Draft for consultation: Quality of natural health products guide: Quality and controls: Characterization, Performance
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Product quality is a core regulatory requirement. This section of the guide will help you make informed decisions to define your product's quality parameters and ensure that only high-quality NHPs are available for sale in the Canadian market.
This section of the guide provides guidance on the quality parameters you should consider at various stages of product manufacturing, based on scientific standards that apply to the quality of NHPs. This includes:
- characterization of medicinal ingredients at the research and development stage
- testing for impurities and suitability of raw materials
- testing for performance, identity, quantity and potency, and purity of finished products
- stability testing to determine the shelf life of the finished product
Establish the specifications for your NHP in accordance with the requirements described in this guide. This guide should be your starting point for that purpose. It will also help you maintain and update the FPS for your product.
Characterization
Medicinal ingredient characterization is a key part of product research and development. Characterizing a medicinal ingredient involves looking at its physical, biological and microbiological properties. Understanding these properties enables you to design a high-quality NHP. By adequately characterizing a medicinal ingredient, you can better assess the relevance of historical data and scientific studies to your NHP. Characterization also supports the development of the quality controls required in the FPS.
NHPs can be vitamins, minerals, amino acids and essential fatty acids, whose medicinal ingredients are typically well characterized.
NHPs may also contain medicinal ingredients derived from a large variety of other sources. For example, biological sources such as plants, animals, marine organisms and microorganisms. Such a diversity may result in a multitude of compounds with diverse chemical structures.
Therefore, you should understand and document the characteristics of the medicinal ingredient(s) in your product. This includes the distinguishing features and special qualities of the medicinal ingredients, which are determined through physical and chemical techniques.
Maintain information on the characterization of the medicinal ingredient(s) in your product to demonstrate their identity and purity. This evidence supports the safety and efficacy of your NHP. For example, if you claim that a medicinal ingredient is micronized, you must have documentation confirming the micronization process and particle size distribution test results for the micronized medicinal ingredient.
As previously noted, characterization forms part of product research and development. Therefore, characterization information is not typically found in FPS or batch records.
Plants or plant materials, algae, bacteria, fungi and non-human animal materials
Plants, algae, bacteria, macroscopic fungi and non-human animal materials are fundamentally complex and difficult to characterize solely by chemical testing. You should put adequate quality control measures in place at all stages of manufacturing to ensure consistency between batches.
You may characterize crude materials with:
- a description of how they were obtained, harvested, cleaned, processed and stored
- for further details on preparing materials from botanicals, refer to:
- information about the harvesting or purifying process
- such as whether the materials are dried or kept fresh, or whether the materials are kept whole, cut or powdered
- documentation on the identity, physical, chemical and microbial purity and stability of the materials
- this is especially important when crude materials are added to finished products directly, without further processing
You will find characterization requirements for bacteria and non-macroscopic fungi in the probiotics (live microorganisms) section.
Extracts
You should fully characterize plant material, algae, bacteria, fungi and non-human animal materials prior to their extraction. You should further characterize the crude materials prior to and during any additional processing steps such as harvesting, processing and extraction. You should also establish adequate process parameters (for example, time, temperature, pressure) and IPC tests for all extraction steps. This will ensure batch-to-batch consistency of the extract.
An extract is partially characterized by the ratio of the crude equivalent of the plant material to the extract quantity. Note the following:
- For a liquid extract, a ratio of 1:5 means that 1 gram of crude material was used to prepare 5 milliliters of extract.
- For a solid extract, a ratio of 5:1 means that 5 grams of crude material was used to prepare 1 gram of extract.
- The first number in the ratio is always the proportion of crude material and the second number is always the proportion of extract.
Standardized extracts
The characterization process of an extract may involve identifying specific chemicals referred to as markers, which are used to help manufacture a consistent product. Markers (for example, Panax ginseng with a marker of ginsenosides) are chemically defined constituents or groups of constituents used to control batch-to-batch consistency of the finished product. These markers can either be an active constituent marker with therapeutic activity or an analytical marker. For additional information, refer to:
- USP General chapter <561> Articles of botanical origin
- USP General chapter <563> Identification of articles of botanical origin
- EMA Reflection paper on markers used for quantitative and qualitative analysis of herbal medicinal products and traditional herbal medicinal products
We say an ingredient is standardized if it is manufactured to consistently meet a predetermined concentration of a specific marker or set of markers.
Refer also to the glossary for a description of the term "marker".
Fortified extracts
You may fortify an extract as long as you declare the amount of the fortifying component added as a separate medicinal ingredient.
- For example, a product containing a caffeine-fortified extract of green tea should list on the product label both the caffeine from the green tea extract as well as the added caffeine.
To learn more about extract types, refer to:
- USP General chapter <565> Botanical extracts
- EMA Guideline on declaration of herbal substances and herbal preparations in herbal medicinal products/traditional herbal medicinal products
Isolates, vitamins, amino acids, essential fatty acids, synthetic duplicates and minerals
Describe medicinal ingredients used in NHPs, such as isolates and synthetic duplicates, vitamins, minerals, amino acids and essential fatty acids, by their chemical name, as well as their Chemical Abstracts Service (CAS) registry number if available. General properties to characterize these medicinal ingredients may include appearance, colour, physical form (such as powder, crystalline), and melting point. If a pharmacopoeial monograph exists for a medicinal ingredient, refer to the monograph for applicable tests for its characterization and identification.
Characterization of processed medicinal ingredients should include the methods and controls used to process the ingredient. There should be adequate process controls and process parameters (for example, drying time, temperature, steam pressure, speed of rotation, micronization techniques) at all stages of manufacturing. This will ensure batch-to-batch consistency.
Characterization of highly processed medicinal ingredients should include a full description and flow chart of the manufacturing and processing steps of the raw starting materials (for example, a botanical starting material). Clear descriptions of the manufacturing process parameters for fermentation, esterification and hydrolyzation of raw ingredients are essential.
For the characterization of proteins and enzyme preparations and their testing, refer to:
Probiotics (live microorganisms)
Characterization of live microorganisms should include culture conditions such as:
- growth times
- strain viability
- growth temperatures
- cell collection method
- specific growth media used
- antibiotics used in the growth media (if applicable)
You can identify a microbial strain by its culture collection catalog number (for example, American Type Culture Collection (ATCC) number). A strain should not be sub-cultured more than 5 passages removed from the original culture.
In addition to phenotypic and genotypic methods for identity testing, further research is necessary on live microorganism strains during product development. That research helps to fully describe a strain's purity, quality and virulence characteristics. A well-documented strain-specific analysis should include:
- demonstration of the microorganism's survivability in the human gut, established through the following as applicable:
- in vitro gastric acid and bile resistance testing, and/or trial-derived beneficial effects from supplementation
- documentation of the absence of virulence of the microorganism, established through the following (as applicable):
- comparison of the antibiotic/antifungal resistance profile of the strain to typical species resistance profiles as published by an internationally recognized panel or in the literature
- whole genome sequence analysis and up-to-date searches of internationally recognized databases to explain the genetic basis for each atypical antibiotic/antifungal resistance or to demonstrate the absence of all known genetic mechanisms of resistance
- documentation of the presence of atypical antibiotic/antifungal resistance gene(s) in plasmids, genomic islands, and on other areas of the core genome in proximity to any mobile genetic elements
- demonstration of the lack of horizontal antibiotic/antifungal resistance transfer ability
- such as through mating experiments
- demonstration of the absence of genetic elements responsible for the production of virulence factors that are characteristic to the genus
- including the lack of enzymatic activity (that is, production of enzymes) known to the genus for their association with antimicrobial resistance, such as beta-lactamase and carbapenemase
- for strains susceptible to translocation (for example, strains of Lactobacillus rhamnosus used in high-risk circumstances*), demonstration of a lack of translocation across mucosal barriers via a reproducible assay should be documented
- *meaning high-risk use, hospital use, and use in specific vulnerable sub-populations (such as in premature infants and immunocompromised individuals). The term serious health risk (high level of risk) is described in the guide Pathway for licensing natural health products making modern health claims.
- examination of the whole genome sequence that should also include:
- identification of genes coding for, or contributing to, the resistance to critically and highly important antimicrobials, as defined and identified by the WHO
- further analysis at the strain level of any identified potential resistance gene (for example, via broth microdilution minimum inhibitory concentration (MIC) assays) to determine if the resistance is active
- comparison of databases (for example, Comprehensive Antibiotic Resistance Database (CARD), ResFinder, AMRFinderPlus)
- demonstration of the susceptibility to therapeutic concentrations of at least 2 commercially available first line antimicrobial/antifungal agents available in a typical clinical setting in Canada
- availability and access to antimicrobial susceptibility testing (AST) reports and/or antibiograms, for healthcare providers upon their request
- demonstration of the lack of toxigenic activity (that is, production of toxins) known about the genus
- in the case where live microorganisms can interfere with microbial impurity testing, a detailed scientific rationale on how the finished product complies
- rationale should include measures for distinguishing live microorganisms at the finished product stage along with a detailed explanation of how quality controls are put into place to ensure microbial purity
It is also important to verify the safety of the live microorganism strain(s) by documenting the genetic stability of the loci that are critical for biological activity or potency. This should include documentation regarding the production of any antimicrobials from the strain itself.
The characterization of medicinal ingredients in probiotics may include proprietary data, such as the identification of microorganisms using phenotypic and genotypic information. In such situations, NHP manufacturers (or PL holders) may need to rely instead on the raw material supplier for the information. Use mechanisms such as quality agreements and NHP-MFs to support such arrangements.
- Refer to the NHP MAP for more information on NHP-MFs.
- Refer to the NHP GMP guide for more information on quality agreements.
- The roles and responsibilities section also provides relevant information.
Performance
Product performance tests establish the availability of a medicinal ingredient. Your NHP must reliably deliver a uniform dose of each medicinal ingredient declared on its label.
Include performance tests and acceptance criteria in the FPS for your product as described in this section of the guide. Refer also to table 11 in appendix 4 and table 14 in appendix 5.
Ensure label claims about product performance are truthful and supported by evidence. Perform appropriate tests to demonstrate the performance of the NHP when representations regarding the product action and performance appear on its label.
Note that there are product-performance indicating specifications that you may be able to establish during product development. For example, during product development:
- evaluate the re-suspendability of suspension dosage forms (those that can settle over time) to establish a minimum shaking time
- evaluate the hardness of tablets and particle size distribution of granules to plot the disintegration time
Disintegration and dissolution
Your FPS for solid oral dosage forms must include tests for dissolution and disintegration, as explained in this section. These tests are designed to:
- assess the performance characteristics of the finished product
- detect issues with variations in non-medicinal ingredient qualities and quantities
- detect manufacturing process variations that may affect the medicinal ingredient release characteristics of the finished product
For immediate release solid oral dosages, you may choose to perform only disintegration testing as a quality control test if they contain highly water-soluble medicinal ingredients (that is, dissolution rate of the ingredient is greater than 80% in 15 minutes at physiological pH ranges 1.2, 4.0 and 6.8).
Solid oral dosage forms must meet the disintegration standards as per one of the following:
- Official method: Determination of the disintegration time of tablets
- USP General chapter <2040> Disintegration and dissolution of dietary supplements
- a method from a Schedule B listed pharmacopoeia or from another internationally recognized standard
In general, you do not need a disintegration test when your product is designed to be chewed (for example, chewing gums). This exemption does not apply to chewable gels (commonly called gummies), as you need disintegration testing to ensure the medicinal ingredient(s) can be released from the matrix of the product. Disintegration testing is not required for chewable gel NHPs when dissolution testing is performed as outlined in a Schedule B listed pharmacopoeia or in another internationally recognized standard.
Dissolution testing is a product-specific test and depends on the product characteristics and intended release profile. You may use data from dissolution tests to ensure that the medicinal ingredient(s) from different batches of the product have a similar dissolution profile. Also, a given batch must have similar bioavailability to the batch of product used in clinical studies, where applicable.
Differences that can contribute to variations in the dissolution profile of your product include the following:
- manufacturing variables
- such as granule size, tablet hardness and moisture content
- components of the product
- such as the type and quantity of binder, filler, disintegrant, lubricant and coating agent
Establish an appropriate product-specific dissolution test for your finished product in order to confirm the availability of the medicinal ingredient(s).
For slow-dissolving medicinal ingredients or modified-released dosage forms, you should usually establish appropriate dissolution testing during product development. This developmental dissolution testing includes testing at a range of physiological pH to simulate the gastrointestinal tract (for example, pH 1.2, 4.5 and 6.8). You should include at least 3 time points at about 20-30%, 50% and 80-85% release points in the test method to demonstrate release of all medicinal ingredients contained in the dosage form. A single-sided limit (for example, not less than (NLT) 85%) is appropriate at the last test point to demonstrate full release of the medicinal ingredients.
For highly-soluble medicinal ingredients, we recommend dissolution testing of the product in a single medium (for example, pH 1.2 or 6.8) that mimics physiological conditions relevant to the medicinal ingredient absorption. For immediate-release multi-medicinal ingredient products, you should justify the use of a single point test or a dissolution range based on the solubility of each medicinal ingredient.
Once a product shows a consistent and predictable dissolution profile through well-characterized and comprehensive developmental studies, a single pH dissolution test can be sufficient for routine quality control of the product.
You must select a robust, discriminatory and meaningful method to test for product performance. Refer to table 2 for test requirements and acceptance criteria for product performance in common solid oral NHPs. An alternate disintegration or dissolution method that shows compliance with the prescribed release requirements may be used. However, you must properly verify the appropriateness of the test method.
For tests to determine your product's performance, refer to the following:
- USP General chapter <701> Disintegration
- USP General chapter <711> Dissolution
- USP General chapter <724> Drug release (for transdermal system products)
- USP General chapter <1004> Mucosal drug products: Performance tests
- USP General chapter <1094> Capsules: Dissolution testing and related quality attributes
- USP General chapter <1711> Oral dosage forms: Performance tests
- USP General chapter <1771> Ophthalmic Products: Performance tests
- USP General chapter <2040> Disintegration and dissolution of dietary supplements
- Ph.Eur. General chapter 2.9.25. Dissolution test for medicated chewing gums (for products packaged in oral pouches)
- Official method: Determination of the disintegration time of tablets
- other method from a Schedule B listed pharmacopoeia, such as Ph.Eur. General chapter 2.9.3. Dissolution test for solid dosage forms
| Dosage form | Test methods | Test parameters | Acceptance criteria |
|---|---|---|---|
Immediate release – Hard shell / soft shell capsules |
|
Testing at pH 4.5 only may be justified |
Disintegrates in not more than (NMT) 30 minutes or conforms to pharmacopoeial limits |
Immediate release – Soft shell capsules containing semisolid or liquid |
|
Rupture test |
Rupture time in NMT 15 minutes or conforms to pharmacopoeial limits |
Immediate release –Sublingual and buccal (such as tablets and films) |
|
Dissolution test as applicable Disintegration test for orally disintegrating tablets |
Disintegrates in NMT 30 seconds |
Sustained release – Buccal, sublingual or oromucosal products (such as cough lozenges) |
|
Dissolution test as applicable Disintegration test for lozenges, for orally disintegrating tablets |
Conforms to pharmacopoeial limits when available, or is in accordance with the intended release profile |
Immediate release – Oromucosal products in pouches and chewing gums |
|
See pharmacopoeial or internationally recognized standards, when available |
Conforms to pharmacopoeial limits |
Immediate release – Tablets, other solid oral dosages, chewable gels (commonly called gummies) |
|
Uncoated tablets |
Disintegrates in NMT 45 minutes |
Plain coated tablets |
Disintegrates in NMT 60 minutes |
||
Chewable gels |
Disintegrates in NMT 15 minutes, or conforms to pharmacopoeial limits when dissolution is used |
||
Modified release dosages (delayed, extended, long acting, enteric coated, controlled or sustained) |
|
Delayed release: Two-stage testing (using different media in succession or in parallel, as appropriate) |
No disintegration after 60 minutes in gastric fluid and disintegrates in less than 60 minutes in simulated intestinal fluid, or conforms to pharmacopoeial limits |
|
Extended release: Multiple time point sampling |
Meets individual product specifications for dissolution profile |
|
Vitamin-mineral combination solid oral dosage forms (containing folic acid, vitamin A or water-soluble vitamins and minerals) |
|
As per USP General chapter <711> Dissolution, or USP General chapter <2040> Disintegration and dissolution of dietary supplements |
More than 75% of the labelled content of vitamin A, folic acid, and the index vitamin or the index element from the units tested is dissolved in 1 hour |
Dosage forms containing plants and plant materials (test for dissolution) |
|
As per USP General chapter <2040> Disintegration and dissolution of dietary supplements |
More than 75% of the labelled content of the index or marker(s) or the extract (index or analytical) compounds dissolved in 1 hour |
Uniformity of dosage unit
You must ensure an equal quantity of all medicinal ingredients in every single dose of your product. For this, conduct performance tests for the uniformity of dosage units. Follow USP General chapter <905> Uniformity of dosage unit or Ph.Eur. General chapter 2.9.40. Uniformity of dosage units. Your tests must meet the testing specification criteria described in these pharmacopoeial methods.
A test for content uniformity (CU) is necessary to ensure that consumers take a precise dose of the medicinal ingredient(s) per dosage unit. This is especially critical for solid dosage forms containing highly potent medicinal ingredients in very small amounts (for example, 5 mg or less per tablet).
You may use a weight variation (WV) test as an alternative for a CU test for solid dosage forms that contain 25 mg or more of the medicinal ingredient and comprising 25% or more by weight of the dosage unit. For multi-medicinal ingredient products:
- the test for WV can only apply to medicinal ingredients above the 25 mg or 25% threshold
- use a CU test for all other medicinal ingredients below the 25 mg or 25% threshold
You should conduct WV testing for capsules (hard or soft shell) and tablets (coated or uncoated) as per USP General chapter <2091> Weight variation of dietary supplements. Note the following:
- base the acceptance criteria on the information in Table 1. Weight variation tolerances for uncoated tablets, film-coated tablets, and coated tablets (other than film-coated tablets)
- a tolerance limit of NMT 7.5% of the target weight for chewable gels (commonly called gummies) is recommended
Table 3 provides a summary of the test methods and acceptance criteria to establish the uniformity of dosage units in solid dosage forms.
| Dosage form | Test methods | Test parameters | Acceptance criteria |
|---|---|---|---|
Discrete single-unit dosage forms, including:
|
|
Weight variation (WV), or Content uniformity (CU) |
Conforms to pharmacopoeial limits Individual unit target weight of NMT ± 10% of average target weight (or NMT ± 7.5% for chewable gels) as per USP <2091> Weight variation of dietary supplements, or conforms to pharmacopoeial limits |
For tablets that can be split into 2 or more split portions, an accurate fractional dose must be delivered in each split portion. For guidance on testing for uniformity of dosage units and testing for loss of weight, refer to USP General chapter <1705> Quality attributes of tablets labelled as having a functional score.
Some NHPs are packaged in non-discrete dosage forms that consumers themselves measure before use (for example, protein powders, creams, ointments). In these cases, define the standard dosage unit as the measured amount of the finished product used in a single, standardized dose (for example, 1 teaspoon, 5 mL, 1 drop, 1 spray). Demonstrate the performance characteristics of non-discrete dosage forms by conducting performance tests, such as those described in USP General chapter <1724> Semisolid drug products: Performance tests.
For NHPs that do not require a measured dose, a consumer may use an unspecified amount of product. The medicinal ingredient(s) quantity in non-discrete dosage forms must be expressed as percentages in appropriate units as defined in the USP General notices and requirements. When using percentages (such as, % v/v, % w/w or % w/v) to describe the strength of the product, you must take into consideration the amount of any non-medicinal ingredients added during the manufacturing process (such as pH adjusters). See also the quantity section for additional information.
Performance summary table by dosage form
Performance tests should take into account the finished product dosage form. This will ensure your NHP reliably delivers the medicinal ingredient(s) per dosage unit as declared on its label, at release and at expiry.
Refer to table 4 to determine which performance tests apply to your product based on its dosage form.
Consider other data obtained during product development. For example:
- for a relatively viscous solution or suspension, it may be appropriate to include viscosity/specific gravity testing
- product development information may allow you to exclude a specific performance test from the FPS
- data generated during product development may support rotational testing (also known as skip testing)
- refer to the NHP GMP guide for more information on rotational testing
In table 4, we denote performance tests required at product release by R and those required in the determination of product stability by S.
| Performance test |
Dosage form | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Solid dosage forms (tablets, caplets, hard lozenges, chewable tablets) | Soft dosage forms (soft capsules, soft lozenges) | Chewable gels (commonly called gummies) | Pouches, Chewing gums | Granules, Powders | Liquids | Suspensions | Semisolids (creams, ointments, lotions, gels, pastes, clays, peats) | Sterile | Transdermal patches | Metered dose delivery systems (sprays, aerosols, drops) | |
Disintegration |
R, S |
R, S |
R,S |
N/A |
N/A |
N/A |
N/A |
N/A |
N/A |
N/A |
N/A |
Dissolution |
R |
R |
R |
N/A |
N/A |
N/A |
R |
R |
N/A |
N/A |
N/A |
Hardness |
R, S |
N/A |
N/A |
N/A |
N/A |
N/A |
N/A |
N/A |
N/A |
N/A |
N/A |
Re-suspendability |
N/A |
N/A |
N/A |
N/A |
N/A |
N/A |
R |
N/A |
N/A |
N/A |
N/A |
Homogeneity |
N/A |
N/A |
N/A |
N/A |
R, S |
R, S |
R, S |
R, S |
N/A |
N/A |
N/A |
Particle size distribution, fineness |
N/A |
N/A |
N/A |
N/A |
R |
N/A |
R |
R |
N/A |
N/A |
R |
Viscosity/specific gravity |
N/A |
N/A |
N/A |
N/A |
N/A |
R, S |
R, S |
R, S |
N/A |
N/A |
R, S |
pH |
N/A |
N/A |
R |
N/A |
N/A |
R, S |
R, S |
R, S |
R, S |
N/A |
R, S |
Peel force and adhesive strength |
N/A |
N/A |
N/A |
N/A |
N/A |
N/A |
N/A |
N/A |
N/A |
R |
N/A |
Performance quality, dose delivery testsFootnote 2 |
N/A |
N/A |
R |
R |
N/A |
N/A |
N/A |
R, S |
N/A |
R |
R, S |
|
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