Draft for consultation: Quality of natural health products guide: Quality and controls: Identity, Quantity and potency

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• Identity
• Quantity and potency

Identity

In accordance with paragraph 44(2)(b) of the regulations, your FPS must contain detailed identity information for each medicinal ingredient. Include identity tests and acceptance criteria in the FPS of your NHP as described in this section of the guide. Refer also to table 11 in appendix 4, and table 12 in appendix 5.

Physical description of the finished product

Document the description of the dosage form in the FPS. Tests for physical description of the finished product should include organoleptic tests (that is, sensory characteristics such as taste, odour, feel) and visual examination (such as shape, appearance, colour, clarity).

Identification of the medicinal ingredient(s)

Ensure your NHP contains the medicinal ingredient(s) as listed in the PL. This is done through identification. The identity tests that you use must be specific and discriminatory in order to distinguish the medicinal ingredient(s), species or source material(s) from possible adulterants.

Ensure identity tests are performed at the finished product stage, or at the raw material stage when you have a scientific rationale. Identity testing at the finished product stage is not always possible, such as for botanical and/or animal materials in multi-medicinal ingredient products. Similarly, identity testing at the finished product stage is typically not possible for medicinal ingredient(s) of homeopathic medicines.

As mentioned earlier in this guide, homeopathic medicines must meet the specific quality requirements described in appendix 5 of the guide Evidence for homeopathic medicines as well as the general quality requirements described in the quality and controls section of this guide. Therefore, refer to both documents for guidance on the identity testing of homeopathic medicines.

Plants or plant materials, algae, bacteria, fungi or non-human animal materials

Quality principles, including Good Agricultural and Collection Practices (GACP) for materials of botanical origin, should be used throughout the supply chain to ensure proper identification, quality control, and batch-to-batch consistency. Implement controls at all stages of pre-manufacturing (growing, harvesting, processing) and manufacturing. These are especially necessary when you have a medicinal ingredient where the constituents responsible for the biological activity are unknown.

You may need to apply multiple techniques for the identification of botanical materials, including plants, plant materials, algae and macroscopic fungi. These techniques may include:

• chemical procedures
• deoxyribonucleic acid (DNA) and other biological analysis
• macroscopic and microscopic descriptions

To identify botanical materials unambiguously, you should ensure that GACP for the collection of plant materials are followed. Ensure the details of plant identification and authentication are documented. The recommended identification procedures for botanical ingredients are dependent on the form of the plant, algae or fungi and the manufacturing stage.

When using GACP for botanical materials (including those for the preparation of extracts), refer to the following:

• American Herbal Products Association: Good agriculture and collection practices
• EMA Guideline on good agricultural and collection practice for starting materials of herbal origin
• WHO Guidelines on good agricultural and collection practices for medicinal plants

Techniques for the identification of botanicals include the following:

• Macroscopic, organoleptic techniques: These techniques include defined morphological and anatomical characteristics of the whole plant or plant part (such as colour, fracture, smell, taste)
  • determine the characteristics at the source material stage, before the original form is changed during the production process
    • you may use references to flora and field guides and comparison to voucher specimens if flowering plants are obtained
• Microscopic techniques: The use of high magnification, special light or staining techniques are required to examine raw materials for previously established characteristics
  • compare these examinations to in-house reference materials or authoritative technical descriptions (such as pharmacopoeias)
• Biochemical identification: These are techniques that can distinguish even minor differences including the origin of the material, including:
  • gravimetry
  • spectrometry
  • chromatography
  • DNA fingerprinting
  • near-IR spectroscopy
  • capillary electrophoresis
  • Fourier-transform IR spectroscopy
  • genomic, proteomic and metabolomic studies

Choose a combination of source material characteristics and biochemical identification tests to eliminate misidentification of the medicinal ingredient. Collectively, they can detect the substitution of a similar species (for example, black cohosh (Actaea racemosa) is sometimes misidentified as other species within the Actaea genus).

Similar to botanical materials, identify non-human animal materials by using multiple techniques. This can include evaluating physical characteristics against certified reference materials using macroscopic and microscopic descriptions and using biochemical identification tests.

Identify bacteria and non-macroscopic fungi by using the techniques indicated in the probiotics section.

Extracts

An extract can be derived from botanical material (plants, plant materials, algae, fungi), non-human animal materials, or bacteria. It is defined by factors including the starting material(s), the nature of the solvent(s) used, and the physical conditions under which the extraction is performed.

Complete identification of extracts should include details of the source material, the extraction processes, and identity testing of the medicinal ingredient. Establish extraction process controls to ensure batch-to-batch consistency of the extract.

Use a combination of techniques to identify extracts from botanical materials. Combine macroscopic and microscopic techniques used to identify the source material prior to the extraction processes with one of the following:

• identification of an analytical or active constituent marker
• chemical identification of the constituents in the extract

Perform chemical identification test(s) on the extract when the source material(s) cannot be identified through morphological characteristics.

For test methods used in the identification of extracts from botanical materials, also commonly known as botanical substances, refer to the following:

• USP General chapter <203> High-performance thin-layer chromatography procedure for identification of articles of botanical origin
• USP General chapter <1064> Identification of articles of botanical origin by high-performance thin-layer chromatography procedure

Where the medicinal ingredient can be identified by the presence of analytical or active constituent marker(s), perform chemical identification tests. For example, you could perform a high-performance liquid chromatography-mass spectrometry analysis (HPLC-MS) to compare the peak retention time of the analytical or active constituent marker(s) with that of a primary reference standard.

Isolates and synthetic duplicates

Identify isolates and synthetic duplicates at the raw material stage using:

• appropriate chemical identification tests (such as IR spectroscopy)
• physical description (such as colour, crystalline form, melting and boiling point, optical rotation)

Identity testing can occur at the finished product stage, but it must be specific enough to discriminate between compounds of closely related structure that are likely to be present, related impurities, degradation products and adulterants.

Vitamins and minerals

The identification requirements for isolates and synthetic duplicates also apply to vitamins and minerals. Identify them at the raw material or finished product stage by physical description and appropriate chemical identification tests.

Amino acids, enzymes and proteins

The identification requirements for isolates and synthetic duplicates also apply to amino acids, enzymes and proteins. Identify them at the raw material stage by physical description and appropriate chemical identification tests. Identity testing for proteins should also include an appropriate analytical procedure to confirm the amino acid profile.

For enzymes, provide the Enzyme Commission number and enzyme nomenclature, as implemented by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology.

Identity testing can occur at the finished product stage only when other ingredients do not interfere with the test. This can happen when multiple proteins provide the same amino acids.

Essential fatty acids

The identification requirements for isolates and synthetic duplicates also apply to essential fatty acids. Identify them at the raw material stage by physical description and appropriate chemical identification tests. Identity testing can occur at the finished product stage, but it must be specific enough to distinguish the ingredient from any adulterants. Refer to:

• USP General chapter <202> Identification of fixed oils by thin-layer chromatography
• USP General chapter <401> Fats and fixed oils for applicable assays and limits

Probiotics (live microorganisms)

For products containing live microorganisms, strain identification and both qualitative and quantitative description of the probiotic culture are necessary. Identity testing should occur at raw material stage, and at the finished product stage when possible.

Determine the identity of probiotic strains unambiguously using the most current methodology and verify the identity on samples taken from a production culture, which is not more than 5 passages beyond the original strain or the ATCC (or ISO 17034 accredited) reference culture. This is provided that full traceability throughout the process is available. Follow internationally recognized standards throughout the manufacturing process to ensure high-quality products.

Ensure the following when applying appropriate identity tests and methodologies:

• the species Latin binomial identification (for example, Bifidobacterium longum) must be up-to-date and validated
  • refer to the United States National Institutes of Health (NIH)'s Approved lists of bacterial names
• the microorganism must be identified by phenotype and genotype
  • phenotyping must be assessed based on characteristics routinely used to distinguish the species from other species
    • this includes a series of testing for sufficient confirmation of observable traits of the species or strain
  • genotyping must be assessed using the following:
    • species identification by comparison of genome sequence homology in percentage to both identical and closely related type strains
      • these should be obtained from an internationally recognized culture collection or sequence database
    • strain characterization through an up-to-date complete/whole genome sequencing method (for example, Bifidobacterium longum ATCC#1234)
      • phenotyping and genotyping should be sufficient to distinguish the strain from other strains of the same species
• the absence of non-probiotic bacteria at the raw material stage

Refer also to table 11 in appendix 4.

Quantity and potency

In accordance with paragraphs 44(2)(b) and (c) of the regulations, your FPS must contain detailed information for each medicinal ingredient regarding its quantity per dosage unit and, where applicable, its potency. Include quantity tests (as well as potency tests, if applicable) and acceptance criteria in the FPS of your NHP as described in this section of the guide. Refer also to table 11 in appendix 4, and table 12 in appendix 5.

Always express the quantities of medicinal ingredients in the appropriate units, as presented in the PL. For example, solutions or suspensions of solids in liquids should appear in percent weight in volume (%w/v).

Quantification by assay

We recommend testing for (assaying) the quantity of medicinal ingredients at the finished product stage.

Products with medicinal ingredients that are single chemical entities or those that contain a marker used to standardize a product, can generally be tested using a quantitative assay at the finished product stage. Quantity testing should be done according to appropriate test methods, such as those described in a Schedule B listed pharmacopoeias.

For homeopathic substances, quantity testing (homeopathic potency) may not be applicable.

Ensure the acceptance criteria for the quantity testing of the medicinal ingredient meet a monograph from one of the Schedule B listed pharmacopoeias. Alternatively, if a pharmacopoeial monograph is not available, your acceptance criteria can be set to no wider than 80-120% of the amount declared on the product label. Base any proposed alternative quantity limits on a scientific rationale driven by data, taking into consideration the safety and efficacy of the product. This includes doing the following:

• document the reason for any alternative quantity limits (for example, test method limitations)
• be ready to demonstrate that any such alternative limits do not mislead consumers regarding the quantity of the medicinal ingredients declared on the label
• document the risk assessment of the alternative quantity limits in a manner that considers:
  • the safety of elevated amounts of any related degradation substances
  • how a lower quantity limit of the medicinal ingredients would not negatively impact the efficacy of the product
  • the safety of higher quantity limits of the medicinal ingredients in affected sub-populations
  • any other available supporting documents

Plants or plant materials, algae, bacteria, fungi or non-human animal materials and their extracts

Botanical ingredients are typically complex as they contain multiple compounds.

When a marker is available, you should assay the marker to determine the quantity of the medicinal ingredient. If no pharmacopoeial method is available for assaying the marker, develop an appropriate test method and determine appropriate acceptance criteria for the marker. Base this on evidence and data regarding the natural variability of the marker as well as the safety and efficacy of the product.

Isolates and synthetic duplicates

Isolates and synthetic duplicates should be tested for quantity at the finished product stage. Ensure the acceptance criteria for the medicinal ingredient meet the pharmacopoeial limits when available. If a pharmacopoeial monograph is not available, your acceptance criteria should be set to no wider than 80-120% of the amount declared on the product label, unless the limit of 80-120% results in a safety concern or loss of efficacy.

Certain NHPs may require strict acceptance criteria for quantity testing. For example, hand sanitizers require 60 to 95% (v/v) ethanol or 70 to 91.3% (v/v) isopropyl alcohol to ensure that the quantity of the medicinal ingredient is within the efficacious range. As a result, a limit of 95-105% of the target concentration would be more appropriate. Refer to:

• Table 2 of the USP General chapter <1072> Disinfectant and antiseptics for effective concentration of chemical disinfectants
• Guide to production of WHO-recommended handrub formulations

Vitamins and minerals

Vitamins and minerals should be tested for quantity at the finished product stage. Use appropriate test methods, such as those described in a Schedule B listed pharmacopoeia or other internationally recognized methods. Acceptance criteria for the quantity of vitamins and minerals should be as per the pharmacopoeial limits for each vitamin and mineral found in the product.

In the absence of a pharmacopoeial monograph, you must have a scientific rationale for quantities that are outside the general limit of 80-120%, unless the limit of 80-120% results in a safety concern or loss of efficacy. We recommend that the lower limit for the quantity test be set at 90% of the amount declared on the product label to ensure an appropriate amount of the medicinal ingredient at the expiry date.

Amino acids

Amino acids should be tested for quantity at the finished product stage. Ensure the acceptance criteria for the medicinal ingredient meet the pharmacopoeial monograph when available. If a pharmacopoeial monograph is not available, your acceptance criteria can be set to 80-120% of the amount declared on the product label, unless the limit of 80-120% results in a safety concern or loss of efficacy.

Essential fatty acids

Essential fatty acids should be tested for quantity at the finished product stage. Ensure the acceptance criteria for the medicinal ingredient meet the pharmacopoeial monograph when available. If a pharmacopoeial monograph is not available, your acceptance criteria can be set to 80-120% of the amount declared on the product label, unless the limit of 80-120% results in a safety concern or loss of efficacy.

Enzymes

Enzyme activity should be tested at the finished product stage. If you are unable to test at the finished product stage due to the complexity of the product formulation, then you must test for enzyme activity at the raw material stage. Consider the following:

• when a product contains multiple enzymes, such as a complex multi-enzyme blend, and you are not able to test the activity of each enzyme using a suitable method due to method interference:
  • test instead for the activity of the key enzyme(s) in the product
    • key enzymes are those whose activities are linked to the health claims on the product label
  • document evidence and have data to demonstrate assaying for each enzyme cannot be done using a suitable method due to test method interference
• if testing for enzyme activity in a multi-enzyme product is not feasible even for the key enzymes:
  • it may be necessary to select appropriate surrogates for total enzyme activity in your product where possible
    • refer to the Best practices guide: Enzyme dietary supplement products, published by the Council for Responsible Nutrition and the Enzyme Technical Association, for additional information

Enzyme activity (expressed in units of enzymatic activity per mg of enzyme) is the quantitative measure of the rate of enzyme catalytic activity. Acceptance criteria for enzyme activity should be 80% to 150% of the amount declared on the product label, unless the limit of 80-150% results in a safety concern or loss of efficacy. Also:

• measure enzyme activity according to the reaction catalyzed by individual enzymes (substrate specificity) and express it in units of activity calibrated against an appropriate reference standard
• use methods and units (such as FCC lipase units, FCC lactase units) specified by the FCC, USP or AOAC

Probiotics (live microorganisms)

Perform enumeration of live microorganisms using selective culture methods at the raw material stage and at the finished product stage. You may also use other internationally recognized methods that reflect those used in the supporting clinical data. Express the total count of the cells as colony forming units (CFU) per dosage unit. More modern units of measure other than CFU may also be acceptable if captured by the NHPID.

When the product contains more than one probiotic medicinal ingredient and they cannot be quantified individually at the finished product stage, the total CFU from the finished product should be divided amongst all live microorganisms in the product in a comparable ratio to input.

If tests to measure individual strain quantities in a multi-strain products are not available (or were not used in the supportive clinical data for the strains in the product), you may:

• replace the quantities of individual probiotic strains by a total CFU count at the finished product stage if the strains were cultured together in production
• list the quantities of individual strains as quantified by input
  • their target quantities would be extrapolated from the total CFU count enumeration from the stability program
    • for example, 5 billion of strain A and 10 billion of strain B at input with a total CFU count of 10 billion at the end of shelf life could be labelled as 3.3 billion of strain A and 6.7 billion of strain B in the finished product

Due to the varying viability of different microorganisms within a product mixture, the quantities of individual strains often cannot be accurately measured. This is why more modern and advanced methods (though currently less accessible) are being developed to quantify individuals strains within mixtures at the end of shelf life. Examples include digital polymerase chain reaction (PCR), quantitative polymerase chain reaction, and flow cytometry.

Probiotics for high-risk use (as described in the guide Pathway for licensing natural health products making modern health claims), hospital use, and use in specific vulnerable sub-populations (such as premature infants or immunocompromised individuals) should:

• conform to 100% of the amount declared on the label for products containing live microorganisms, provided this is the reflected level in the supporting scientific literature
  • this reflects the general expectation that all NHPs must be formulated with the intent to provide 100% of the quantity of each medicinal ingredient declared on the label
  • refer also to table 11 in appendix 4 of this guide for more information

However, for all other probiotics:

• a minimum of 80% of the amount declared on the product label is the expectation
  • this reflects the uncertainties that exist with probiotic quantification and the lower risk associated with such products

Quantification by input

Quantification by input means the quantity of a medicinal ingredient in the finished product is estimated from the amount added to a batch during manufacturing. The medicinal ingredient is not assayed (that is, it is not tested to confirm its quantity) at the finished product stage.

Note that if you use quantification by input for a medicinal ingredient, your FPS should include the target quantity of the medicinal ingredient as a precise value, reflecting the intended amount per dosage unit. Acceptance criteria for the medicinal ingredient quantity should include the statement "quantified by input" to indicate that the quantity is based on the input amount during manufacturing and not on analytical testing.

Quantification by input may be appropriate when:

• a validated or suitable assay method for quantifying the medicinal ingredient is not feasible
• the medicinal ingredient is a plant, plant material, alga, macroscopic fungus or non-human animal material

An exemption to testing for the quantity of a medicinal ingredient at the finished product stage may be justified if you have the following:

• a scientific rationale for using quantification by input
  • explain why assaying the medicinal ingredient in the finished product is not possible, and summarize the research and testing done to support your conclusion
  • for plant, plant material, alga, macroscopic fungus, non-human animal material medicinal ingredients and their extracts, the justification for using quantification by input instead of assaying may be based one of the following:
    • product-type limitations (for example, no recognized analytical marker)
    • confirmation that existing pharmacopoeial or other internationally recognized methods cannot be implemented (refer to the previous bullet for possible reasons)
• data from testing or studies to demonstrate that an assay cannot be implemented using a suitable method despite reasonable efforts to overcome the challenges of test method development and validation. This could be due to:
  • matrix interactions
  • test method interference
  • product-type limitations (for example, no recognized analytical marker)
  • ingredient interactions (between medicinal ingredients or non-medicinal ingredients)
• justification for the determination of product expiry date that includes consideration of expiration dates of all medicinal ingredients in the product, including those quantified by input

When using quantification by input for enzymes, consider the impact of the manufacturing process parameters (such as time, temperature, pressure, pH) on the integrity, activity, functionality and stability of the enzyme. Refer also to the enzymes section for additional information.

For information on quantification by input and probiotics, refer to the probiotics (live microorganisms) section.

When the quantity of a medicinal ingredient in a product is quantified by input, GMP controls and processes must include the following:

• written procedures (standard operating procedures), raw material test results, and batch records that clearly document that the correct amount of each medicinal ingredient was added to the batch to achieve the labelled quantity per dosage unit
• controls on WV during manufacturing (for example, during tableting or encapsulation) and on inter-batch and intra-batch homogeneity if more than one medicinal ingredient is mixed

If you apply quantification by input, you must establish homogeneity of the finished product during manufacturing and show content uniformity at the product release. This is particularly critical for powder mixtures as segregation of powders and demixing is prevalent. Consider following:

• to establish homogeneity of the bulk mix and demonstrate uniformity of the dosage unit, you may use an alternative compound to represent the behavior of other components in the bulk mix
  • an alternative compound is usually chosen among other ingredient(s) (such as one of the non-medicinal ingredients or an added colourant) in the product that are quantifiable by an assay method, or
  • it may be an external compound that can used for this purpose
• the sampling of the mix should be done at the end of mixing, and the sample size will have to reflect the dose to be contained in a dosage unit (for example, a capsule)

Refer also to the NHP GMP guide for more information on quantification by input.

Potency

Potency constituents declared on the PL application form should be quantified using an appropriate test method, such as those described in a Schedule B listed pharmacopoeia, at the finished product stage. Ensure the acceptance criteria for the potency constituent meet the pharmacopoeial monograph when available. If a pharmacopoeial monograph with upper and lower acceptance criteria is not available, your quantity limit for the potency constituent should be set to no wider than 80-120% of the amount declared on the product label.

If you must use acceptance criteria other than those described in a Schedule B listed pharmacopoeia or 80-120% of the amount declared on the product label (for example, due to test method limitations), base your quantity limits for the potency constituent on documented scientific data. Take into consideration the safety and efficacy of the product, and conduct a risk assessment of your proposed limit which should include:

• evidence of the safety of any increase in related degradation substances
• evidence that the lower limit of the potency constituent does not negatively impact the efficacy of the product
• evidence of the safety of higher limits of the potency constituent in affected sub-populations
• a demonstration that the wider limit does not mislead consumers regarding the potency of the medicinal ingredient represented on the product label
• other available supporting documents

When more than 1 medicinal ingredient in your NHP provide the same potency constituent (for example, when 2 or more medicinal ingredients provide caffeine), assay for the total cumulative potency in the finished product. However, if this is not possible, you need to have:

• a scientific rationale to explain why the potency constituent could not be assayed at the finished product stage
• a description of the steps taken to ensure the potency of each medicinal ingredient within the finished product will match what is declared on the product label throughout the shelf life of the product

Plants or plant materials, algae, bacteria, fungi or non-human animal materials

When markers for a non-extracted material are declared on the product label, assay the quantity of these markers (referred to as potency constituents in the PL application) at either the raw material or finished product stage. If the evidence supporting a labelled potency claim is based on the quantity of a particular marker (active component), perform the quantification of that marker at the finished product stage. If an exemption to testing potency of the marker at the finished product stage is necessary, your supporting scientific rationale should meet the requirements described in the quantification by input section.

Extracts

When markers for an extract are declared on the product label, assay the quantity of these markers at either the raw material stage or the finished product stage using appropriate test methods. If the evidence supporting a labelled potency claim is based on the quantity of a particular marker, perform the quantification of that marker at the finished product stage. If an exemption to testing potency of the marker at the finished product stage is necessary, your supporting scientific rationale should meet the requirements described in the quantification by input section.