Draft for consultation: Quality of natural health products guide: Quality and controls: Purity, Stability
On this page
Purity
As required under paragraph 44(2)(a) of the regulations, you must include detailed information about the purity of your NHP in its FPS. You are responsible for making every effort to understand the following:
- the potential for contamination (including from physical, chemical and microbial sources, as well as from adulterants)
- the impact of the presence of contaminants on the different sub-populations (for example, infants and children) using the NHP
Include in the FPS appropriate test methods for physical, microbial and chemical contaminants, along with the method name and source (for example, Ph.Eur. General chapter 2.8.13. Pesticide residues) and the acceptance criteria. We outline the purity test methods in these sections of this guide:
Consider any additional testing for contaminants that may be specific to your product. Include also in the FPS appropriate test methods for contaminants that fall under these categories:
- Specific impurities
- Radioactivity
- Adulterants
- Incidental impurities, related substances and process-related impurities
- Allergens
Refer also to table 11 in appendix 4, as well as table 12, table 13 and table 14 in appendix 5.
If your NHP contains impurities that no longer reflect the most up-to-date scientific knowledge and practices, implement risk mitigation strategies, which may include revising your FPS and amending your PL.
Ensure GMPs are in place so that additional process-related impurities are not introduced in the finished product through the manufacturing process (refer to the NHP GMP guide).
Physical contaminants
Your NHP must be free from foreign matter such as sand, glass, metal and other contaminants. Examine the product for absence of process-related matters including fragments from manufacturing and storage equipment, and particulates from extrinsic or exogenous sources (for example, fibers, insect parts) and intrinsic or inherent sources (for example, fragments of primary packaging materials, container seal, glass lamellae).
The test for foreign matter should be fit for purpose and product-specific. For example:
- a visual inspection is possible for colourless liquids packaged in clear glass containers; but it is not practical for coloured liquids, or all liquids in coloured glass containers or in plastic bottles
- foreign matter in a suspension will likely settle to the bottom of the container; therefore, you may need a specific test to determine physical contaminants in a suspension dosage form
Chemical contaminants
Consider chemical contaminant testing for all products, including homeopathic medicines.
Remember: 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.
Elemental impurities
Elemental impurities include:
- catalysts used during raw material synthesis
- impurities introduced inadvertently through interactions with processing equipment
- environmental contaminants that may be present in raw materials or finished products
Raw material specifications should include tests for purity and, where applicable, the acceptance criteria for testing elemental impurities.
Your NHP must not contain elemental impurities that exceed the permitted daily exposures (PDEs). PDEs are reported in µg/day (micrograms per day) and give the maximum permitted quantity of each element that may be contained in the maximum daily intake of a product.
For the appropriate method to calculate the concentration limits of elemental impurities in your product and the determination of a PDE, refer to:
- ICH guideline Q3D: Elemental impurities
- if the impurity is present in a formulation specifically intended for use by those under 18 years of age (for example, infants, children, pediatric patients, youth, adolescents), you must adjust your calculation for a lower body weight
The 4 main elements of toxicological concern in NHPs are:
- arsenic
- cadmium
- lead
- mercury
Table 5 presents PDEs in units of µg per kilogram of body weight per day. If your FPS list the units for individual elemental impurities in parts per million (ppm) or another unit of measurement:
- use the proposed daily dose (for example, 5 mL per day) and the lowest body weight of the recommended sub-populations (for example, infants) to calculate the elemental impurity daily exposure
- ensure the daily exposure is below the PDE
The maximum allowable limit of each elemental impurity in a product is based on the daily dose of the product. For example, for a product with a maximum daily intake of 10 g/day, the concentration limit for inorganic arsenic is 1.5 µg/g (1.5 ppm); while for a product with maximum daily intake of 1.0 g/day, the concentration limit is 15 µg/g (15 ppm). In both cases, the total daily exposure of inorganic arsenic is below the PDE (see table 5).
| Element | Limit per day (µg/day) (for an adult, 70 kg)Footnote 1 |
Limit per kg body weight per day (µg/kg b.w./day) |
|---|---|---|
Total arsenic or Inorganic arsenic Organic arsenic |
< 15.0 µg/day < 15.0 µg/day < 1.4 mg/day |
< 0.214 µg/kg b.w./day < 0.214 µg/kg b.w./day < 20.0 µg/kg b.w./day |
Cadmium |
< 5.0 µg/day |
< 0.07 µg/kg b.w./day |
Lead |
< 5.0 µg/day |
N/AFootnote 2 |
Total mercury |
< 15.0 µg/day |
< 0.214 µg/kg b.w./day |
Methylmercury |
< 2.0 µg/dayFootnote 3 |
< 0.029 µg/kg b.w./day |
|
||
You may test elemental impurities individually at either the finished product or raw material stage. Base the test methods on a Schedule B listed pharmacopoeia (for example, USP General chapter <2232> Elemental contaminants in dietary supplements, USP General chapter <233> Elemental impurities: Procedures), or on another internationally recognized standard.
If a plant species is known to accumulate high concentration of an ICH class 2A, class 2B, or class C elemental impurity, the raw ingredient of the plant or the finished product must be tested for that elemental impurity in addition to the above tests for the ICH class 1 elemental impurities. These limits should conform to those in the specific pharmacopoeial monograph when one exists, or alternatively to those in a pharmacopoeial general chapter (such as USP General chapter <232> Elemental impurities).
When testing at the raw material stage, calculate the total daily exposure in the finished product. You will find examples of this type of calculation in USP General chapter <2232> Elemental contaminants in dietary supplements. Base your calculation on:
- the daily dose of the product
- the quantity of each ingredient present in the product
- the maximum potential contamination based on the proposed limits for each raw material
You may use a cumulative method, or summation of the impurities from all ingredients, to calculate elemental impurity levels in your finished product. Do so by applying the level calculated for each of the ingredients used to make the finished product. If the calculation results in a level equal to or below that set out in this guide, and no elemental impurities were added during the manufacturing process, you do not need to test the finished product for elemental impurities. Maintain records of the testing for the individual ingredients, including the calculations, as justification for why you did not test at the finished product stage.
Pay special attention to the following elemental impurities:
- Arsenic (As): If the impurity in the product exceeds the acceptance limit of 15 µg/day (taking into account dosage and sub-population):
- conduct additional testing to determine the arsenic species
- demonstrate that the daily dose:
- does not exceed 15 µg/day of inorganic arsenic
- does not exceed 1.4 mg/day of organic arsenic
- you may use the methods in USP General chapter <211> Arsenic and the FCC's Arsenic limit test for the determination of inorganic versus organic arsenic in botanical ingredients
- Chromium (Cr) VI: Hexavalent chromium [Cr (VI)] compounds (for example, lead chromate) may be present in contaminated agricultural ground waters and soils close to agricultural lands that use chromium-containing industrial processes. Cr (VI) can enter the raw materials (for example, ginger, cumin, curry, cinnamon, turmeric) through water or soil. Cr (VI) compounds are classified as Group 1 carcinogenic to humans as per the International Agency for Research on Cancer risk classification.
- test for it, if suspected
- does not exceed 0.29 µg/kg b.w./day, for all products (with the exception of topical products)
- test for it, if suspected
For additional information on the limits of various elemental impurities in other dosage forms (for example, products for inhalation), refer to ICH guideline Q3D: Elemental impurities.
Elemental impurities in topical products
The limits for elemental impurity concentrations in topical products are different from those of oral products.
- Refer to table 6 for the acceptance limits for elemental impurities in topical products.
- For additional information on the limits of various elemental impurities in topical products, refer to tables A.5.1 and A.5.2 of ICH guideline Q3D: Elemental impurities.
| Element | Limit in parts per million (ppm) for a 10 g daily dose | Permitted daily exposure (PDE) limit (μg/day) |
|---|---|---|
Antimony |
NMT 90 ppm |
NMT 900 |
Arsenic |
NMT 3 ppm |
NMT 30 |
Cadmium |
NMT 2 ppm |
NMT 20 |
Lead |
NMT 5 ppm |
NMT 50 |
Total mercury |
NMT 3 ppm |
NMT 30 |
Ensure that the limits of elemental impurities in the finished product meet the requirements described in this guide.
Pesticide residues
Test your finished product for the presence of pesticide residues when:
- a pesticide may have been used in the treatment of the raw materials
- for example, on plants
- any pesticide residue is suspected and may carry over to the finished product
You may not need to test your finished product for pesticide residues if you test your ingredients of botanical or animal origin at the raw material stage. In this case, ensure scientific rationales and calculations are available to demonstrate the limits of pesticide residues in the finished product remains below the established maximum residue limits (MRLs).
Extraction solvents and preparation methods may modify the content of pesticides in a finished product. Therefore, botanical extracts, tinctures or other preparations might contain pesticide residues at enriched levels compared to their starting raw materials (for example, crops). You should calculate the limits for pesticide residues in extracts of botanical preparations as recommended by the USP General chapter <561> Articles of botanical origins and USP General chapter <565> Botanical extracts.
An MRL is the highest amount of pesticide residue that may remain in the finished product. Health Canada's Pesticides Regulatory Directorate (PRD) has published guidelines on how to establish MRLs on human health products and food. The PRD database contains the MRLs for specific pesticides residues. Under the Pest Control Products Act, the PRD conducts extensive evaluations and cyclical reviews of pesticides. The PRD may update these limits as new information becomes available. Note the following:
- when no specific limit is set, pesticide residues must singly or in any combination be below 0.1 ppm. This is commonly known as the general or default MRL.
- see paragraph B.15.002(1)(a) of the Food and Drug Regulations
- for more information, refer to MRLs, human health, and food safety: How MRLs are set
You may also refer to the FAO/WHO Codex Alimentarius - Pesticide index for limits on specific pesticides, insecticides, fungicides or herbicides used on various NHP ingredients.
Test pesticides in plants or plant materials, algae, fungi, non-human animal materials, or their extracts, using appropriate test methods. Multi-residue methods based on gas chromatography-mass spectrometry or high-performance liquid chromatography-mass spectrometry analysis (HPLC-MS) are routinely used for the analysis of pesticides.
- For additional information on testing for pesticide residues, refer to Ph.Eur. General chapter 2.8.13 Pesticide residues and USP General chapter <561> Articles of botanical origin.
Also, you may not need to test your NHP for pesticide residues if 1 or more of the following applies:
- its ingredients are all synthetic
- all its botanical ingredients are organic
- you must have evidence of organic certification from one of the certification bodies under the Canada Organic Regime
- it has a certified organic content of ≥ 95% (w/w)
For additional information on qualitative and quantitative analysis of pesticide residues, refer to the following sources:
- European Union (EU) Guidance document on pesticide analytical methods for risk assessment and post-approval control and monitoring purposes
- FAO/WHO Pesticide residues in food 2021
- US FDA Pesticide analytical manual volume 1
- WHO Quality control methods for medicinal plant materials
- WHO/FAO Codex Alimentarius - Recommended methods of sampling for the determination of pesticide residues for compliance with MRLs
- for food ingredients: testing of pesticide residues with methods as defined in section A.01.010 of the Food and Drug Regulations and presented in Health Canada's Compendium of analytical methods
Residual solvents
ICH class I solvents (for example, benzene) are known to cause toxicities and are not appropriate for NHPs. Avoid all ICH class I solvents in the production of ingredients of NHPs. You may only use such solvents under exceptional circumstances when supported by a scientific rationale, which includes a risk-benefit assessment of the results of residual solvent testing on the raw materials.
You should also limit the use of solvents associated with less severe toxicity (for example, ICH class II solvents) to protect consumers from potential adverse effects.
Wherever possible, use only the least toxic solvents (for example, ICH class III solvents or water).
- The list of ICH residual solvent classes is available in ICH guideline Q3C: Impurities: Guideline for residual solvents.
Test for residual solvents using methods from Schedule B listed pharmacopoeias (for example, USP General chapter <467> Residual solvents). The acceptance criteria for solvent residues should conform to pharmacopoeial limits, which are also listed in ICH guideline Q3C. USP General chapter <467> Residual solvents also provides guidance on determining PDEs. When a solvent is present in a product formulation specifically intended for pediatric use, adjust your calculation for a lower body weight.
You may use a cumulative method to calculate residual solvent levels in your finished product. Do so by applying the level calculated for each of the ingredients used to make the finished product. If the calculation results in a level equal to or below that set out in ICH guideline Q3C, and no solvents were used in the finished product manufacturing process, you do not need to test the finished product for residual solvents.
Maintain supporting documents (for example, the certificate of analysis from your supplier) to demonstrate 1 of the following:
- the ingredients in your product meet an appropriate pharmacopoeial grade
- the product was tested for residual solvents at the raw material or finished product stage
- no solvents (other than water, if applicable) were used in the manufacture of the raw materials or the finished product
Ideally, you should also maintain a letter of attestation, along with supporting documentation, confirming the following:
- your product meets the requirements described in ICH guideline Q3C
- you did not use any ICH class I solvents in the manufacturing of any ingredient or the finished product
If you use only ICH class III solvents to manufacture your NHP, you may test for residual solvents using an loss on drying (LOD) method (for example, USP General chapter <731> Loss on drying). An LOD result of no more than 0.5% is acceptable. If the LOD exceeds 0.5%, identify and quantify the residual solvents using USP General chapter <467> Residual solvents or an equivalent test.
Microbial contaminants
To ensure your product meets established specifications for microbiological quality, you must apply GACP, when applicable, and GMP to raw materials. Do not rely on microbial reduction techniques as a substitute for GMP. These techniques cannot replace the role of GMP in ensuring that the finished product meets its specifications for microbial contamination (refer to the NHP GMP guide).
The Ph.Eur. and the USP provide guidance on which microorganisms you must test for in your product. Common tests may include:
- total aerobic microbial count (TAMC)
- total combined yeasts and moulds count (TYMC)
- absence of (not an exhaustive list):
- Salmonella species
- Escherichia coli
- Staphylococcus aureus
- Pseudomonas aeruginosa
- bile-tolerant gram-negative bacteria (for example, Enterobacteriaceae, Pseudomonads and Aeromonas)
- Burkholderia cepacia complex (BCC) (as applicable, see water quality section)
For a given preparation, it may be necessary to test for other microorganisms.
Perform testing for microbial contamination at the finished product stage. If not performed on the finished product, maintain a scientific rationale and supporting data to justify a reduction from these tests. Base your rationale on a combination of factors, including (not an exhaustive list):
- the route of administration of the product
- the nature and microbial control program of the starting materials
- the susceptibility of the formulation to support microbial viability or growth
- for example, solid, nonaqueous or dry dosage forms that do not support microbial viability or microbial growth due to low water activity
Refer to table 7 for pharmacopoeial references of required tests and limits of microbial contamination in NHPs. These test methods and the acceptance criteria reflect the inherent risk associated with the product dosage form and the route of administration.
| NHP type | Testing reference | |
|---|---|---|
| Ph.Eur. methods and acceptance criteria | USP methods and acceptance criteria | |
Oral non-sterile dosage forms: isolates, synthetic duplicates, vitamins, minerals, amino acids and essential fatty acids |
|
|
Oral non-sterile dosage forms: plants, plant materials, algae and their extracts |
|
|
Non-oral non-sterile dosage forms |
|
|
Live microorganisms (probiotics) |
|
|
Homeopathic medicines |
|
|
Sterile products |
|
|
Animal-derived raw materials and products |
|
|
Multi-ingredient products containing plants and plant materials, live microorganisms, minerals or animal ingredients |
|
|
For microbial limits applicable to botanical raw materials, ingredients and products, refer to table 2 of USP General chapter <2023> Microbiological attributes of nonsterile nutritional and dietary supplements.
For products with multiple medicinal ingredients (such as botanicals, vitamins, probiotics) that each have unique microbial limits, generally base the acceptance criteria for the product on the least stringent (that is, widest) limits.
Water quality
Manufacturers of NHPs use water extensively, including as a non-medicinal ingredient. Choose a type of water that suits its intended use, does not negatively affect the quality of the product, and meets the specifications for chemical and microbiological purity.
For oral and dermal NHPs, you may use potable water that meets, at a minimum, all the requirements for drinking water in the Canadian drinking water guidelines or in the Guidelines for drinking-water quality set by the WHO.
For specific requirements for water used in sterile and other non-oral NHPs, refer to:
- USP General chapter <1231> Water for pharmaceutical purposes
- EMA Guideline on the quality of water for pharmaceutical use
Large volumes of water or saline-based solutions are often administered in open wounds and body cavities. This water must be non-pyrogenic and should meet the standards of the USP monograph for Sterile water for irrigation. The monograph requires the water to be tested as per the USP General chapter <85> Bacterial endotoxins test, with an allowable endotoxin limit of NMT 0.25 endotoxin units/mL.
Microorganisms from BCC can survive in the water used to manufacture finished products because they resist certain preservatives and antimicrobial agents. These opportunistic species have appeared in topical and oral antiseptic products containing povidone iodine, benzalkonium chloride and chlorhexidine gluconate. If you manufacture products for inhalation or aqueous preparations for oral, oromucosal, topical or nasal use, include procedures in your quality assurance program to address the risk of BCC in the water system used in the manufacturing. For additional information, refer to USP General chapter <60> Microbiological examination of nonsterile products – Tests for Burkholderia cepacia complex.
Water activity
Your product may contain both free and bound water within its matrix. Determine the total water content as described in USP General chapter <921> Water determination.
Free water molecules may lead to hydrolysis or support microbial growth. Therefore, you may need to monitor the water activity (aw) of your product if the amount of free water (that is, excess water in the product) impacts critical quality attributes, including the following:
- product degradation
- hardness or friability
- microorganism growth
- product dissolution or disintegration
Refer to USP General chapter <922> Water activity to determine the aw of raw materials and finished products. Testing for aw can be an IPC test to monitor the product quality.
Note that USP General chapter <921> Water determination and USP General chapter <922> Water activity are not the same as USP General chapter <731> Loss on drying.
- USP <731> is a test to determine the amount of water, all or part of the water of crystallization, or volatile matter of any kind (for example, organic residual solvents) in the sample, which is removed during the drying.
- For implications and applicability of USP <731>, refer to the residual solvents section of this guide.
Products from animal-derived raw materials
The production of animal-derived raw materials must be subject to strict controls. Extracting raw materials from animal tissues requires certain precautions.
Assess non-sterile oral products that contain animal by-products mixed with non-animal ingredients for the presence of microorganisms, in accordance with Ph.Eur. General chapter 5.1.4. Microbiological quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use when a specific pharmacopoeial monograph (from either the Ph.Eur. or the USP) for the ingredient or product is not available.
- Refer to table 5.1.4.1. of Ph.Eur. General chapter 5.1.4 for special provisions regarding oral dosage forms containing raw materials of animal origins for which antimicrobial pretreatment is not feasible.
In general, you should not "mix" microbial test requirements from different pharmacopoeias when testing microbial contaminants in NHPs. However, for multi-ingredients products containing plant and animal materials, you may combine the requirements of USP General chapter <2023> Microbiological attributes of nonsterile nutritional and dietary supplements for the plant materials with those of Ph.Eur. General chapter 5.1.4. Microbiological quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use for the animal material. Note the following:
- microbial testing should occur for all markers of all the ingredients
- the widest acceptance criteria for TAMC and TYMC may be used (see table 7)
- This exception applies only to multi-ingredient products containing animal-derived raw materials.
Products containing live microorganisms (probiotics)
For products containing live microorganisms (probiotics), use a method for enumerating viable members of the family Enterobacteriaceae (consult table 7 for references). Selective testing for coliforms or for members of the genus Enterobacter (a subset of the family Enterobacteriaceae) is not sufficient. Selective testing may fail to screen for other gram-negative facultative rods that belong to the same family of Enterobacteriaceae. These could include known pathogens such as members of the genera Klebesiella and Shigella.
Table 11 in appendix 4 of this guide provides additional information on the microbial requirements for products containing live microorganisms. If your probiotic product contains an organism that interferes with one of the required tests in table 11, you should implement alternative tests when possible. You may also need to conduct searches for related pathogens (for example, using molecular methods to detect related virulence genes at the finished product stage).
Mycoplasma
Test cell cultures substrates for mycoplasmas to ensure your probiotic is not contaminated. You must test for mycoplasmas for all probiotics used in high-risk clinical settings (such as hospitals) or in vulnerable sub-populations (for example, premature infants). This is especially important for probiotics used in body cavities where certain mycoplasma (such as Mycoplasma genitalium, Mycoplasma pneumoniae and Ureaplasma) may cause infection. For additional information, refer to:
- USP General chapter <63> Mycoplasma tests
- Ph.Eur. General chapter 2.6.7 Mycoplasmas
Sterile products
Sterile NHPs are subject to sterile manufacturing process requirements that minimize the risks of microbial and particulate contamination. Sterile manufacturing must strictly follow carefully established and validated methods of preparation and procedures that ensure sterility. To ensure product sterility, you cannot rely solely on testing your finished product for sterility.
- Refer to the NHP GMP guide and Annex 1 to the Good manufacturing practices guide – Manufacture of sterile drugs (GUI-0119) for more information.
- Health Canada is also an active member of the Pharmaceutical Inspection Cooperation Scheme (PIC/S) and adopted PIC/S Annex 1 Manufacture of sterile medicinal products of the Guide to good manufacturing practice for medicinal products.
- This PIC/S document also describes how to manufacture sterile products to comply with Health Canada's regulatory requirements.
Sterile products (such as ophthalmic products) must meet the criteria outlined in USP General chapter <71> Sterility tests or Ph.Eur. General chapter 2.6.1 Sterility. Sterility tests take into consideration the dosage form and route of administration of the NHP.
- For example, products for open wounds or burned areas (such as sterile water or saline solution) and products used in body cavities (such as a sterile nasal spray or a sterile inhaler) must follow specific sterility testing requirements.
Young children, especially newborns, are a vulnerable sub-population and can have difficulties fighting off infections because their immune systems are not yet fully developed. Microbial contamination in NHPs could result in harm to newborns and is potentially most hazardous when administered into body cavities such as eyes, nose and ears.
Treat sterile NHPs in the same manner as sterile pharmaceutical drugs.
- Refer to the NHP GMP guide for more information on requirements to implement a sterile manufacturing process.
Specific impurities
NHP ingredients may contain naturally occurring impurities or impurities introduced while raising, growing or processing the source materials. Avoid or minimize impurities as outlined in this section of the guide.
Mycotoxins
Mycotoxins (for example, aflatoxins) are toxic compounds that are naturally produced by certain types of moulds (fungi). Exercise extreme care when handling and storing any materials of plant, nut, seed or grain (for example, wheat, oat, barley, rye) origin. Use the Schedule B listed pharmacopoeias or other internationally recognized standards to identify products needing mycotoxin testing. Test for mycotoxins if an ingredient has documented cases of fungal contamination or if fungal contamination is considered likely.
You may find aflatoxins, which are highly dangerous mycotoxins, on many agricultural crops due to poor agricultural practices and storage conditions. Table 8 sets out Health Canada's limits for aflatoxins in finished products.
| Aflatoxin | Maximum level |
|---|---|
Aflatoxin B1 |
<5 µg/kg (ppb) |
Total aflatoxins (B1+B2+G1+G2) |
<20 µg/kg (ppb) |
Test for aflatoxins as per USP General chapter <561> Articles of botanicals origin, Ph.Eur. General chapter 2.8.18 Determination of aflatoxin B1 in herbal drugs or another internationally recognized standard, in products that contain the following ingredients (not an exhaustive list):
- Peanuts (Arachis hypogaea)
- Ashwagandha (Withania somnifera)
- Tienchi ginseng (Panax notoginseng)
- Rhodiola rosea (also known as Rhodiola and Roseroot)
- Chinese salvia (Salvia miltiorrhiza) (also known as Danshen)
- Chinese skullcap (Scutellaria baicalensis) (also known as Radix Scutellariae)
- Radix saposhnikoviae (Saposhnikovia divaricate) (also known as Fang feng in Chinese)
You may also refer to the European Food Safety Authority (EFSA) Risk assessment of aflatoxins in food for more information.
While aflatoxins are common mycotoxin contaminants, there are other mycotoxins that are of concern including ochratoxin A, fumonisins, aflatoxin M1, fusarium mycotoxins (such as T-2 and HT-2 toxins), deoxynivalenol, and patulin. Determine which mycotoxins may be present in your product and the appropriate test methods and acceptance criteria for testing.
Some NHP ingredients (for example, liquorice root) may contain ochratoxin A.
- Ph.Eur. General chapter 2.8.22 Determination of ochratoxin A in herbal drugs provides information on testing for this mycotoxin. The Ph.Eur. sets out a maximum limit of:
- 20 µg /kg of ochratoxin A in liquorice root (Liquiritiae Radix)
- 80 µg /kg of ochratoxin A in liquorice dry extract used for flavoring purposes
- If your product contains Liquiritiae Radix, you must test for the presence of ochratoxin A.
The Joint FAO/WHO Expert Committee on Food Additives (JECFA) has stated that adverse effects may occur from fumonisin exposure and recommends a reduction of exposure to fumonisin and other toxins produced by Fusarium verticillioides.
- JECFA established a limit of 2 µg/kg bw for fumonisins (FB1 + FB2 + FB3), alone or in combination.
- If contamination with fumonisin is suspected for an ingredient in your NHP, you must test it for this mycotoxin.
Cyanobacterial toxins
Cyanotoxins are toxins produced by cyanobacteria (also known as blue-green algae or Aphanizomenon flos-aquae). NHPs that contain certain freshwater cyanobacteria have a history of contamination with a group of hepatotoxic compounds called microcystins.
Health Canada has set a permitted daily dose limit of 0.02 µg microcystin-LR/kg b.w./day. The limit of microcystin-LR or total microcystin in each raw material must not exceed 1 ppm (1 µg/g), with a total consumption per day of less than 0.02 µg microcystin-LR/kg b.w. when calculated for the finished product.
Test your finished product for microcystin-LR using an appropriate test method. You must also test cyanobacterial products for other microcystins if there is a history of potential contamination.
- For additional information, refer to US FDA Blue-green algae products and microcystins.
Testing Cannabis sativa
Cannabis sativa is classified as an NHP under Schedule 1, item 1 (a plant or a plant material) of the regulations, when the ingredient is not included in the definition of cannabis as referred to in Schedule 2 to the Cannabis Act:
- A non-viable seed of a cannabis plant
- A mature stalk, without any leaf, flower, seed or branch, of such a plant
- Fibre derived from a stalk referred to in item 2
- The root or any part of the root of such a plant
- A derivative made by processing parts of such a plant referred to in items 1, 3 or 4, or a product made from that derivative, and
- A derivative made by processing a stalk referred to in item 2, or a product made from that derivative, that does not contain an isolated or concentrated phytocannabinoid
The above ingredients must not contain more than 10 ppm delta-9-tetrahydrocannabinol (THC), phytocannabinoids that have been isolated or concentrated, or synthetic duplicates of phytocannabinoids. The determination of the THC concentration must take into account the potential to convert delta-9-tetrahydrocannabinolic acid to THC.
In the Industrial Hemp Regulations, industrial hemp is defined as a cannabis plant - or any part of that plant - in which the concentration of THC is 0.3% w/w or less in the flowering heads and leaves. As such, hemp in NHPs is expected to be from an approved cultivar set out in the List of Approved Cultivars, published by the Government of Canada on its website, as amended from time to time. Additional cultivars may be permitted, such as varieties recommended for certification by the Association of Official Seed Certifying Agencies, which are also meeting the definition of industrial hemp as set out in the Industrial Hemp Regulations.
It is however a non-NHP when the ingredient meets the definition of cannabis in the Cannabis Act:
- Any part of a cannabis plant, including the phytocannabinoids produced by, or found in, such a plant, regardless of whether that part has been processed or not, other than a part of the plant referred to in Schedule 2 to the Cannabis Act,
- Any substance or mixture of substances that contains or has on it any part of such a plant, and
- Any substance that is identical to any phytocannabinoid produced by, or found in, such a plant, regardless of how the substance was obtained
Phytocannabinoids are also listed on the Prescription drug list as follows:
- Phytocannabinoids produced by, or found in, the cannabis plant and substances that are duplicates of such phytocannabinoids, except anything referred to in Schedule 2 to the Cannabis Act that contains no more than 10 µg/g THC and that does not contain an isolated or concentrated phytocannabinoid or a synthetic duplicate of that phytocannabinoid
If your NHP contains Cannabis sativa, your FPS must include information that confirms that the Cannabis sativa used in the NHP complies with the regulatory requirements of an NHP substance as per Schedule 1 and Schedule 2 of the regulations. Adherence to one of the Schedule B listed pharmacopoeia or to another internationally recognized standard for, as an example, the limit of total cannabidiol (CBD) may only be used if the limits and parameters required by those references do not contravene the provisions of the Food and Drugs Act and all its associated regulations, including the Cannabis Regulations, as well as the Prescription drug list.
Your FPS must include details about the methods used to test the Cannabis sativa ingredient and the tolerance limits for total THC and total CBD. Specifically:
- testing for total THC and total CBD at the raw material stage
- note: the regulatory requirements to ensure Cannabis sativa is an acceptable NHP substance are specific to the ingredient and not the finished product
- the test method for THC must test for total THC and have a limit of detection of 10 ppm or a value less than 10 ppm
- the limit of detection cannot be an interval
- include in the specifications the chromatographic instrumentation (for example, HPLC) as well as the detection method (for example, high-performance liquid chromatography-ultraviolet (HPLC-UV), HPLC-MS)
- the tolerance limit for total THC must be "10 ppm", "no more than 10 ppm" or a value of less than 10 ppm
- ensure the test methods have limits of detection and/or quantification suitable to meet the stated tolerance limits
- the test method for CBD must test for total CBD and have a limit of detection of 10 ppm or a value less than 10 ppm
- the limit of detection cannot be an interval
- include in the specifications the chromatographic instrumentation (for example, HPLC) as well as the detection method (for example, HPLC-UV, HPLC-MS)
- the tolerance limit for total CBD must be "not detected"
For additional information, refer to section 3.4 of the guide Health products containing cannabis or for use with cannabis: Guidance for the Cannabis Act, the Food and Drugs Act, and related regulations.
Acid insoluble ash test
The acid insoluble ash (AIA) test is a part of the total ash test that measures the content of siliceous and other acid insoluble non-combustible compounds present in raw materials of plant, algal or fungal origin. Determine if testing for these environmental contaminants is necessary. Conduct this testing if an ingredient has documented cases of contamination or if contamination is considered likely.
- Refer to USP General chapter <561> Articles of botanical origin for the AIA test when determining the amount of inorganic impurities that are present in plant, algal or fungal materials at the raw material stage.
Impurities in animal-derived raw materials
You should use animal-derived raw materials that are sourced from food-producing animals or other animals suitable for human consumption. Furthermore, the animal-derived raw materials, including those used in homeopathic medicines, must be free from the impurities outlined in these sections of this guide:
Hormones
Hormone-producing non-human animal materials that may be used in NHPs include:
- ovaries
- hypothalamus
- prostate gland
- mammary gland
- pituitary gland
- adrenal gland
- orchic gland
Consistent with subsection 2(2) and Schedule 2 of the regulations, these materials should not contain any of the hormones set out in:
- the Prescription drug list
- Schedule D to the Food and Drugs Act
- Schedule IV to the Controlled Drugs and Substances Act
Specified risk materials
Transmissible spongiform encephalopathies (TSEs) are infectious diseases that commonly include:
- scrapie in sheep
- bovine spongiform encephalopathy in cattle and bovine
- chronic wasting disease in caribou, deer, elk, moose (among others)
TSEs are caused by prions that are transmissible and found in infectious tissues associated with the disease, also called specified risk materials (SRMs). Specifically, SRMs in cattle refer to:
- the distal ileum of cattle of all ages
- the skull, brain, trigeminal ganglia, eyes, tonsils, spinal cord and dorsal root ganglia of cattle aged 30 months or older
Ensure that all NHPs are free from TSE-causing agents.
- Refer to section B.01.047.1 of the Food and Drug Regulations for information on the restrictions for SRMs.
Health Canada strongly advises against the use of tissues that are susceptible to TSE-causing agents. Those tissues include bones of cattle, sheep, goat and deer as well as elk velvet antlers. Do not use vertebral column or skull bones from any of these animals.
The following alternatives are recommended for use in NHPs:
- plant-based gelatins
- plant-based collagens
- materials that are not made from the skin or hides of any animal
- materials from animals that are not susceptible to TSEs (for example, pigs)
When an ingredient is sourced from an animal susceptible to TSE-causing agents, you must maintain one of the following supporting documents for that ingredient:
- a valid European Directorate for the Quality of Medicines and HealthCare TSE Certificate of suitability
- a veterinary certificate and an attestation providing the following information:
- evidence that source animals are fit for human consumption
- materials can be traced back to a source (herd or animal)
- evidence that cross-contamination with high-infectivity tissues during sourcing was avoided
- manufacturing procedures that are known to reduce infectivity (if any) are implemented
- for example, procedures that are in accordance with Ph.Eur. General chapter 5.2.8. Minimizing the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products
If you use gelatin sourced from the bones of animals susceptible to TSE-causing agents, you must have evidence that demonstrates risk mitigation through adequate quality controls. This may include evidence that the alkaline process has the following steps:
- bones are finely crushed, degreased with hot water, and demineralized with dilute hydrochloric acid (>4%, pH<1.5) for a minimum of two days to obtain collagen
- an alkaline treatment with saturated lime solution (pH>12.5) for at least 20 days is used
- the gelatin is extracted, washed, filtered and concentrated
- a heat treatment (sterilization at 138-140°C, for 4 seconds) is applied
For information on how to mitigate the risk of TSE-causing agents, refer to the Official Journal of the European Union (OJEU) Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products.
Drug residues
Raw materials from animal origins (such as honey, royal jelly, eggs, dairy, meat and poultry) must meet the following:
- the respective MRLs established by Health Canada must not be exceeded
- they must not contain drugs in Health Canada's List of banned veterinary drugs
- These include:
- clenbuterol and its salts and derivatives
- chloramphenicol and its salts and derivatives
- synthetic diethylstibestrol and other synthetic stilbene compounds
- 5-nitroimidazole compound: metronidazole, ornidazole and ronidazole
- 5-nitrofuran compound: furazolidone, furaltadone, nitrofurantoin and nitrofurazone
- Refer also to sections B.01.048 and C.01.610.1 of Food and Drug Regulations.
- These include:
Ensure that any raw materials from animal origin in your product are free from drugs listed on the Prescription drug list or their residues.
If you complete testing for this purpose, you must maintain testing records that demonstrate the absence of drug residues in your NHP. Alternatively, you must maintain a scientific rationale for why the testing is not needed.
For more information, refer to OJEU Commission implementing regulation (EU) 2021/808 on the performance of analytical methods for residues of pharmacologically active substances used in food-producing animals and on the interpretation of results as well as on the methods to be used for sampling and repealing.
Antibiotic residues in probiotics
Products containing live microorganisms (probiotics) should be free of any antimicrobials, including antibiotics and antifungals of clinical relevance. This includes antimicrobials that are:
- introduced during the manufacturing of the product
- produced by the microorganisms themselves (for example, bacitracin from Bacillus subtilis)
For the most up-to-date list of antimicrobials of clinical relevance, refer to:
- WHO List of critically important antimicrobials
- WHO Critically important antimicrobials for human medicine: 6th revision
- WHO Ranking of antimicrobials according to their importance in human medicine: A critical step for developing risk management strategies to control antimicrobial resistance from food animal production
Thiaminase (horsetail)
Thiaminase is an enzyme that degrades thiamine. This enzyme can be found in Equisetum arvense, more commonly known as horsetail. When horsetail is an ingredient in your NHP, you must perform testing to ensure the absence of thiaminase-like activity.
Marine oils
Fish oil and omega-3 fatty acids derived from fish oil must be tested for specific contaminants. These include:
- furans
- polychlorinated dibenzofurans (PCDFs)
- polychlorinated dibenzo-para-dioxins (PCDDs)
- dioxin-like polychlorinated biphenyls (dioxin-like PCBs)
Use the test methods outlined in the USP monograph for Fish oil containing omega-3 acids, or in other internationally recognized standards for fish oil.
Refer to table 9 for the acceptance limits of dioxins and dioxin-like polychlorinated biphenyls in fish oil and omega-3 fatty acids derived from fish oil.
| Dioxin and dioxin-like polychlorinated biphenyl contaminants | Maximum levelFootnote 1 |
|---|---|
Sum of PCDDs and PCDFs |
2.0 pg TEQ TEF/g oil |
Sum of PCDDs and PCDFs and Dioxin-like PCBsFootnote 2 |
10.0 pg TEQ TEF/g oil |
|
|
For more information, refer to OJEU Commission regulation (EU) No 1259/2011 amending Regulation (EC) No 1881/2006 as regards maximum levels for dioxins, dioxin-like PCBs and non dioxin-like PCBs in foodstuffs.
Oxidative stability in oils
It is important to evaluate the oxidative stability of the oils used in your NHP, as some oils degrade quickly when exposed to air. This can impact both product quality and shelf life. Oxidative stability testing is applicable to all oils that have a high degree of unsaturation.
Where oxidative stability tests are required by a pharmacopoeial monograph, use the acceptance criteria as per the monograph. Base any proposed alternative to pharmacopoeial limits on a scientific rationale supported by data.
Tests for peroxide value (PV) and anisidine value (AV), and the calculation of total oxidation value (TOTOX), should be according to the AOAC OMA, or other appropriate test methods such as USP General chapter <401> Fats and fixed oils.
Refer to table 10 for acceptance limits for oxidative stability parameters in marine oils for oral products.
| Parameter | Acceptance limit |
|---|---|
Acid valueFootnote 1 |
NMT 3.0 KOH/g NMT 45.0 KOH/g (for Krill oil and calcaneus oil) |
Peroxide value (PV) |
NMT 5.0 mEq active oxygen/Kg oil |
Anisidine value (AV) |
NMT 20.0 |
Total oxidation value (TOTOX)Footnote 2 |
NMT 26.0 |
|
|
These limits are appropriate for raw ingredients, but they may not be appropriate for a finished product when medicinal or non-medicinal ingredients could interfere with the testing. In such cases, you should:
- maintain scientific evidence (including a summary of the laboratory studies performed and data demonstrating the unsuccessful efforts) to show that you could not use a test method from a Schedule B listed pharmacopoeia or from another internationally recognized standard
- develop product-specific acceptance criteria, such as colour and odour, to ensure the stability of the oil in the finished product
For additional information, refer to section 3.3 of the FAO/WHO Codex Alimentarius standard for fish oils.
Antioxidants, when used as non-medicinal ingredients, may help preserve the product's integrity by protecting it from oxidative stress. Certain oil-based products (such as unsaturated oils, pegylated lipids, flavors and essential oils) may include antioxidants as stabilizers to slow down or prevent oxidative reactions that could otherwise damage the product (for example, cause rancidity). You should not add non-medicinal ingredients indiscriminately to your product formulation. Therefore, assess whether an alternative formulation without an antioxidant is viable.
Carefully consider and justify the use of antioxidants, notably in products used in pediatric and other vulnerable sub-populations. When justified, use antioxidants at the lowest feasible concentration levels, sufficient to provide the intended function. The performance-related properties of antioxidants should adhere to pharmacopoeial or internationally recognized standards, such as USP General chapter <1059> Excipient performance.
Where an antioxidant is added to a product, you should determine its antioxidant efficacy or oxidative protection by appropriate test methods for physical and chemical properties of the product. The results will establish the effectiveness of antioxidant protection on the product. You should also establish the oxidative stability index of your oil and fat-based products to determine the antioxidant efficacy, as per ISO 6886 Animal and vegetable fats and oils – Determination of oxidative stability (accelerated oxidation test) or another appropriate test method.
Test fats and oils in your product as per USP General chapter <401> Fats and fixed oils.
Antimicrobial preservatives
Antimicrobial preservatives prevent or slow the growth of microorganisms. NHP manufacturers may add them as non-medicinal ingredients to non-sterile dosage forms to protect the product from microbial contamination introduced during or after manufacturing. However, do not use antimicrobial preservatives as a substitute for GMP (refer to the NHP GMP guide).
Antimicrobial preservatives play a critical role in maintaining the sterility of multidose products (such as ophthalmic products) by preventing microbial contamination introduced through repeated use.
Where antimicrobial preservatives are added to a product, testing must demonstrate the effectiveness of antimicrobial protection on the product. Use test methods and acceptance criteria from a Schedule B listed pharmacopoeia, and perform them on the finished product. Refer to:
- USP General chapter <51> Antimicrobial effectiveness testing
- Ph.Eur. General chapter 5.1.3. Efficacy of antimicrobial preservation
You should perform antimicrobial preservative effectiveness testing during the product development phase to determine the minimal effective preservative level. Additionally, test a single commercial-scale stability or regular production batch of the product for antimicrobial preservative effectiveness at appropriate intervals using the method specified in the pharmacopoeia.
The concentration of the preservatives shown to be effective in the finished product should be:
- below a level that may be toxic to humans
- at the lowest concentration necessary to preserve the product
Carefully consider and justify the use of antimicrobial preservatives, notably in products used in pediatric and other vulnerable sub-populations.
Once you have determined the minimal effective preservative level, verify preservative content during finished product testing and in the stability program. At a minimum, test for preservative content at the initial time point and at the expiry date.
- Refer to the NHP GMP guide for more information on stability programs.
Radioactivity
You should perform radiochemical analysis to quantify the concentration of radionuclides in your raw materials if you suspect that they were exposed to radiation (for example, due to a previous industrial accident in the area or natural radionuclides in drinking water). A radiation exposure risk assessment may include evaluating the type of suspected radionuclide, its physical half-life, and the route of administration of the finished product.
For guidance on radiation risk assessments, refer to:
- International Atomic Energy Agency (IAEA)'s Radiation protection and safety of radiation sources: International basic safety standards
- Guidelines for Canadian drinking water quality: Radiological parameters
Note the following:
- as per the IAEA's general safety requirements, an individual's annual dose should generally not exceed a reference level of 1 millisievert (mSv)
- additional information on standards for risk assessment and risk management of radionuclides can be found in the relevant publications issued by the FAO/WHO Codex Alimentarius Commission
For guidance on the reference concentrations and methods of analyses for natural radionuclides (for example, Cesium 137, Iodine 131, Lead 210, Radium 226, Radium 228), refer to the:
- OJEU Commission implementing regulation (EU) 2020/1158 on the conditions governing imports of food and feed originating in third countries following the accident at the Chernobyl nuclear power station
- Guidelines for Canadian drinking water quality: Radiological parameters
- If you suspect that your raw material or finished product was exposed to radionuclides, maintain test records demonstrating that your product does not exceed the levels set out in these references or have a scientific rationale for why the testing is not needed.
Adulterants
Adulteration is to intentionally or unintentionally modify an NHP to contain substances that are not declared on its label. This includes pharmaceutical drugs, unexpected medicinal ingredients or harmful substances, as well as spoilage that make a product unfit for usage.
- For more information, refer to Adulteration of natural health products.
Adulterants in an NHP may be non-NHP substances (or the salts, isomers or salts of isomers) or other NHP substances (for example, undeclared serotonin in a melatonin product). In this guide, the term adulterant also refers to undeclared substances (such as drugs added to enhance perceived potency). Therefore, we distinguish the term adulterant from contaminant.
Adding adulterants to NHPs can lead to serious adverse health effects, including death.
Adulteration of a product can occur and present itself in many ways, including:
- lack of quality controls
- ineffective pest control measures
- deficiencies in premises or equipment cleaning
- use of poor quality raw materials or packaging materials
- adding melamine and bisphenol A (in milk-derived or dairy products
- adding prescription drug substances in sexual health, sleep aid, physical performance or weight management products
Adulterants also include levels of diethylene glycol (DEG) or ethylene glycol above 0.10% in raw materials, such as:
- DEG stearates
- glycerin
- hydrogenated starch hydrolysate
- maltitol solution
- non-crystalizing sorbitol solution
- polyethylene glycol
- polyethylene glycol 40 castor
- propylene glycol
- sorbitol sorbitan solution
Ensure your product is free from adulterants.
For additional information, refer to USP General chapter USP <2251> Screening for undeclared drugs and drug analogues.
Incidental impurities, related substances and process-related impurities
Processing or purification steps may introduce organic or inorganic impurities (such as intermediates, other isomers, racemic compounds, reagents, catalysts and degradation products) in a product. Control for this by:
- listing all known related impurities, unknown impurities, and total impurities in the raw material and finished product specifications
- include the associated tests methods and acceptance criteria
If the impurity profile of an isolated or synthetic medicinal ingredient changes due to a new source material or manufacturing process, you may need to submit revised FPS to Health Canada. These specifications should include the updated impurities, their acceptance criteria, and revised total impurity limits. The regulations prohibit the sale of any lot or batch affected by the change unless you have amended the PL accordingly.
- For post-licensing changes, modifications, and associated regulatory requirements to amend your PL, refer to the NHP MAP.
Certain substances may only develop during the manufacturing of an ingredient or the product itself. For example:
- Hydrogen cyanide:
- detected in ethanol (produced through the fermentation of feedstocks used in bioethanol production) from plants where cyanide is a naturally occurring metabolite due to presence of cyanogenic glycosides
- Nitrosamines:
- are impurities of concern
- certain synthetic processes and materials may produce unacceptable levels of potentially carcinogenic nitrosamine impurities in ingredients and products
- To learn more about nitrosamines, refer to Health Canada's guidance on Nitrosamine impurities in medications.
If you learn that a process or ingredient source could introduce a prohibited or restricted substance into your product, take immediate steps to address the impurity risk. This may involve selecting a different synthetic pathway for manufacturing the ingredient or sourcing materials that do not pose the same risk.
Allergens
Test methods for allergens must appear on the FPS to support label claims such as gluten-free or sulphite-free. Health Canada has established the following limits:
- 20 ppm for gluten in NHPs labelled "gluten-free"
- 10 ppm for sulphites in NHPs labelled "sulphite-free"
It is important to keep in mind that all allergen-free label claims, including those on homeopathic medicines, must be truthful.
You should disclose to consumers on the product label any ingredients, including cryoprotectants, with allergenic properties.
Packaging materials
Verify the suitability and compatibility of the container and closure system, and primary packaging materials that are in direct contact with the finished product. The packaging materials must not interact chemically with the NHP in a manner that negatively affects its quality. Keep the following in mind as you choose packaging materials for your NHP:
- avoid using certain packaging materials known to increase the risk of nitrosamine impurities in health products
- certain polymers, resin materials, aluminum containers or seals may release leachable substances that migrate into the finished product and pose health risks to consumers
- glass containers carry a risk of delamination from their primary contact surface, especially for liquid, solution and semisolid dosage forms
- for products intended for placement in a body cavity (for example, buccal pouches), you must maintain records of the composition of all packaging materials that come into direct contact with that cavity
- product container and closure systems must be compatible with the product specifications and recommended storage conditions. For example:
- you should use a clear, see-through container if you must test the product by visual inspection
- preservative-free multidose sterile products require a packaging system that reliably maintains sterility throughout the product's shelf life, storage and use
- packaging materials must be suitable when the storage conditions on the product label include statements such as:
- protect from light
- store in airtight container
- store in a light-resistant container
- store protected from light and moisture
- store in a well-closed container at room temperature
During product development, refer to the following on how to establish the suitability and compatibility of the containers and closure systems for your NHP:
- USP General chapter <659> Packaging and storage requirements
- USP General chapter <660> Containers – Glass
- USP General chapter <661> Plastic packaging systems and their materials of construction
- USP General chapter <1469> Nitrosamine impurities
- USP General chapter <1663> Assessment of extractables associated with pharmaceutical packaging/delivery systems
- USP General chapter <1664> Assessment of drug product leachable associated with pharmaceutical packaging/delivery systems
For additional information on packaging materials, refer to the Lists of acceptable polymers for use in food packaging applications.
Stability
A stability study aims to establish the shelf life of an NHP and evaluate how various factors affect its quality, safety and efficacy in its final container closure system. These factors include:
- storage conditions such as temperature, humidity, and light
- packaging materials used in the container closure system
- intrinsic factors such as ingredient interactions and degradation
- manufacturing changes including site, equipment, processes and batch size
Under a typical quality agreement, the PL holder communicates with the manufacturer and/or importer to complete stability studies that confirm the product remains stable until the end of its shelf life. These stability data are essential for establishing the NHP's expiry date, which the regulations require to appear on the product label.
Under paragraph 5(j) of the regulations, a PL applicant must attest that the product is manufactured, packaged, labelled, imported, distributed and stored in accordance with GMP. The PL holder is responsible for ensuring the product remains stable throughout its shelf life. This includes verifying that the manufacturer or importer has evidence of stability testing, as required by the regulations. Storing the finished product under appropriate conditions is also important to maintain the integrity of its packaging and label.
For additional information on stability programs and quality agreements, as well as stability testing, refer to the following respectively:
Stability specifications
The stability specifications for assay and limits may differ from the specifications established for the release of the finished product.
Product stability studies must include testing of the characteristics of the finished product that are susceptible to change during transportation (shipping) and storage and are likely to influence the product's quality, safety or efficacy.
Your stability testing should cover, as appropriate, the physical, chemical, biological and microbiological quality attributes using an appropriate stability-indicating test method. In a stability study, physical description tests should include an assessment of the product appearance (such as colour of a tablet or clarity of a solution) as well as the identification of the type of container and closure system.
Stability and product characteristics
Refer to table 1 for the universal tests and table 4 for the performance tests to determine the applicable stability tests for your product. Use the recommendations for stability tests (denoted by S) in those tables to choose parameters to include in the stability study.
Support the recommended storage conditions with appropriate stability data for each dosage form in each type of packaging of your product.
- Example: a product sold in granule dosage form may need to be stored in the fridge after first opening, but a similar product sold in capsule dosage form may not need to be stored in the fridge after first opening
You should have separate stability studies for the product in each packaging presentation.
- Example: tablets in blister packs versus tablets in plastic bottles
Also note the following product-specific points:
- if using preservatives, antimicrobial or antioxidant preservative content testing should be part of your stability study and performed at the time of release and at the end of the shelf life
- semi-solid dosage forms may be susceptible to phase separation
- document the physical appearance (for example, cracking of emulsion; granular, lumpy or crystal growth; change in viscosity) at the end of the shelf life
- probiotics, enzymes and peptides may be susceptible to significant losses of potency, physicochemical changes or degradation during manufacturing processes and storage
- stability studies must ensure that changes to the physical characteristics, purity, potency or enzymatic activity of these products are quantified appropriately
- accelerated stability studies may not be appropriate for enzymes due to denaturation of enzymes at elevated temperatures
- it may be necessary to select appropriate surrogates for total enzyme activity in multi-enzyme blends
- consider also "worst case" scenarios for time, temperature and pH
- 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
- conduct stability studies under refrigerated conditions (2-8°C) for products with recommend storage conditions of refrigerated temperatures
- you may need additional freeze-thaw stability studies for products that are susceptible to precipitation or changes in product quality at freezing temperatures
- for example, semi-solids, solutions, suspensions, solid dispersions
- when your product has specialized claims related to its use (for example, water/sweat resistant [40 minutes/80 minutes] sunscreen), conduct stability studies according to the recommended conditions of use to demonstrate product performance and dose delivery
In-use period for multiple-dose products
Consumers expect each dose of the product to contain the same amount of the medicinal ingredient(s), from the first dose to the last.
The quality of an NHP can change after opening its original container. During product development, you should assess the quality of multiple-dose products, such as ointments and drops, after repeated use.
If your sterile or non-sterile NHP states an in-use period on its label, such statements must be truthful and supported by appropriate stability study results. Conduct the stability study in a way that mimics consumer use of your product (for example, testing at or near the expiry date after the product has been opened, sampled and closed multiple times throughout the shelf life). This type of study can help determine the in-use shelf life and other storage limitations of your product.
In particular, you should have in-use stability data to support in-use periods for sterile multiple-dose products, such as ophthalmic products and products used in open wounds and burns.
The in-use stability studies on the multidose liquid sterile products in bottles should include studies of the product stored in different orientations (upright and either an inverted or a horizontal position). These studies evaluate container closure integrity to ensure product sterility during storage and use.