/or
chromatographic fingerprinting in the finished product. Spectroscopic methods include,
Evidence for Quality of Finished Natural Health Products 9
among others, Ultra Violet (UV), Infrared (IR), and Mass Spectroscopy, and
chromatographic methods include, among others, High Performance Liquid
Chromatography (HPLC), Thin Layer Chromatography (TLC), and Gas Chromatography
(GC).
Botanical characteristics and other tests that lead to the identification of a plant material,
an alga or a fungus are critical. These characteristics can be confirmed at the raw
material stage, before the original form of the material is changed during the production
process. Identification tests outlined in the pharmacopoeial monographs (such as USP
or Ph.Eur.) or botanical text books can be used as a guiding tool.
鈥? Botanical Characteristics:
o Macroscopic Characteristics 鈥? e.g., plant morphology that defines shape
of leaf, flower etc.
o Microscopic Characteristics 鈥? e.g., plant tissue morphology that defines
cellular characteristics.
鈥? Chemical Identification:
Where possible chemical identification methods should be used (such as
appropriate analytical methods like TLC, HPLC or GC) that characterize a
specific chemical marker or a chemical reaction that is a representative test for a
specific herb. Chromatographic fingerprinting where the proportions of
chromatographic peaks are compared to a known standard can also be used for
identification purposes.
The combination of botanical characteristics and chemical identification tests should be
chosen to eliminate misidentification of the herb (e.g., eliminate use of a different
species or a herbal drug that is likely to be falsified). Extracts of plant material can be
identified by characteristics of the original material as mentioned above prior to the
extraction process and chromatographic fingerprinting of the extract.
Isolates and synthetic duplicates of materials of natural origin (e.g., vitamins and
minerals) should be identified at the raw material stage by physical description and
physical form (e.g., colour, crystalline form, etc.) as well as other physical
characteristics such as melting point, boiling point, optical rotation, etc. Appropriate
identification tests such as Infrared spectroscopy should also be performed at the raw
material stage. Essential fatty acids should be identified at the raw material stage and/or
at the finished product stage by fatty acid composition of the oil, refractive index (for a
liquid) and/or any other appropriate identification tests.
If the medicinal ingredient is an enzyme, it should be characterized at the raw material
stage by chemical name, Enzyme Commission classification and CAS Registry number.
Additional details such as gel electrophoresis, substrate specificity, isoelectric point,
specific activity should also be provided, if available. Testing can be done according to
pharmacopoeial methods or methods approved by the International Enzyme
Commission.
Evidence for Quality of Finished Natural Health Products 10
If the medicinal ingredient is a bacterium which grows in readily visible colonies (e.g.,
cyanobacteria), tests for identity of the bacteria can include microscopic evaluation. A
qualitative description of the bacterium should include parameters such as Latin
binomial name (e.g., Spirulina platensis). The test methods used to identify the
substance (e.g., organoleptic, macroscopic and microscopic) should also be provided in
the raw material specifications. If the bacterium does not grow in readily visible colonies,
the identity of the bacterial strains can be determined by the selective culture method,
direct microscopic analysis, and DNA-based finger printing techniques.
For probiotic cultures, a qualitative description of the probiotic culture should be
provided which should include identity parameters such as Latin binomial name (e.g.,
Bifidobacterium longum). The identity of probiotic strains should be determined
preferably by using phenotyping and genotyping methods at the raw material and/or at
the finished product stage. Identification should ensure the absence of mixed cultures at
the raw material stage. Other commonly used methods for identification of probiotic
strains are selective culture method, direct microscopic analysis, enzyme/metabolite
analysis and DNA-based finger printing techniques. Testing should be done according
to appropriate methods which are specific and reproducible.
2.1.2.2 Specifications for Medicinal Ingredients
A specification or a certificate of analysis for each medicinal ingredient should be
provided with detailed information as to the testing performed to confirm the identity and
purity of the medicinal ingredient.
2.2 Standardized Products
Currently, there is no harmonized definition of standardization. Therefore, given that
some manufacturing and finished product specification requirements differ for
standardized products, this document assumes the definition of standardization used by
NHPD.
Standardization is a process that manufacturers may use to ensure batch-to-batch
consistency of their products. In some cases, standardization involves identifying
specific chemicals (also known as markers) that can be used to manufacture a
consistent product. The standardization process can also provide a measure of quality
control of the product.
2.2.1 Standardized Extracts
Standardization refers to the process of delivering a product with a specified minimum
level or a specified range of one or more of biochemical constituent(s) or marker
compound(s), while maintaining the total characteristics of a product containing plant
material, algae, bacteria, fungi, or non-human animal material. It is achieved by
Evidence for Quality of Finished Natural Health Products 11
characterizing and quantifying one or more biomarkers of either known pharmacological
activity (medicinal or active compound) or unknown pharmacological activity.
Biomarkers are classified as follows:
鈥? Active constituent: A known and acceptable therapeutically active biochemical
component. This specific biochemical constituent can be adjusted by standardization
to a level that is reproducible 鈥? either that naturally found in the plant or more
concentrated in an extract.
鈥? Marker compound: The active biochemical component is not known. The specified
marker compound, which is characteristic of the natural health product, but does not
contribute to therapeutic activity, is adjusted to serve an analytical purpose. Marker
compounds can be used to control batch-to-batch consistency of the finished
product.
The approach to standardization is to manufacture the product to ensure that each
batch contains the same amount of the marker component. It is assumed that other
chemical constituents in a given product will vary in proportion to the marker compound;
if each batch contains the same standardized amount of marker, the content of other
constituents will also be relatively consistent. Standardization of marker content can
also be achieved by blending different batches of raw materials to achieve the target
marker content. According to the American Herbal Products Association (AHPA)
guidelines this is an excellent method for obtaining consistency.
Some methods for identifying and quantifying selected marker or active constituents are
available in, among other sources, the American Herbal Pharmacopoeia and
Therapeutic Compendium or in the scientific literature. When no method exists for the
specific product, or when improved technology allows for a more accurate and precise
method, an alternative method may be used as long as it is validated according to
Organization for Economic Co-operation and Development (OECD's) Principles of Good
Laboratory Practices (GLP), International Conference on Harmonization's (ICH)
guidelines on Validation of Analytical Procedures or submitted to AOAC International for
validation.
Many manufacturers employ various production processes to manufacture health
products containing extracts with a target marker content, either by adjusting the
extraction ratio and/or adding fillers to achieve the targeted marker content. This
practice may be appropriate in cases where it has been established that the marker is
responsible for the pharmacological activity. The extracts could be suitably blended with
excipients such as starch, lactose or dicalcium phosphate. This process affords extracts
of desired strength suitable for formulating into finished dosage forms.
A standardized extract can be characterized by its specifications and the ratio of the
quantity dried equivalent of the herbal drug to the quantity of the extract. For a liquid
extract, a ratio of 1:5 means that 1 g of crude dried material was used to prepare 5 ml of
Evidence for Quality of Finished Natural Health Products 12
extract and for a solid extract a ratio of 5:1 means that 5g of crude dried material was
used to prepare 1g of extract.
The process of standardization as applied to products containing complex materials will
facilitate consistency in quality of finished products in terms of quantity and potency.
Presently, there are no universally accepted standards for the manufacturing of
standardized extracts, however several monographs have been published and it is
recommended that the analytical methods described in these monographs be used
when available. Specifications for standardized products should include identity (e.g.,
chemoprofile, multiple fingerprints), potency and strength (quantity), purity (incidental
compounds/contaminants). Manufacturing processes should be designed to ensure
consistency, which requires controls on both raw materials quality and manufacturing
processes. Standardization does have advantages as indicated below:
鈥? ensuring consistency (i.e., batch-to-batch consistency)
鈥? confirmation of the correct content of extract/dosage unit
鈥? positive control to indicate possible loss or degradation during manufacturing or
shelf-life
2.2.2 Non-Standardized Extract
A non-standardized extract is made by soaking the plant, plant material, alga,
bacterium, fungus, and non-human animal material in a liquid that removes specific
compounds. The liquid can be used as is, or evaporated to make a dry non-
standardized extract.
2.3 Manufacturing Requirements
Manufacturing information is required for certain medicinal ingredients.
Considering the fact that Good Manufacturing Practices (GMPs) are implemented
during processing of the finished product, manufacturing information is not required at
the raw material stage or for the finished products containing a plant/plant material, an
alga, a fungus, a bacterium or a non-human animal material. However, if required,
NHPD may request manufacturing details on a case-by-case basis to support the
quality of the raw materials and the final product.
2.3.1 Raw Material Manufacturing Information
2.3.1.1 Standardized Products
The applicant is requested to provide the standardization method for the standardized
products, e.g., a standardized extract of a plant material. It is recommended that the
applicant choose one of the methods from the list below, which includes the most
commonly used methods to adjust the quantity of marker in a product. This list can be
modified to clarify the procedures used when necessary.
Evidence for Quality of Finished Natural Health Products 13
List of Standardization Methods:
o selecting a specific variety of material with consistent content of marker (i.e., no
adjustment of the product occurs)
o mixing raw material lots (e.g., equivalent amounts of 1 lot at 1% marker and a 2nd lot
at 3% to give 2% marker)
o varying extraction ratio of source material to solvent
o varying extraction conditions (e.g., time, temperature, solvent strength: please
specify)
o normalizing by varying excipient quantity in finished product
o other: please specify
Note: some products may be fortified or spiked with the marker or other ingredient
which is added to the product. This is not to be referred to as a standardized product,
but may be acceptable if declared on the PLA and label as fortified or spiked or with
added ingredient (e.g., rose hips with added vitamin C).
The target marker(s) or active constituent(s) for each standardized extract medicinal
ingredient should be provided with a range for the acceptance criteria for each marker.
It is also necessary to indicate how the success of the standardization method is verified
(i.e., by chemical assay, biological assay or another method which should be specified).
Where a product is standardized to a group of compounds calculated against a single
compound, this should be declared (e.g., Senna leaf standardized to x mg
hydroxyanthracene glycosides, calculated as Sennoside B).
2.3.1.2 Other Extracts
For extracts of a plant or a plant material (e.g., tinctures), alga, fungus, bacteria or non-
human animal material which are not adjusted, it may be necessary to provide basic
manufacturing information such as extraction ratios, weight of the starting material used,
as well as the solvents used in the extraction process.
If an extract conforms to an acceptable grade (e.g., pharmacopoeial grade),
manufacturing information is not required at the raw material stage.
2.3.1.3 Isolates and Synthetic Duplicates
If an isolate or a synthetic duplicate conforms to an acceptable pharmacopoeial grade,
raw material manufacturing information and raw material specifications are not required
to be provided to NHPD.
If the isolate or synthetic duplicate does not conform to an acceptable grade, the
applicant should provide at a minimum the following information:
Evidence for Quality of Finished Natural Health Products 14
鈥? A brief description of the test methods, specification limits (lower and upper
tolerance limits), and demonstration that the ingredient meets the specification limits,
for:
o Identity (physical description and/or chemical analysis);
o Purity with respect to:
鈥? Percentage purity of the medicinal ingredient;
鈥? Process impurities specific to the method of synthesis or isolation;
鈥? Potency where applicable (e.g., where assessed by bioassay).
All of the above information should be provided, but it may be provided by the applicant
in various forms or combinations of documents, such as:
鈥? a copy of the specifications sheet that provides the details outlined above; and/or
鈥? a copy of the Certificate of Analysis or equivalent documents providing the
specifications representative of the lot to be used in the manufacture of the finished
product, providing the details outlined above; and/or
鈥? a sequential description or flow diagram of the manufacturing process, with details
on each manufacturing step including each solvent used (their ratio if in
combination), temperature, pH, impurity profile and any other relevant conditions.
2.3.1.4 Enzymes
If the isolate is an enzyme (e.g., amylase), details of the manufacture of the enzyme at
the raw material stage should be provided which should include source material,
fermentation medium and isolation process. The source material should clearly indicate
whether the enzyme is of microbiological origin and whether it is derived from
genetically modified organisms. The taxonomic and genetic classification of the microbe
should also be provided. In the case of immobilized enzymes, details such as
composition and purity of the immobilizing agent and also the method of immobilization
should be provided.
2.3.1.5 Probiotics
For each probiotic bacterial culture, the applicant should provide at a minimum the
following information:
鈥? A brief description of the test method, specification limits (lower and upper tolerance
limits), and demonstration that the ingredient comes within the specification limits,
for:
o identity (microscopic, phenotypic, genotypic, serotypic methods etc.); and
o purity with respect to:
鈥? total viable count per gram of the raw medicinal ingredient; and
鈥? microbiological contaminants.
All of the above information must be provided, but it may be provided by the applicant in
various forms or combinations of documents, such as:
Evidence for Quality of Finished Natural Health Products 15
鈥? A copy of the specifications sheet or Certificate of Analysis or equivalent documents
providing the specifications representative of the lot to be used in the manufacture of
the finished product, providing the details outlined above; and/or
鈥? A sequential description or flow diagram of the manufacturing process, with details
on preparation of mother culture, fermentation conditions (composition of media,
process parameters such as temperature, pH), mixing, freeze drying and packaging
conditions.
Further, in order to ensure maximum viability of the bacteria, the cells should be kept
under conditions which promote maximum survival (e.g., refrigeration) at every stage of
manufacture.
2.3.2 Proprietary Information Concerning the Manufacturing Process
In cases where the details of the manufacturing process of the medicinal ingredient are
proprietary and have not been provided to the importer or distributor, the proprietary
information can be provided directly to the NHPD in the form of an NHP Master File
(NHP-MF) or to the Therapeutic Products Directorate (TPD) in the form of a Drug
Master File (DMF). This information will be kept confidential and an authorization letter
from the Master File holder is required to allow access by the NHPD on behalf of the
applicant during the assessment of a PLA. For details on using master files, refer to
NHP-MF guidelines or to the TPD DMF guidelines.
Health Canada鈥檚 quality assessment requirements for medicinal ingredients could be
satisfied by a combination of a Certificate of Analysis that describes the tests and
tolerances for the identity and purity of the ingredient, the citation of a manufacturer鈥檚
Master File (MF) in which details of the identities and quantities of the process-specific
impurities have been provided in confidence to Health Canada, and a description of a
further assay that is used to assess potency.
This flexibility in the types of documents that may be used to support quality
requirements will allow applicants to more easily provide Health Canada the required
information while allowing industry to protect confidential manufacturing details that are
not necessary for Health Canada鈥檚 assessment of the product鈥檚 safety, efficacy, and
quality.
2.3.3 Finished Product Manufacturing Information
Good Manufacturing Practices should be implemented at all stages of the
manufacturing process. Manufacturing information is generally not required for the
finished product manufacturing process. However for certain technically complex
dosage forms or for dosage forms of NHPs with limited stability, e.g., vitamins and
probiotics, NHPD may request manufacturing details of the finished product if required.
Evidence for Quality of Finished Natural Health Products 16
The NHPD would permit the use of the following processes to reduce the
microbiological load of medicinal ingredients that are not susceptible to degradation as
indicated. Manufacturing information may be requested for products where the following
processes are used.
Sterilization: Sterilization may be allowed for certain products provided a
scientific justification is included that ensures the potency of the medicinal
ingredient is maintained. Sterilization method(s) and conditions, such as
temperature and time, should be provided for sterilized raw materials or finished
products.
Irradiation of Natural Health Product: Irradiation is not permitted as a method
for microbiological reduction or as a sterilizing procedure where the finished
products contain vitamins or amino acids, which are generally sensitive to this
process. Irradiation may be permitted as a method for microbiological reduction
or as a sterilizing procedure where the finished products contain plant/plant
materials.
Pasteurization: Pasteurization may be allowed for certain products provided a
scientific justification is included that ensures the potency of the medicinal
ingredient is maintained. Pasteurization conditions, such as temperature and
time, should be provided. Appropriate reduction of microbial load under the
proposed conditions should be demonstrated.
2.4 Finished Product Specifications Requirements
Finished product specifications must be provided for every natural health product. They
must include information on the identity, purity and quantity of the finished product along
with corresponding tolerances. Additional specific tests that may need to be
documented on the finished product specifications are detailed in Section 3 and not
covered in this section. The specifications should indicate which tests are carried out
routinely on each batch of the finished product, and for those which are not carried out
routinely, the frequency of the testing should be stated on the specification sheet.
2.4.1 Analytical Methods
Analytical methods used for testing should be indicated on the specifications by
referring to the appropriate method number and the type of test involved, e.g., EPA
Method 7000A (Graphite Furnace AAS). Where house methods are used, the QSR
should include a brief description of the method and where appropriate, a literature
reference to the origin of the method, e.g., HPLC method; Hoffmann, J.L. (1986)
Biochemistry 25: 4444-4449.
2.4.2 Identity Testing on the Finished Product
Evidence for Quality of Finished Natural Health Products 17
Physical identification tests should be done on the final dosage form and should be
documented in the finished product specifications. Tests for physical identification of the
finished product might include tests such as organoleptic evaluation (sensory
characteristics e.g., taste, odour, feel, appearance (colour and shape of the capsule or
tablet), etc.). Where the medicinal ingredient is a defined chemical entity, or where a
marker is present, chemical identification tests (e.g., comparison of a retention time of
an HPLC peak with a standard) should be used.
If the medicinal ingredient conforms to an acceptable grade (e.g., USP, Ph.Eur., NHPD
Compendial specifications), other than the pharmacopeial requirements, only physical
identity testing of the finished product is required.
2.4.3 Purity
Under section 44 (2) (a) of the Regulations, the finished product specifications shall
contain detailed information regarding the purity of the natural health product, including
statements indicating its purity tolerances. The finished product specifications should
include tests and methods and tolerance limits for the microbial and chemical
contaminants as outlined in the following Microbial Contaminants and Chemical
Contaminants sections.
Tolerances for purity must conform to the limits listed in Tables 1 and 2 of Appendix 4.
The tolerance limits for microbiological contaminants and mycotoxins have been
adapted from international standards such as World Health Organization (WHO) and
National Sanitation Foundation (NSF). The microbial tolerance limits for a multi-
component product would be based on the medicinal ingredient in the finished product
that has the least stringent limit, however limits should be reduced if warranted by
routine analysis showing lower levels of contamination.
If the applicant provides test methods and tolerance limits for the chemical
contaminants at the raw material stage or if the medicinal and non-medicinal ingredients
conform to an acceptable Pharmacopoeial grade, NHPD will accept this as exemption
of testing at the finished product stage as long as a scientific rationale is provided
ensuring that the finished product is free from any additional chemical contaminants.
If the applicant proposes purity testing that is not performed using a well-recognized
method (e.g., an in-house method is proposed), the applicant may be required to
provide additional information on the proposed method. When no method exists for the
testing of a specific product, or when improved technology allows for a more accurate
and precise method, an alternative method may be used as long as the method is
validated.
Validation of analytical procedures should include a method description, justification for
the use of the method and validation data. Copies of the validation report for the
analytical procedures used during the development as well as those proposed for
routine testing should be kept on file by the testing laboratory.
Evidence for Quality of Finished Natural Health Products 18
If testing for microbiological contamination is not performed on the finished product, the
applicant must provide a scientific rationale justifying exemption of these tests.
2.4.3.1 Microbial Contaminants
NHPD applies limits to the following organisms:
鈥? Total viable aerobic plate count
鈥? Contaminating fungus (yeast and mould)
鈥? Salmonella spp.
鈥? Escherichia coli
鈥? Staphylococcus aureus
Testing should be done according to Pharmacopoeial (USP, Ph. Eur. etc.), WHO
methods or any other internationally recognized methods.
Methods should be appropriate for the product and the expected bioburden, e.g.,
hypertonic solutions should not be tested using pharmacopoeial methods appropriate
for purified water, as inhibition of microbial growth by the solution should be taken into
account.
Pseudomonas Aeruginosa testing is required for liquid products unless alcohol is
present at concentrations greater than 50%. Applicants should also consider carrying
out other appropriate tests if required due to known issues of contamination or if another
organism is considered a more appropriate indicator organism (e.g., Enterococcus,
Campylobacter, Shigella or Listeria species).
For Probiotic products, the Total viable aerobic plate count is replaced by
Enterobacteriaceae testing as a method of detecting specific microbial contamination. A
method of enumerating viable members of the family Enterobacteriaceae should be
used, e.g., USP <2021> "Enterobacterial count (Bile tolerant gram negative bacteria)" or
the Health Canada test MFLP-43 "Determination of Enterobactericeae".
2.4.3.2 Chemical Contaminants
In addition to considering the following contaminants to which the NHPD applies limits,
applicants should also consider appropriate testing of the finished product for additional
contaminants (e.g., aflatoxins in nuts and microcystin in cyanobacteria).
Chemical contaminant testing is not required for finished products containing only
probiotics cultures.
Heavy Metals (i.e., arsenic (inorganic), cadmium, lead and total mercury): These
should be tested individually or as total heavy metals expressed as lead at the finished
product stage or at the raw material stage if all medicinal and non-medicinal ingredients
Evidence for Quality of Finished Natural Health Products 19
are tested. Testing should be done according to Pharmacopoeial or any other
internationally accepted methods. Some commonly used methods are:
鈥? Inductively Coupled Plasma-Atomic Emission Spectrophotometry (ICP-AES);
鈥? Inductively Coupled Plasma-Mass Spectroscopy (ICP-MS);
鈥? Atomic Emission Spectrophotometry (AES);
鈥? Atomic Absorption Spectrophotometry (AAS).
The tolerance limits for arsenic, cadmium, lead and total mercury are consistent with
relevant international standards. In Canada these limits are based on the following body
weights: adult: 70 kg; 12-year-old child: 40 kg; six-year-old child: 20 kg. Please refer to
the example of calculations given in Appendix 5. Limits for heavy metals should be
provided in 碌g/kg b.w./day. When levels for individual metals are provided in ppm, the
tolerance level for daily dose should not exceed to 9.8 碌g for Arsenic, 6.3 碌g for
Cadmium, 20.3 碌g for Lead and 20.3 碌g for Mercury (calculated for 70 kg adult). The
maximum daily intake should be documented in the Quality Summary Report and used
to justify the proposed limit.
NHPD is willing to accept the use of the USP <231> test for total heavy metals under
certain circumstances. The tolerance limit of not more than 10 ppm for the total heavy
metals at the finished product stage is not uniformly applicable to all NHPs, since the
intake of heavy metals would vary significantly depending on the quantity of natural
health products consumed. The USP Heavy metal test is not considered equally
sensitive for all heavy metals which react with Thioacetamide, hence the sum of the
NHPD tolerances for individual heavy metals is not considered valid for determining the
Tolerable Daily Intake (TDI) or Tolerable Daily Amount (TDA) that would signify the
toxicological impact. There is no known TDI value established by any scientific expert
committee or working group for total heavy metals.
However, since the method is based on comparison with a lead standard, the limit of not
more than 10 ppm will be acceptable provided that the permitted daily exposure is less
than 20.3 碌g/day (dose of approximately 2 g of the dosage form per day) and that the
following caveats are also noted.
1. The USP <231> test should be shown to be appropriate for the matrix tested.
2. If the exposure level is greater than 20.3 碌g/day, calculated as lead equivalents,
the USP <231> test with a limit of not more than 10 ppm may be acceptable
where the applicant can demonstrate based on testing of representative batches
of the product that no individual metals approach the NHPD tolerance limits.
3. For traditional medicines, individual heavy metal limits should be tested using a
quantitative method, due to known incidences of contamination, particularly with
Arsenic and Mercury.
4. In the case of plants and algae which are known to selectively absorb and
accumulate heavy metals, the product should be tested for individual heavy
metals, or additional justification why the USP <231> test is valid should be
provided.
Evidence for Quality of Finished Natural Health Products 20
5. A commitment from the applicant that, if the product fails the USP <231> test, the
product will be tested for the individual heavy metals using an appropriate
quantitative test.
If the USP <231> test is not considered appropriate (e.g., in the case of fish oils where
testing of total Mercury is required due to known issues of contamination), NHPD will
continue to ask for individual heavy metal testing.
Mycotoxins (e.g., aflatoxins): Testing is required for products containing ginseng and
peanuts or any substance derived from these sources. Ginseng and peanuts may be
contaminated with aflatoxins due to poor agricultural practices and storage conditions.
Testing should be done according to internationally accepted methods. Appropriate
measures should be taken at the raw material stage in order to ensure that the finished
products do not contain such toxins. Other products where mycotoxin testing may be
required are Evening Primrose Oil, Sugar Cane and Sugar Beets, Cottonseed and
Corn-derived products. The need for mycotoxin testing will be evaluated on a case-by-
case basis during the product assessment. Justification will be requested if a product
has documented cases of fungal contamination.
Cyanobacterial Toxins (where applicable), Microcystin: Testing is required for algal
products (e.g., blue green algae). The methods used and their limits should be
provided.
Solvents: Solvents known to cause unacceptable toxicities (International Conference
on Harmonization of Technical Requirements for Registration of Pharmaceuticals for
Human Use (ICH Class I)) should be avoided in production unless their use can be
strongly justified in a risk-benefit assessment report showing adequate supporting data
for safe use. Solvents associated with less severe toxicity (ICH Class II) should be
limited in order to protect consumers from potential adverse effects. Wherever possible,
less toxic solvents (ICH Class III) should be used. This class list is available in
International Conference on Harmonization of Technical Requirements for Registration
of Pharmaceuticals for Human Use: Guidelines for Residual Solvents, harmonized
tripartite guidelines.
Testing for solvents should be done according to Pharmacopoeial (USP, Ph.Eur.)
methods using GC and HPLC techniques. Tolerance limits for solvent residues should
conform to ICH or pharmacopoeial limits.
Incidental Impurities, Related Substances and Process Impurities: Processing or
purification steps may introduce organic or inorganic impurities (e.g., intermediates,
other isomers, racemic compounds, reagents and catalysts) in the product. As well,
other related substances (e.g., degradation products) may be present. All known
impurities present in the raw material at significant levels should be listed on the raw
material specifications with their associated tests and tolerance limits.
Evidence for Quality of Finished Natural Health Products 21
When conformance to an acceptable standard is declared, (e.g., USP, BP),
manufacturers should be aware that the potential impurities declared on the monograph
may not be the same as those found in the medicinal ingredient due to differences in
the manufacturing process. Where differences in the impurity profile exist, the applicant
should provide additional testing for impurities where applicable.
If the impurity profile of an isolated or synthetic medicinal ingredient is altered due to a
change in the source material or manufacturing process, revised specifications with the
new tolerance limits for the impurities must be submitted to NHPD.
Pesticide Residues: Testing for pesticides in plant or plant materials, algae, fungi, or
non-human animal materials (e.g., fish and marine mammals (e.g., seal)) or extracts
derived thereof, should be done according to the multi-residue method outlined in the
European Pharmacopoeia, United States Food and Drug Administration鈥檚 Pesticide
Analytical Manual 1 or WHO methods for pesticide screening l. Multi-residue pesticide
screening is preferential. The pesticide residues that are routinely tested should be
those pesticides which were used in treatment of the plant or any pesticides where
residues are suspected and may carry over to the final dosage form.
Pesticide testing is not required for products with a certified organic content of 95% or
more as long as certification from an accredited certification body is provided.
The limits specified in USP, Ph. Eur., or WHO for pesticide residues are considered to
be acceptable.
2.4.3.3 Additional Tests
Foreign matter: This test is important to ensure that the plant/plant material, alga or
fungus is entirely free from visible signs of contamination such as sand, glass and
metal. Testing should be done according to internationally recognized methods.
Tolerance limits for foreign matter should be as specified in International standards such
as WHO.
Determination of acid insoluble ash: Acid insoluble ash is important to determine the
amount of inorganic impurities in the form of extraneous (non-physiological) materials in
a plant/plant material. Testing and tolerance limits for acid insoluble ash should be as
specified in International standards.
Water Content: This test is required where the material is known to be hygroscopic.
Acceptance criteria should be justified by data on the effects of moisture absorption on
the product (e.g., potency and stability). A 鈥榣oss on drying鈥? procedure may be adequate,
but in some cases (e.g., plants containing essential oils), specific tests such as the Karl
Fischer method may be required.
Contaminants in oils of animal origin: Testing for polychlorinated dibenzo-para-
dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and polychlorinated biphenyls
Evidence for Quality of Finished Natural Health Products 22
(PCBs) in products isolated from fish and marine mammals (e.g., seals) is required
where bioaccumulation of these products exists in fatty tissues. Tolerance limits for
PCBs, PCDDs and PCDFs were developed from Canadian food residue levels that are
set by the Food Directorate, Health Canada. Testing should be performed using
appropriate analytical methods. Applicants are advised to consult the Council for
Responsible Nutrition (CRN) monograph on fish oils for futher information.
Antibiotic residues in honey and royal jelly: Since chloramphenicol and 5-nitrofuran
compounds are prohibited substances in honey products according to the Food and
Drugs Act and Regulations, C.01.610.1, NHPs should not contain any of these
antibiotics or their residues. Nitrofuran metabolites/residues from Furazolidone,
Furaltadone, Nitrofurantoin, and Nitrofurazone in particular are of concern. Further
information on analysis can be found in several articles, the most recent being:
鈥楧etermination and confirmation of nitrofuran residues in honey using LC-MS/MS鈥?
JOURNAL-OF-AGRICULTURAL-AND-FOOD-CHEMISTRY. FEB 21 2007; 55 (4):
1103-1108, Lopez-MI; Feldlaufer-MF; Williams-AD; Chu-PS. Applicants will be
requested to provide a test for the detection of 5-nitrofuran residues and
chloramphenicol in honey and royal jelly. Alternatively a justification for why the testing
is not required may be submitted.
Organic products: An application for finished products containing organic ingredients
must be accompanied by a proof of certification. Organic ingredients should comply with
the Organic Products Regulations of Canada, December 2006. Certification of the
plant/plant material or fungi (e.g., organic mushrooms) by accredited agencies is
considered to be acceptable.
Note: Organic products must not contain the same ingredients in both organic and non-
organic forms. Ingredients that do not meet the organic requirement may be used only
when they make up less than 5% of the total ingredients and when the following
information is supplied: a description of efforts made in good faith to locate or develop a
source of the certified organic form of the ingredient, and progress made over the years
to eliminate non-organic material.
Radioactivity: In specific circumstances where there is a risk of radioactive
contamination, it may be necessary to test for radioactivity. Tolerance limits for
radioactivity (if irradiation has been used to reduce microbiological load) have been
adapted from European Commission Directive (Recommendation 2003/120/EC).
Enzyme preparations: Enzyme preparation and testing should be done in compliance
with the joint Food and Agriculture Organization (FAO) and WHO Expert Committee on
Food Additives publication General Specifications for Enzyme Preparations Used in
Food Processing. Enzymes derived from microbial sources should be tested for
antimicrobial activity at the raw material stage. Antimicrobial activity should be absent.
Established methods for screening for microbial activity or USP <81> showing negative
results can be used where appropriate.
Evidence for Quality of Finished Natural Health Products 23
2.5 Quantity
Under section 44 (2) (b) (c) of the Regulations, the finished product specifications shall
contain detailed information for each medicinal ingredient respecting its quantity per
dosage unit.
The tolerance limits for the quantity of medicinal ingredients should conform to the
relevant pharmacopoeial standard or in its absence to 80% to 120% of the label
amount. The exceptions are enumerated below. If 鈥渜uantification by input鈥? is used as
described below, then this limit does not apply; rather the amount of medicinal
ingredient added is controlled as described in the section 鈥渜uantification by input鈥?. If the
applicant provides test limits for quantities that are outside the tolerance limits, a
scientific rationale is required justifying these test limits.
2.5.1 Quantification by Assay
In the case of medicinal ingredients with constituents of known biological activity,
quantitative assay tests can be done at the finished product stage according to
appropriate analytical methods.
For most isolates, (e.g., amino acids and essential fatty acids) and synthetic duplicates,
quantitative tests at the finished product stage should be conducted according to
appropriate analytical methods described in the pharmacopoeia (e.g., USP, Ph. Eur.).
The quantity is expressed as the weight (e.g., mg) of the medicinal ingredient.
All quantitative and potency tests for a standardized extract should be done at the
finished product stage according to appropriate analytical methods. When the active
constituents or markers are known and measurable, the amount in which they are
present (potency) should be declared in the specifications.
2.5.2 Quantification by Input
In the case of medicinal ingredients where there is no known method of analysis of the
medicinal ingredient, or the non-medicinal ingredients interfere with analysis,
quantification by 鈥渋nput鈥? is considered to be acceptable. In this case the active ingredient
in the finished product is not assayed. The objective evidence that a quantity of a
medicinal ingredient (e.g., a plant material) has been added to the finished product is
calculated from a manufacturing batch record and controlled by appropriate application
of GMP and in-process controls. Generally, the quantity of medicinal ingredient is
expressed as the theoretical weight (e.g., mg) of the processed substance in each unit
of the dosage form. Other tests on the finished product as required by this guidance are
still to be performed (e.g., microbial testing).
Whenever quantification by input rather than assay is used, justification should be
provided in the PLA. Justification should include a survey of methods which could be
Evidence for Quality of Finished Natural Health Products 24
used to assay the medicinal ingredient and an assessment of the risk not assaying the
compound.
Certificates of analysis or raw material specifications for the medicinal ingredient(s) to
be quantified by input are required to indicate that adequate control of the medicinal
ingredient is in place.
A batch record or a description of controls that are in place during manufacturing to
ensure the labelled amount of medicinal ingredient should be provided in the product
licence application. These documents should indicate the target quantity for the
medicinal ingredient (i.e., 100% of the label claim) and include controls on weight
variation during tabletting or encapsulation. Generally a 5% variation in weight for
individual dosages is acceptable. A description of how batch homogeneity will be
controlled should also be provided if more than one medicinal ingredient is mixed, or if
the medicinal ingredient is mixed with non-medicinal ingredients.
Vitamins and minerals
For vitamins, quantitative tests should be done on the finished product according to
appropriate analytical methods described in an acceptable pharmacopoeia (USP,
Ph.Eur.). The quantity of vitamins should be expressed as follows: Biotin (mg), Folate
(mcg), Pantothenic acid (mg), Niacin (mg), Vitamin A (mg and IU), Thiamine (mg),
Riboflavin (mg), Vitamin B6 (mg), Vitamin B12 (mcg), Vitamin C (mg), Vitamin D (mcg
and IU), Vitamin E (mg and IU) and Vitamin K (mcg).
Tolerance limits for the quantity of vitamins and minerals should be as per United States
Pharmacopoeia limits for the individual vitamins and minerals. If the applicant provides
test limits for quantity that are outside the tolerance limits, a scientific rationale is
required justifying the test limits.
Overage is used to compensate for the loss of vitamins during manufacture of the NHPs
or loss/degradation of vitamins during shelf-life of the finished product. Applicants
should provide justification when overages are used for vitamins, in formulating the
NHPs. For example, when an applicant uses a 50% overage of Vitamin C (in
comparison to the label claim) in the product to compensate for the loss due to heat
treatment of the product, this fact should be clearly stated in the application and the
results to justify the overage should be provided. The acceptance limits for overages
should not be greater than the upper limit for content as per the pharmacopoeial
standards.
Bacteria and Probiotics
Enumeration of probiotic cultures should be performed using selective culture methods
at the raw material and also at the finished product stage. The total count of the cells
should be expressed as colony forming units (CFU) per gram.
Evidence for Quality of Finished Natural Health Products 25
Tolerance limits for the quantity of bacteria and probiotic cultures should be 80% to
300% (excluding cyanobacteria for which the limit is 80%-120%). If 鈥渜uantification by
input鈥? is used as described in the previous section, then this limit will not apply. If the
applicant provides test limits for quantity that are outside the tolerance limits, a scientific
rationale justifying these test limits is required.
For bacteria, quantification by input is considered to be acceptable only in the case of
cyanobacteria. If the bacterium does not grow in readily visible colonies, enumeration
of the bacteria should be performed using selective culture methods at the raw material
and the finished product stage. The total count of the cells should be expressed as
colony forming units (CFU) per gram or mL.
Enzymes
Tolerance limits for quantity of enzymes should be 80% to 150% of the label amount.
For enzymes, the quantity per dosage unit should include the activity of the enzyme.
The activity is measured according to the reaction catalyzed by individual enzymes
(substrate specificity). For digestive enzymes the activity is expressed in the Food
Chemicals Codex (FCC) units (e.g., FCC Lipase Units, FCC Lactase Units). Other
enzymes should be indicated as International units (IU), or activity units (U). Tests using
High Pressure Liquid Chromatography or other appropriate analytical methods are
necessary to determine compliance with the declared representations of enzyme
activity.
2.6 Stability Testing
Stability testing of natural health products is required by Section 52 of the Regulations.
Applicants should provide a description of the tests which have been completed or will
be performed in order to determine the shelf-life (i.e., the post-approval stability protocol
for the product). These tests should be listed in the finished product specifications. If
tests are only performed during stability testing, and not for release of the finished
product, then the tests should be marked as such, or a separate specification for
stability testing can be used.
Typical tests used to demonstrate that a product is stable include chemical assays of
medicinal ingredients, fingerprint chromatograms showing that the proportional content
of the product does not change with time, organoleptic tests, tests for specific
degradation products, microbial tests or other applicable tests. The appropriate use of
tests to demonstrate stability should be justified by the applicant.
A commitment to perform all tests listed in the stability protocol after storage as labelled
on the finished product and to meet the specifications for the finished product at the end
of the shelf-life should be provided. The conclusions of the testing and the justification of
the expiry period and storage conditions should be kept on file by the applicant and may
be requested by NHPD.
Evidence for Quality of Finished Natural Health Products 26
Oxidative stability in oils: Testing should be done according to AOAC and/or
Pharmacopoeial analytical methods for peroxide, anisidine, and totox values of
fish/seal oils or omega-3 fatty acids derived from fish/seal oils to ensure the oxidative
stability of the fish oils/omega-3 fatty acids. This requirement is applicable to all oils that
have a high degree of unsaturation to ensure stability.
Oxidative Stability Parameters for Fish/Seal oils
Peroxide value (PV) max. 5 mEq/Kg
Anisidine value (AV) max. 20
Totox value max. 26 Calculated as 2 x PV + AV
Where oxidative stability tests are required by pharmacopoeial monographs, the
acceptance criteria as per the appropriate monograph may be used.
Probiotics: Where a viable count for the probiotic culture is included on the labelling of
the product, the applicant should have evidence of the stability of that culture under the
storage conditions.
Evidence for Quality of Finished Natural Health Products 27
SECTION 3. SPECIFIC TESTS AND CRITERIA FOR FINISHED
PRODUCTS
Tests other than those listed in the aforementioned chapters of this document may be
needed in specific situations or as new information becomes available. Specific tests
may be applicable on a case-by-case basis and must be conducted when these tests
affect the quality of the products. The procedures used to conduct such tests should be
pharmacopoeial, if possible, when no method exists for the testing, or when improved
technology allows for a more accurate and precise method, an alternative method may
be used as long as it is specific and reproducible. A summary of physical test
requirements or certain dosage forms is summarized in Appendix 8.
The information provided below was incorporated from Evaluation of Medicinal Products
(EMEA): Note for Guidance on Quality of Herbal Medicinal Products
(CPMP/QWP/2819/00, 26/7/2001) and Note for Guidance on Specification: Test
Procedures for Herbal Drugs, Herbal Drug Preparations and Herbal Medicinal Products
(CPMP/QWP/2820/00, 26/7/2001).
3.1 Disintegration
Under section 103 (and also section 15) of the Regulations, the tablet disintegration
times should be provided for NHPs intended to be swallowed whole whether uncoated
and plain coated tablets or hard and soft gelatin capsules. Applicants are required to
comply with these tablet disintegration times as tested by the official method DO-25 or
Pharmacopoeial methods.
For rapidly dissolving NHPs (dissolution > 80% in 15 minutes at pH 1.2, 4.0, 6.8) that
are highly soluble throughout the physiological range (dose/solubility volume < 250 ml
from pH 1.2 to 6.8), disintegration testing may be substituted for dissolution testing. The
disintegration test is not required when the product is to be chewed or when it is a liquid
extract. Oil-soluble vitamins (A, D, E, K) do not have to be subjected to disintegration or
dissolution tests.
3.2 Dissolution
This test is used to measure the release of an active substance (usually a single
ingredient) from solid oral dosage products i.e., tablet or capsule dosage forms.
Single-point measurements are normally considered suitable for immediate-release
dosage forms. For modified-release dosage forms, appropriate sampling procedures
should be followed under suitable test conditions. For example, multiple-point sampling
should be performed for extended-release dosage forms, while two-stage testing (using
different media in succession or in parallel, as appropriate) may be appropriate for
delayed-release dosage forms.
Evidence for Quality of Finished Natural Health Products 28
For extended-release NHPs, in vitro or in vivo correlation may be used to establish
acceptance criteria when human bioavailability data are available for formulations
exhibiting different release rates. When such data are not available, and release cannot
be shown to be independent of in vitro test conditions, then acceptance criteria should
be established on the basis of available batch data.
For products whose active constituents are not highly soluble throughout the
physiological pH range, dissolution may not be always necessary but could be done as
a periodic test. Applicants are expected to provide evidence to support the selection of
dissolution versus disintegration testing.
3.3 Uniformity of Dosage Units
Uniformity of dosage units refers to both the mass of the dosage form and the content of
the active substance in the dosage form. The specifications should include one or the
other, or both where the active constituent is less than 5% of the total weight.
Acceptance criteria should be set for weight variation, fill volume or uniformity of fill.
When appropriate, tests may be performed as in-process controls; however, the
acceptance criteria should be included in the specifications.
A standard weight or volume measure is normally used. However, if the actual dosage
unit a person takes is controlled, it may be either measured directly or calculated, based
on the total measured weight or volume of the NHP, divided by the total number of
doses expected. If dispensing equipment, such as a medicine dropper or bottle dropper
tip is used, this equipment may be used to measure the dose. For inhalation and nasal
products, the limits should be based on the target delivery amount of NHP per
actuation, with corrections as necessary to convert from per-dose amounts to per-
actuation amounts. For powders that are reconstituted, uniformity of mass testing is
generally considered acceptable.
Note: The most commonly used dosage forms that are acceptable by the NHPD are
listed in Appendix 6.
3.4 Sterilization
The sterility of a product cannot be guaranteed by testing; it has to be assured by the
application of valid method(s) of sterilization. NHPD requires the use of appropriate
sterilization procedures only when the route of administration of the finished product is
ophthalmic or when a finished product makes a sterile claim on the label.
The current United States Pharmacopoeia (USP <1211>) defines the methods of
terminal sterilization. The choice of the appropriate method for a given finished dosage
form requires a knowledge of the sterilization techniques and information concerning
any effects of the process on the material being sterilized. Validation of the sterilization
technique may be requested to support the application.
Evidence for Quality of Finished Natural Health Products 29
3.5 Antimicrobial Effectiveness Testing
Antimicrobial preservatives are ingredients added to dosage forms to protect them from
microbiological growth or from microorganisms which may be introduced either:
鈥? inadvertently during or subsequent to the manufacturing of the finished dosage form;
or
鈥? from repeatedly withdrawing individual doses.
Where antimicrobial preservatives are added to a product, NHPD is requesting that
tests to demonstrate the effectiveness of antimicrobial protection are performed on the
product. Test methods used and acceptance criteria should be as specified in an
acceptable Pharmacopoeia (e.g., current USP <51>; Ph. Eur. 5.1.3), and should be
performed on the final dosage form with suitable limits included. This test should be
performed at a minimum at the end of the shelf life, but is usually performed at several
stages during product development.
The concentration of the preservatives shown to be effective in the final dosage form
should be below a level that may be toxic to human beings, and should be at the lowest
concentration necessary to preserve the product.
Evidence for Quality of Finished Natural Health Products 30
SECTION 4. HOMEOPATHIC MEDICINES
This chapter outlines the quality requirements for all homeopathic medicines. In order to
complete a full submission package for a product licence, applicants for homeopathic
medicines will also need to consult the following documents:
鈥? Evidence for Homeopathic Medicines Guidance Document;
鈥? Good Manufacturing Practices Guidance Document;
鈥? Evidence for the Safety and Efficacy of Finished Natural Health Products Guidance
Document;
鈥? Site Licence Guidance Document.
4.1 Definition of a Homeopathic Medicine
To be considered a homeopathic medicine, a product must meet two criteria. It must be:
1) Manufactured from, or contain as medicinal ingredients, only substances referenced
in a homeopathic monograph in one of the following homeopathic pharmacopoeiae, as
they are amended from time to time:
鈥? Homeopathic Pharmacopoeia of the United States (HPUS);
鈥? Hom枚opathische Arzneibuch (German Homeopathic Pharmacopoeia)(HAB);
鈥? Pharmacop茅e fran莽aise (French Pharmacopoeia) (PhF);
鈥? European Pharmacopoeia (Eur. Pharm.);
鈥? British Homeopathic Pharmacopoeia (BHP);
鈥? Indian Homeopathic Pharmacopoeia.
2) Prepared in accordance with the methods outlined in one of the above-mentioned
homeopathic pharmacopoeiae, as they are amended from time to time.
4.2 Overview of Quality Specifications for Homeopathic Medicines
The quality requirements for homeopathic medicines should include specifications for
the following:
鈥? Identity (prior to dilution);
鈥? Microbial purity (at the finished product stage);
鈥? Chemical purity (not required if the medicinal ingredients are diluted 2X or above).
Applicants are required to provide the specifications details at the raw material and/or at
the finished product stage as outlined below.
4.2.1 Manufacturing
GMPs must be followed during the manufacture of homeopathic medicines. (For more
information on GMP requirements, please refer to the Good Manufacturing Practices
Evidence for Quality of Finished Natural Health Products 31
Guidance Document.) Applicants are not required to provide details of the manufacture
of homeopathic medicines. However, NHPD reserves the right to request manufacturing
details when it deems this information to be warranted.
4.2.2 Specifications
4.2.2.1 Identification
Identification of the medicinal ingredients should be conducted at the raw material stage
as outlined in pharmacopoeial monographs. The medicinal ingredients used in the
product should be identified at the raw material stage by identification tests such as
chromatographic methods (High Performance Thin Layer Chromatography (HPTLC),
HPLC, or GC), or spectroscopic methods and/or any other applicable chemical
identification test. Physical identity of the medicinal ingredient (for example, organoleptic
evaluation) is not required.
4.2.2.2 Purity
Homeopathic medicines should be tested for microbiological contaminants at the
finished product stage, as outlined in chapter 2.4.3.1 above. Each medicinal ingredient
used in the product should also be tested for the chemical contaminants, as outlined
above, at the raw material stage. If the applicant does not test the medicinal ingredients
for the microbiological and chemical contaminants, then a rationale citing scientific
evidence should be provided justifying the test exemption.
4.2.2.2.1 Microbial Contaminants
Microbial testing is required at the finished product stage. The requirements for specific
testing and acceptance criteria are the same as for all NHPs as described in Section
2.4.3.1.
NHPD may allow skip-lot testing of microbial contaminants in the case of a few
homeopathic products (such as pills that are not used for direct consumption).
Applicants will be required to provide the details of the characteristics of the product, the
history of the microbial contamination in the product and other relevant details to
support the reduced testing regime.
4.2.2.3 Nosodes
Nosodes are homeopathic preparations of pathological organs or tissues, causative
agents such as bacteria, fungi, ova, parasites, virus particles and yeast as well as
disease products, excretions and secretions. Because nosodes are, by nature, prone to
microbiological contamination the NHPD requires assurance of their sterility at the raw
material stage. Nosodes are only listed as monographs in the HPUS, and therefore,
must comply with the sterility requirements as per the HPUS guidelines.
Evidence for Quality of Finished Natural Health Products 32
4.2.2.4 Chemical Contaminants
Testing of chemical contaminants is not required if the medicinal ingredient is diluted
above 2X. Otherwise, testing of these should be performed as stated in Section 2.4.3.2.
Heavy metal tests are not required when the medicinal ingredient is a heavy metal itself.
For example, if mercury is the medicinal ingredient, the raw material does not need to
be tested for mercury.
Evidence for Quality of Finished Natural Health Products 33
SECTION 5. REFERENCES
5.1 Health Canada documents
Product Master Files. Therapeutic Products Directorate guidance. Available by writing to
dmf_enquiries@hc-sc.gc.ca
Product Licensing Guidance Document available at http://www.hc-sc.gc.ca/dhp-
mps/prodnatur/legislation/docs/index_e.html
Master File Procedures available at http://www.hc-sc.gc.ca/dhp-
mps/prodnatur/legislation/docs/index_e.html
Compendium of Monographs available at http://www.hc-sc.gc.ca/dhp-
mps/prodnatur/legislation/docs/index_e.html
Official method DO-25 available at http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-
dgpsa/pdf/prodpharma/tab_com_e.pdf
5.2 Related documents
American Herbal Pharmacopoeial and Therapeutic Compendium. American Herbal
Pharmacopoeia, P.O. Box 66809, Scotts Valley, CA; (1997-2002).
Association of Analytical Chemists International. Official Methods of Analysis, 17th
edition. Association of Analytical Chemists International, 481 Frederick Avenue, Suite
500, Gaithersburg, MD; 2000.
British Herbal Medicine Association. British Pharmacopoeia, P.O.Box 304,
Bounemouth, Dorset, BH7 6JZ, England; 1996.
European Commission Recommendations. On the protection and information of the
public to exposure resulting from the continued radioactive caesium contamination of
certain wild food products as a consequence of the accident at the Chernobyl nuclear
power station. Official Journal of the European Union (2003/120/EC).
European Agency for the Evaluation of Medicinal Products. Evaluation of Medicinal
Products for Human Use. Note for Guidance on Quality of Herbal Medicinal Products
(CPMP/QWP/2819/00, 26/7/2001).
European Agency for the Evaluation of Medicinal Products. Evaluation of Medicinal
Products for Human Use. Note for Guidance on Specification: Test Procedures for
Herbal Drugs, Herbal Drug Preparations and Herbal Medicinal Products
(CPMP/QWP/2820/00, 26/7/2001).
Evidence for Quality of Finished Natural Health Products 34
General Specifications for Enzyme Preparations Used in Food Processing JECFA
Compendium of Food Additive Specifications, FAO Food and Nutrition Paper No. 52,
Addendum 7. FAO, Rome, 1999.
International Atomic Energy Agency. Assessment of doses to the public from ingested
radionuclides, Vienna, Austria; 2000.
International Union of Biochemistry and Molecular Biology. Enzyme Nomenclature:
Recommendations of the Nomenclature Committee of IUBMB, Academic Press, NY;
1992.
International Conference on Harmonization. Technical Requirements for Registration of
Pharmaceuticals for Human Use. Guidelines for Residual Solvent, harmonized tripartite
guideline; 1997.
NSF International. NSF International Standard/American National Standard on Dietary
Supplements, NSF/ANSI 173-2006. NSF-International, Ann Arbor, MI ; 2006.
Organization for Economic Co-operation and Development. Principles on Principles of
Good Laboratory Practices. Series on Principles of Principles of Good Laboratory
Practices and Compliance Monitoring. Env/MC/Chem (98)17, Paris, FR.; 1997.
United States Environmental Protection Agency. Method 1613, Revision B. Tetra-Octa
CDDs and CDFs by Isotope Dilution HRGC/HRMS. EPA 821-B-94-005; USEPA,
Washington, DC; 1994.
United States Environmental Protection Agency. Methods for Determination of Metals in
Environmental Samples, Supplement 1-EPA/600/R-94-111; USEPA, Washington, DC;
1994.
United States Environmental Protection Agency. Microwave-assisted Acid Digestion of
Sediments, Sludges, Soils and Oils, EPA Method 3510, USEPA, Washington, DC;
1994.
United States Food and Drug Administration. Pesticides Analytical Manual 1 (PAM 1).
U.S. Department of Health and Human Services, Public Health Service, Food and Drug
Administration, Rockville, MD; 1999.
United States Pharmacopeial Convention Inc. United States Pharmacopeia USP 30-NF
25., United States Pharmacopeial Convention Inc., 121601 Twinbrook Parkway,
Rockville, MD; 2007.
World Health Organization. Quality Control Methods for Medicinal Plant Materials,
World Health Organization, Geneva, Switzerland; 1998.
Evidence for Quality of Finished Natural Health Products 35
APPENDIX 1. GLOSSARY
Alga. A member of the biological kingdom Protista, consisting of unicellular, colonial or
relatively simple multicellular eukaryotes that have a cell wall containing cellulose or
silica, that usually produce their own food by photosynthesis using various chlorophylls
and accessory pigments (some may also be heterotrophic under appropriate
conditions), that are essentially aquatic and that lack multicellular dependent embryos.
Animal. A member of the biological kingdom Animalia, consisting of complex
multicellular eukaryotes whose cells have a membrane but no wall, that have muscle
and nervous tissue in most members, that are heterotrophs that mostly ingest food into
a specialized cavity where it is digested, and that reproduce sexually by means of motile
sperm and larger, nonmotile eggs (in some animals there is also asexual reproduction).
Amino acid. An organic molecule containing amino and carboxylic groups attached to
same carbon atom. Amino acids are building blocks of proteins (chief constituents)
found in a plant or a plant material, an alga, a bacterium, a fungus, or a non-human
animal material.
Bacterium. A member of the biological kingdom Bacteria, one of the three domains of
life, consisting of usually unicellular (sometimes aggregated, colonial or simple
multicellular) prokaryotes whose cells lack nuclei or other internal compartmentalization.
Most species have a cell wall external to the plasma membrane, composed primarily of
peptidoglycan. Bacteria have diverse means of nutrition; the group consists mostly of
chemoheterotrophs, but there are also chemoautotrophs, photoautotrophs and
photoheterotrophs. They reproduce by binary fission.
Chemical name. The name an ingredient is referred to in the International Union of
Pure and Applied Chemistry Nomenclature.
Common name. For any medicinal or non-medicinal ingredient contained in a NHP, the
name by which it is commonly known and is designated in a scientific or technical
reference.
Dosage form. The final physical form of the NHP which may be used by the consumer
without requiring any further manufacturing.
Enzyme. An organic catalyst, usually a protein, increasing the rate at which a specific
biochemical reaction occurs. Enzymes may be derived from a plant or a plant material,
an alga, a bacterium, a fungus, or a non-human animal material.
Essential amino acid. An amino acid that cannot be synthesized in the body and has
to be supplied through the diet or a supplement to meet human needs. Current
knowledge indicates that there are eight amino acids that are regarded as essential for
humans: isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan,
and valine.
Evidence for Quality of Finished Natural Health Products 36
Essential fatty acid. A fatty acid that cannot be synthesized in the body and has to be
supplied through the diet or a supplement. Current knowledge indicates that there are
only two essential fatty acids: linoleic acid and alpha-linolenic acid.
Extract. A substance prepared by treating a plant or a plant material, an alga, a
bacterium, a fungus, or non-human animal material with solvents to remove any
constituents.
Finished product. A product that has undergone all stages of production, including
packaging in its final container and labelling.
Fungus. A member of the biological kingdom Fungi, consisting mostly of complex
multicellular eukaryotes with a cell wall, usually composed primarily of chitin. Fungi are
heterotrophs that absorb nutrients from their surroundings after decomposing organic
material. They reproduce by unicellular spores produced sexually and/or asexually.
Isolate. A purified constituent of a defined molecular structure obtained from a plant or
a plant material, an alga, a bacterium, a fungus or a non-human animal material.
Manufacturer. Corporation or person who fabricates or processes a NHP for the
purpose of sale, but does not include a pharmacist or other health care practitioner who,
at the request of a patient, compounds a NHP for the purpose of sale to the patient.
Marker compound. A constituent that occurs naturally in the material and that is
selected for special attention (e.g., for identification or standardization purposes) by a
researcher or manufacturer. Marker compounds are not necessarily pharmacologically
active.
Mineral. Natural minerals are naturally occurring solid, inorganic substances with a
definite and predictable chemical composition and physical properties. Synthetic
minerals are produced by synthesis.
Non-human animal material. A body part or secretion obtained from an animal other
than humans that is used to prepare a NHP, including attenuations used in homeopathic
medicine. For homeopathic medicines, non-human animal materials must be listed in
one of the homeopathic pharmacopoeias of the United States, France, Germany or
Europe.
Organic. A labelling and advertising term denoting a plant or plant material, alga,
fungus or non-human animal material certified to have been produced in accordance
with the production, processing, packaging, storage and distribution provisions of the
National Standard of Canada for Organic Agriculture. Certification according to other
organic standards is also acceptable. Products not within the scope of agricultural
standards (e.g., aquatic non-human animal material, alga, cyanobacteria (鈥渂lue algae鈥?))
Evidence for Quality of Finished Natural Health Products 37
must be certified to have been produced in accordance with an aquacultural or other
applicable organic standard.
Plant. A member of the biological kingdom Plantae, consisting of complex multicellular
eukaryotes with a cell wall composed primarily of cellulose. Plants produce their own
food by photosynthesis using chlorophylls a and b (secondarily lost in parasites), are
mostly terrestrial and have multicellular reproductive structures producing dependent
embryos.
Potency. The amount per dosage unit of the standardized component(s), which helps
characterize the quantity of the ingredient. It must be provided only when a potency
claim appears on the product label or when the literature supports a specific product
with that standardized component.
Primary molecular structure. The chemical structure of a substance isolated from a
plant or a plant material, an alga, a bacterium, a fungus, or non-human animal material,
obtained in its original, unaltered form.
Probiotic. A monoculture or mixed culture of live microorganisms, which when
administered in adequate amounts, confers a health benefit in humans.
Product licence applicant. An individual with legal ownership of and responsibility for
the NHP. The product licence applicant may be located in or outside of Canada.
Applicants who are located outside of Canada must identify a Canadian representative.
Proper name. In respect of an ingredient of a NHP, one of the following:
(a) if the ingredient is a vitamin, the name for that vitamin set out in item 3 of Schedule 1
(Natural Health Products Regulations, 2003);
(b) if the ingredient is a plant or a plant material, an alga, a bacterium, a fungus, a non-
human animal material or a probiotic, the Latin nomenclature of its genus and, if any, its
specific epithet; and
(c) if the ingredient is other than one described in paragraphs (a) or (b), the chemical
name of the ingredient.
Quantity. The amount of medicinal ingredient(s) per dosage unit. It is always required
for a product, as it is the amount of medicinal ingredient in the product.
Specifications. Quality standards referred to in the proposed Regulations and which
describe tests and methods (analytical and biological), tolerances and/or acceptance
criteria which are numerical limits, ranges or other criteria for the tests described.
Specifications establish the criteria to which a finished product must conform in order to
be considered acceptable for its intended use.
Evidence for Quality of Finished Natural Health Products 38
Standardization. The application of product knowledge, good agricultural or
wildcrafting practices, and good manufacturing practices to minimize inherent variations
in the composition of natural substances in order to ensure a consistent product from
one batch to the next.
Synthetic duplicate. A substance that shares an identical chemical structure and
pharmacological properties with its natural counterpart. 鈥淣atural鈥? means a product that
is isolated or comes from a natural source (e.g., plant or mineral). 鈥淪ynthetic鈥? means a
product that is chemically produced. For example Epinephrine is a synthetic duplicate of
the epinephrine produced by the human body.
Vitamin. Naturally occurring organic substances required in small amounts by the body
to maintain health.
Evidence for Quality of Finished Natural Health Products 39
APPENDIX 2. SCHEDULE 1 OF THE NATURAL HEALTH
PRODUCTS REGULATIONS
Schedule 1 (Subsection 1(1))
Includes Natural Health Product Substances
Item Substances
A plant or a plant material, an alga, a bacterium, a fungus or a non-human animal material
1
An extract or isolate of a substance described in item 1, the primary molecular structure of
2
which is identical to that which it had prior to its extraction or isolation
Any of the following vitamins 1 :
3
biotin
folate
niacin
pantothenic acid
riboflavin
thiamine
vitamin A
vitamin B6
vitamin B12
vitamin C
vitamin D
vitamin E
An amino acid
4
An essential fatty acid
5
A synthetic duplicate of a substance described in any of items 2 to 5
6
A mineral
7
A probiotic
8
1
Vitamin K (K1 & K2) has been recently added to the list of acceptable vitamins with a
maximum permissible limit of 120 碌g.
Evidence for Quality of Finished Natural Health Products 40
APPENDIX 3. QUALITY REQUIREMENTS OF MEDICINAL
INGREDIENTS USED IN HOMEOPATHIC MEDICINE
Test Test Method(s) Tolerances Limits
Parameters
Identity Chemical fingerprinting TLC, HPTLC or HPLC or Characteristic for the
(raw material) GC, and/or spectroscopic item
< 1 X 104 CFU/g or mL
Contaminating fungus Pharmacopoeial or WHO
(yeast and mould)**
Purity
< 1 X 105 CFU/g or mL
Total Aerobic Count** Pharmacopoeial or WHO
Microbial Pharmacopoeial or WHO Absent
Escherichia coli**
contaminants
(Finished Salmonella spp.** Pharmacopoeial or WHO Absent
product)
Pharmacopoeial or WHO Absent
Staphylococcus aureus**
Pharmacopoeial or WHO Absent
Pseudomonas aeruginosa**
< 0.14 渭g/kg b.w./day
Purity Arsenic Pharmacopoeial or WHO
< 0.09 渭g/kg b.w./day
Cadmium Pharmacopoeial or WHO
Chemical
contaminants
<0.29 渭g/kg b.w./day
Lead Pharmacopoeial or WHO
(Raw
material/Finished
<0.29 渭g/kg b.w./day
Total mercury Pharmacopoeial or WHO
product)
Pesticides Pharmacopoeial or WHO
Mycotoxins AOAC-International Aflatoxins < 20 ppb
(Association of Analytical
Chemists)
** Microbial tests are not required when the finished product is available in a solvent
containing equal to or greater than 50% ethanol.
Pseudomonas aeruginosa test is only required for the finished products in liquid form.
Preservative efficacy should be demonstrated at the end of the shelf-life for
homeopathic products in liquid form unless they are sterile products and packaged in a
single-dose format.
Evidence for Quality of Finished Natural Health Products 41
APPENDIX 4. ACCEPTABLE LIMITS FOR MICROBIAL AND
CHEMICAL CONTAMINANTS
Table 1. Acceptable limits for microbial contaminants in finished products
Total
Schedul
Contaminatin viable Salmonella Enterobact P.
E. coli S. aureus
e 1 List
g Fungus aerobic spp. eriaceae aeruginosa
Item
count
< 1 X 104 < 1 X 105 < 1 X 102
Absent for Absent N/A N/A
1
all internal for all (except for
use except internal bacteria:
N/A** for
< 1 X 102)
for teas, use except
bacteria
decoctions for teas,
or topical decoctions
dosage or topical
form: dosage
< 1 X 102 forms:
< 1 X 104
< 1 X 104 < 1 X 105 Absent Absent Absent N/A Absent
2
(except for
enzymes
< 1 X 102)
< 3 X 102 < 3 X 103 Absent Absent Absent N/A Absent
3
< 3 X 102 < 3 X 103 Absent Absent Absent N/A Absent
4
4 5
< 1 X 10 < 1 X 10 Absent Absent Absent N/A Absent
5
2 3
< 3 X 10 < 3 X 10 Absent Absent Absent N/A Absent
6
2 3
< 3 X 10 < 3 X 10 Absent Absent Absent N/A Absent
7
4 2
< 1 X 10 N/A Absent Absent Absent < 1 X 10 N/A
8
** N/A: not applicable
Notes:
1. Units are in Colony Forming Units (CFU) per gram or per millilitre.
Absent means < 1 X 101 CFU/g or CFU/mL for Total viable aerobic count,
2.
Enterobacteriaceae and Yeast and Mould count, not detected in 10 g or 10 mL
for Salmonella spp. and not detected in 1 g or 1 mL for E. coli, P. aeruginosa and
S. aureus
3. For a multi-component product, the tolerance limits for the finished product would
generally be based on the least stringent limit.
Evidence for Quality of Finished Natural Health Products 42
Table 2. Acceptable limits for chemical contaminants
Contaminants Tolerance Limits
< 0.14 渭g/kg b.w./day
Arsenic
< 0.09 渭g/kg b.w./day
Cadmium
< 0.29 渭g/kg b.w./day
Lead
< 0.29 渭g/kg b.w./day
Total mercury
Mycotoxins Aflatoxins: < 20 碌g/kg (ppb) of substance
(when applicable)
Solvent residues ICH or Pharmacopoeial limits
(when applicable)
Related substances and No undeclared impurity, Pharmacopoeial limits (as per monograph for
process impurities medicinal ingredient or finished product)
(when applicable)
Pesticides Pharmacopoeial limits
(when applicable)
Specific toxins PCDDs & PCDFs < 2 pg/kg b.w./day
PCBs < 0.13 渭g/kg b.w./day
(when applicable)
Radioactivity 600 Becquerels/kg of substance
(if suspected)
Antibacterial activity (for None
microbiologically- derived
enzymes)
Oxidative Peroxide AOCS Official Method Cd 8-53 max. 5 mEq/kg
Stability Value (PV)
Tests for
p-Anisidine AOCS Official Method Cd 18- max. 20
fish/seal oil
Value (AV) 90
Totox Value max. 26 (calculated as 2 x PV
+AV)
Evidence for Quality of Finished Natural Health Products 43
APPENDIX 5. CALCULATIONS
(a) Chemical Contaminants
Example of calculation for lead content of a finished NHP intended for adults:
Weight of Tablet: 250 mg
Recommended dosage: 2 tablets/ 3 times per day
Amount of lead in the product: 0.002 mg Pb/g (2 ppm) of product
Amount of Pb consumed per day: 0.003 mg or 3 mcg
Amount of Pb consumed per day based on body weight: 0.043 mcg/kg b.w/day (NHPD
tolerance limit 0.29 mcg/kg b.w/day)
Notes: This calculation assumes a body weight of 70 kg for an average adult. If the
dosage is intended for children, the appropriate body weight for the age of the child in
the recommended use or purpose should be used.
Evidence for Quality of Finished Natural Health Products 44
APPENDIX 6. LIST OF ACCEPTABLE DOSAGE FORMS
Aerosol Powder for Solution
Aerosol, Metered-Dose Powder for Suspension, Extended Release
Bar, Chewable Powder for Suspension
Bulk / Loose Powder, Metered Dose
Capsule Shampoo
Capsule, Combined Release Soap, Bar
Capsule, Delayed Release Soap, Liquid
Capsule, Extended Release Solution
Cream Solution, Extended Release
Cream, Liposomal Sponge
Compact Spray
Concealer Spray, Metered Dose
Dentifrice, Gel Stick
Dentifrice, Paste Strip
Douche Succus
Dressing Suppository
Elixir Suppository, Extended Release
Emulsion Suspension
Enema Suspension, Liposomal
Floss Syrup
Fluid Extract Syrup, Extended-Release
Foundation Tablet
Gel Tablet, Chewable
Gel, Extended Release Tablet, Combined Release
Globules Tablet, Delayed Release
Granule Tablet, Effervescent
Granule, Effervescent Tablet, Extended Release
Granule, Delayed Release Tablet, Rapid Dissolving
Gum, Chewing Tea, Herbal
Jam Tincture
Kit Vapour from Liquid
Lotion Vapour from Solid
Lozenge Wafer
Makeup Wipe
Mouthwash / Gargle
Ointment
Pad
Paste
Patch
Patch, Extended-Release
Pellet
Pencil
Piece, Chewable
Plaster
Powder
Powder, Effervescent
Powder, Delayed Release
Powder for Gel
Evidence for Quality of Finished Natural Health Products 45
APPENDIX 7. FINISHED NATURAL HEALTH PRODUCT
SPECIFICATION TEMPLATE
Name of the Finished Product:________________________________
Name of Manufacturer of Finished Product:______________________
Assessment Criteria Test Test Method NHPD鈥檚 Accepted
Tolerance Limits
Physical Description
Identity
(e.g., shape, colour)
Chemical identification May be tested at the raw
of the medicinal material stage if
ingredient (e.g., HPLC) justified.
Disintegration and/or 鈮? 45 min (uncoated)
Perfomance tests
Dissolution (when 鈮? 60 min (plain coated)
applicable) Dissolution profile to be
provided for controlled-
release products
Enteric coated tablets to
be tested in accordance
with the pharmacopoeia
(USP or Ph.Eur.)
Particle Size
Distribution, (if
applicable, e.g., tea)
Purity Chemical Arsenic < 0.14 碌g /kg b.w./day
Contaminants
Cadmium < 0.09 碌g /kg b.w./day
Lead < 0.29 碌g /kg b.w./day
Total Mercury < 0.29 碌g /kg b.w./day
Specific PCDDs, Dioxins < 2 pg/kg
tests for PCDFs b.w./day;
fish oil, Pharmacopoeial
when
applicable PCBs PCBs < 0.13 碌g/kg
b.w./day
Oxidative Peroxide 鈮? 5 mEq/kg
Stability Value
Tests for (PV)
fish oil
鈮? 20
p-
Anisidine
Value
(AVI)
Totox 鈮? 26 (calculated as 2 x
Value PV +AVl )
Evidence for Quality of Finished Natural Health Products 46
Assessment Criteria Test Test Method NHPD鈥檚 Accepted
Tolerance Limits
Pesticides (if Pharmacopoeial or
applicable) WHO
Mycotoxins or Aflatoxins: < 20 碌g/kg
afloxtoxins when (ppb) of substance
applicable
Solvent Residues ICH Q3C or
(when applicable) pharmacopoeial
Other impurities Pharmacopoeial limits
(Product and/or
process related
impurities, if applicable
(e.g., co-extracted
substances, inactive
isomers, degradation
product, intermediate
product, reagents,
catalysts)
Loss on Drying (for Pharmacopoeial limits
plant materials, e.g.,
herbs as such and tea)
Foreign Matter (for Pharmacopoeial limits
plant materials, e.g.,,
herbs as such and tea)
Ash Contents (for plant Pharmacopoeial limits
materials, e.g., herbs
as such and tea)
Microbial Total Viable Aerobic Pharmacopoeial as per Table 1,
Contaminants Count Appendix 3 of the
Quality guidance
document
Contaminating fungus
(Yeast & Mold)
Escherichia coli
Salmonella spp.
Staphylococcus
aureus
Enterobacteriaceae
(for enzymes and
probiotics)
Pseudomonas
aeruginosa (if product
is in liquid form and
<50% aqueous
Evidence for Quality of Finished Natural Health Products 47
Assessment Criteria Test Test Method NHPD鈥檚 Accepted
Tolerance Limits
ethanol)
Other indicator
organisms (when
applicable)
Quantity (e.g., weight As per Section 2.5
Quantity/Potency
in mg) of each
medicinal Ingredient
per dosage unit
Tablet/Capsule weight Pharmacopoeial limits
variation
Evidence for Quality of Finished Natural Health Products 48
APPENDIX 8. PHYSICAL TESTS REQUIRED FOR DIFFERENT DOSAGE FORMS
Dosage Description Disintegration Dissolution Weight Average Uniformity Preservative Adhesive Peel
Efficacy 1
Form or Dissolution Variation Weight of Dosage Strength Force
Unit
Tablet,
X X X X
Caplet
Capsule, etc. 2
Tablet, rapid
X X X X
dissolving
Tablet or
Capsule,
X X X X X
sustained 3
release
Tablet or
Capsule,
X X X X
delayed 4
release
Oral solutions
and X X
suspensions
Topical
X X
Preparations
Transdermal
X X X X
Patches
1
This test is not generally included in the routine specifications, but is tested during development and during stability studies.
2
This includes all immediate release dosage forms except those which state or imply a rapid onset or rapid release of the medicinal ingredient.
3
Sustained release dosage forms include extended release, combined release, timed release dosage forms.
4
Extended release dosage forms include enteric coated tablets and capsules.
Evidence for Quality of Finished Natural Health Products 49
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