Draft for consultation: Quality of natural health products guide: Appendices 4 and 5

Identity of each species

(Phenotyping tests)^{Footnote 15}

Biochemical testing of characteristics specific to the species that can include but are not limited to the following:

• Gram-staining
• API sugar fermentation
• enzymatic activity
• fatty acid profile
• proteome profile

Identity of each species and strain

(Genotyping tests)^{Footnote 15}

Species identification:

• Nucleic acid-based identification: PCR using published strain specific primers and conditions (for example, pharmacopoeial strain specific primers and conditions) (USP General chapter <64>Probiotics tests),or
• By comparison to identical and non-identical type strains obtained from an internationally recognized culture collection (for example, ATCC, NCTC) or sequence database (for example, NCBI). Genome sampling/sequencing through a method that is adequate for the species, demonstrating either:
  • A minimum homology of 98.65% to an identical type strain's 16S sequence, and below 98.65% to non-identical type strains. In cases in which the species has a very similar 16S sequence to phylogenetic neighbouring species, additional protein coding genes (for example, gyrB, rpoB, recA) and analysis should be used for species authentication, as can phylogenetic treeing (for example, using more than 30 house-keeping core genes)^{Footnote 1}, or
  • A minimum ANI of 95% or digital DNA-DNA hybridization (dDDH) of 70% to an identical type strain and below these amounts to non-identical type strains.^{Footnote 1}

Strain characterization:

Whole genome in vitro sampling/sequencing through a method that is adequate for the species, to allow independent confirmation of the strain designation (for example, NGS, RAPD-PCR, PFGE, ERIC-PCR, rep-PCR)

Virulence tests: AST

Antibiotic/antifungal resistance

• Broth microdilution or other equivalent non-clinical method. MIC below up-to-date species limits, as published by an internationally recognized panel (for example, EFSA, CLSI)
• Identification of antibiotic/antifungal resistance gene(s) using whole genome sequence analysis and up-to-date resistance databases (for example, CARD, ResFinder, AMRFinderPlus). When analysis suggests resistance to important antimicrobials as defined by the WHO, additional MIC testing is necessary to ensure susceptibility

Antibiotic/antifungal resistance transferability

For microorganisms with active antibiotic/antifungal resistance gene(s):

• In vitro conjugation experiments (such as solid or filter mating assays) assessing transferability of antibiotic/antifungal resistance
• Identification of mobile genetic elements (such as plasmids, genomics islands, integrons, transposons) in relation to the antibiotic/antifungal resistance gene(s) using assembled, whole genome sequence information

Virulence tests: Ingredient-specific test parameters (Virulence factor production)

(for example, factors involved in evasion, compliance, biofilm formation, invasion, and toxin production)

• Absence of the genetic elements responsible for the production of virulence factors characteristic to the species/genus.
• Whole genome sequence analysis against standards specific to the strain, species, or genus to identify the presence of known and potential virulence factor genes. Internationally recognized highly curated databases and genomic-scale analytical resources should be used (as well as use of other internationally recognized analytical tools that target horizontally acquired loci, mobilization structures, and associated content within respective genomes).

Toxigenic activity

(for example, endotoxin, exotoxin, hemolysin, other residual toxic component production)

• Confirmatory published in vitro method adequate for the species, or other internationally recognized methods (for example, Vero cell assay, hemolysis on blood agar).
• Absence of toxin production known to the species/genus (for example, enteric, emetic) and any other hemolytic activity known to the species.

Mycoplasma

• For products that, through their intended use, present a serious health risk3: absent in cell culture substrates

Physical description of the finished product

• General tests for physical description of the finished product (for example appearance, colour, form such as liquid, freeze dried powder), free from foreign matter (see identity section of this guide), and
• Specific description of products containing live microorganisms including names and strains designations

Performance tests

• See applicable performance tests as per table 4 for the dosage form

Chemical contaminants

(finished product or raw material stage)

• Elemental impurities, residual solvents or other chemical contaminants (such as toxins or drug residues), if suspected and applicable

Quantity

(Total viable cell count in CFU)

• Pharmacopoeial or internationally recognized method

• Conforms to 80% of labelled claim at the end of shelf life
• For products or ingredients that, through their intended use, present a serious health risk^{Footnote 3}: conforms to 100% of labelled claim at the end of shelf life

Water activity

• USP General chapter <922> Water activity, or other acceptable pharmacopoeial reference (such as Ph.Eur. 11.0 LBP4)

• Conforms to pharmacopoeial limits (required only for products or ingredients that, through their intended use, present a serious health risk^{Footnote 3})

Total aerobic plate count^{Footnote 5}

• Pharmacopoeial or internationally recognized method

• For products or ingredients that, through their intended use, present a serious health risk^{Footnote 3}:
  • Aqueous preparations and/or non-oral/non-rectal (USP General chapter <1111>Microbiological examination of nonsterile products: Acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use, Ph.Eur. 11.0 LBP^{Footnote 4}) ≤ 100 CFU/g or mL^{Footnote 6}
  • Oral products containing only yeast/mould (fungi) (USP General chapter <64>Probiotics tests) ≤ 1000 CFU/g or mL
  • All other products ≤ 1000 CFU/g or mL (Ph.Eur. 11.0 LBP4, USP General chapter <1111>Microbiological examination of nonsterile products: Acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use)^{Footnote 6 Footnote 7}
• All other products: ≤ 5000 CFU/g or mL^{Footnote 7 Footnote 8}

Total yeast and mould count (fungi)^{Footnote 9}

• Pharmacopoeial or internationally recognized method

• For products or ingredients that, through their intended use, present a serious health risk^{Footnote 3}: aqueous preparations and/or non-oral/non-rectal: ≤10 CFU/g or mL (USP General chapter <1111>Microbiological examination of nonsterile products: Acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use, Ph.Eur. 11.0 LBP^{Footnote 4})^{Footnote 10}
• All other products^{Footnote 7}: ≤100 CFU/g or mL (USP General chapter <64>Probiotics tests, USP <61> Microbiological examination of nonsterile products: Microbial enumeration tests)

Enterobacteriaceae andbile tolerant Gram-negative bacteria^{Footnote 11}

• Pharmacopoeial or internationally recognized method

• For products or ingredients for infants and that, through their intended use, present a serious health risk^{Footnote 3}: absent^{Footnote 7 Footnote 8}
• All other products: ≤ 100 CFU/g or mL

Salmonella spp.

• Pharmacopoeial or internationally recognized method
• Recommended: 25 g or 25 mL sample size, 60 sample units^{Footnote 7 Footnote 8}

• Absent^{Footnote 7} (USP General chapter <64>Probiotics tests)

Escherichia coli

• Pharmacopoeial or internationally recognized method

• Absent (USP General chapter <64> Probiotics tests)

Staphylococcus aureus

• Pharmacopoeial or internationally recognized method

• Absent^{Footnote 7} (USP General chapter <64>Probiotics tests)

Pseudomonas aeruginosa^{Footnote 10}

• Pharmacopoeial or internationally recognized method

• Absent (Ph.Eur. 11.0 LBP4, USP General chapter <64>Probiotics tests)

Bacillus cereus^{Footnote 12}

• Pharmacopoeial or internationally recognized method

• For products or ingredients used in infants and that, through their intended use, present a serious health risk^{Footnote 3}: absent (Ph.Eur. 11.0 LBP4)
• All other products: as required^{Footnote 7}

Listeria monocytogenes

• Pharmacopoeial or internationally recognized method
• Recommended: 25 g or 25 mL sample size, 10 sample units^{Footnote 7}

• For products used in pregnancy and in infants, and other products or ingredients that, through their intended use, present a serious health risk^{Footnote 3 Footnote 7}: absent (USP General chapter <64>Probiotics tests)
• All other products: as required^{Footnote 7}

Cronobacter sakazakii

(formerly Enterobacter sakazakii)

• Pharmacopoeial or an acceptable test method

• For products used in infants and other products or ingredients that, through their intended use, present a serious health risk^{Footnote 3 Footnote 7}: absent (USP General chapter <64>Probiotics tests)
• All other products: as required^{Footnote 7} (USP General chapter <64>Probiotics tests)

Clostridia spp.

• Pharmacopoeial or internationally recognized method
• Recommended: 2 g or 2 mL sample size (USP <62>)

• For products used in infants and other products or ingredients that, through their intended use, present a serious health risk^{Footnote 3}: absent (USP General chapter <64>Probiotics tests, USP General chapter <62>Microbiological examination of nonsterile products: Tests for specified microorganisms)
• All other products: as required (USP General chapter <64>Probiotics tests)

Candida albicans^{Footnote 13}

• Pharmacopoeial or internationally recognized method
• Recommended: 1 g or 1 mL sample size (USP <62>)

• Absent (Ph.Eur. 11.0 LBP4, USP General chapter <62>Microbiological examination of nonsterile products: Tests for specified microorganisms)

Endotoxins

• Pharmacopoeial or internationally recognized method

• For products that, through their intended use, present a serious health risk^{Footnote 3}: USP General chapter <85> Bacterial endotoxins test orICH guideline Q4B Annex 14: Bacterial endotoxins test general chapter

Antibiotic residues^{Footnote 14}

• Absent

Physical identity (physical description of the finished product)

For all products

Conforms to standard

Identification of medicinal ingredients

For all medicinal ingredients

Conforms to reference material

Live microorganisms (probiotics):

• Both genotyping and phenotyping tests are required^{Footnote 1}

Phenotyping

Conforms to the reference material^{Footnote 2}

Genotyping

For nucleic acid-based identification using PCR:

• conforms to strain specific primers and conditions

For genome sampling/sequencing through a method that is adequate for the species:

• minimum homology of 98.65% to an identical type strain's 16S sequence, and below 98.65% to non-identical ones, or
• a minimum ANI of 95% or dDDH of 70% to an identical type strain and below these amounts to non-identical type strains

Quantity

Most medicinal ingredients

Pharmacopoeial limits or, in their absence, 80% to 120% of labelled claim

Enzymes

80% to 150% of labelled claim

Vitamins, minerals

Pharmacopoeial limits or, in their absence, 80% to 120% of labelled claim

Live microorganisms (probiotics)

80% of labelled claim at the end of shelf life

For products or ingredients that, through their intended use, present a serious health risk^{Footnote 3}:

• conforms to 100% of labelled claim at the end of shelf life

Lutein

95% to 130% of labelled claim

Potency (for standardized extracts)

Most constituents

Pharmacopoeial limits or 80% to 120% of labelled claim

Enzymes (if quantity was declared by weight)

80% to 150% of labelled claim

Vitamins, minerals

Pharmacopoeial limits or, in their absence, 80% to 120% of labelled claim

Lutein

95% to 130% of labelled claim

Zeaxanthin

90% to 260% of labelled claim

Purity – Microbial

Microbial contaminants

Oral non-sterile products containing isolates, synthetic duplicates, vitamins, minerals, amino acids and essential fatty acids

Limits from USP General chapter <1111> Microbiological examination of nonsterile products, USP General chapter <2023> Microbiological attributes of nonsterile nutritional and dietary supplements, BP Appendix XVI D Microbiological quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use, or Ph.Eur. General chapter 5.1.4. Microbiological quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use^{Footnote 4}

Oral non-sterile products – plants, plant materials, algae, fungi and their extracts

Limits from USP General chapter <2023> Microbiological attributes of nonsterile nutritional and dietary supplements, BP Appendix XVI G Microbiological quality of herbal medicinal products for oral use and extracts used in their preparation, or Ph.Eur. General chapter 5.1.8. Microbiological quality of herbal medicinal products for oral use and extracts used in their preparation^{Footnote 4}

Non-oral non-sterile products

Limits from USP General chapter <1111> Microbiological examination of nonsterile products: Acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use, BP Appendix XVI D Quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use, or Ph.Eur. General chapter 5.1.4. Microbiological quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use^{Footnote 4}

Oral non-sterile products – Non-human animal material

Limits from USP General chapter <2023> Microbiological attributes of nonsterile nutritional and dietary supplements, BP Appendix XVI D Microbiological quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use, or Ph.Eur. 5.1.4. Microbiological quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use^{Footnote 4}

Non-oral non-sterile products – Non-human animal material

Limits from USP General chapter <1111> Microbiological examination of nonsterile products: Acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use, BP Appendix XVI D Microbiological quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use, or Ph.Eur. General chapter 5.1.4. Microbiological quality of herbal medicinal products for oral use and extracts used in their preparation^{Footnote 4}

Homeopathic medicines

Limits from USP General chapter <1111> Microbiological examination of nonsterile products: Acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use, BP Appendix XVI D Microbiological quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use, or Ph.Eur. General chapter 5.1.4. Microbiological quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use^{Footnote 4}

Multi-ingredient products containing plants and plant materials, live microorganisms, minerals or animal-derived ingredients

Microbiological tests for all markers for all ingredient types

The widest acceptance criteria for TAMC and TYMC may be used

Ph.Eur. General chapter 5.1.4. Microbiological quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use (for animal materials), USP General chapter <2023> Microbiological attributes of nonsterile nutritional and dietary supplements, and USP General chapter <1111> Microbiological examination of nonsterile products: Acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use

Sterile products

Limits from USP General chapter <71> Sterility tests, BP Appendix XVI A Test for sterility, or Ph.Eur. General chapter 2.6.1. Sterility^{Footnote 4}

Total aerobic plate count^{Footnote 5}

Products containing live microorganisms (probiotics) (see exceptions below)

For products or ingredients that, through their intended use, present a serious health risk^{Footnote 3}:

• Aqueous preparations and/or non-oral/non-rectal (USP General chapter <1111>Microbiological examination of nonsterile products: Acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use, Ph.Eur. 11.0 LBP^{Footnote 10}): ≤ 100 CFU/g or mL^{Footnote 6}
• Oral products containing only yeast/mould (fungi) (USP General chapter <64>Probiotics tests): ≤ 1000 CFU/g or mL
• All other products: ≤ 1000 CFU/g or mL (Ph.Eur. 11.0 LBP10, USP General chapter <1111>Microbiological examination of nonsterile products: Acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use)^{Footnote 6 Footnote 11}

All other products: ≤ 5000 CFU/g or mL^{Footnote 11 Footnote 13}

Total yeast and mould count^{Footnote 7}

Products containing live microorganisms (probiotics) (see exception below)

For products or ingredients that, through their intended use, present a serious health risk^{Footnote 3}:

• aqueous preparations and/or non-oral/non-rectal: ≤10 CFU/g or mL (USP General chapter <1111>Microbiological examination of nonsterile products: Acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use, Ph.Eur. 11.0 LBP10)^{Footnote 12}

All other products^{Footnote 11}: ≤ 100 CFU/g or mL (USP General chapter <64> Probiotic tests)

Salmonella spp.

Products containing live microorganisms (probiotics) (see exception below)

Absent^{Footnote 11} (USP General chapter <64>Probiotics tests)

Escherichia coli

Products containing live microorganisms (probiotics)

Absent (10 g or 10 mL)

Staphylococcus aureus

Products containing live microorganisms (probiotics)

Absent^{Footnote 11} (recommended 10 g or 10 mL)

Enterobacteriaceae and bile-tolerant gram-negative bacteria^{Footnote 8}

Products containing live microorganisms (probiotics) (see exception below)

For products or ingredients that, through their intended use, present a serious health risk^{Footnote 3}: absent^{Footnote 11 Footnote 13}

All other products: ≤ 100 CFU/g or mL

Exception: Products or ingredients containing live microorganisms (probiotics) that, through their intended use, present a serious health risk^{Footnote 3}

Absent (USP General chapter <64> Probiotics tests)

Pseudomonas aeruginosa

Vaginal and liquid preparation products containing live microorganisms (probiotics)

Absent (Ph.Eur. 11.0 LBP^{Footnote 10}, USP General chapter <64>Probiotics tests)

Bacillus cereus

Products or ingredients that, through their intended use, present a serious health risk^{Footnote 3} containing Bacillus spp. spores

For products or ingredients that, through their intended use, present a serious health risk^{Footnote 3}: absent (Ph.Eur. 11.0 LBP^{Footnote 10})

All other products: as required^{Footnote 11}

Listeria monocytogenes

Products containing live microorganisms (probiotics) and indicated for use during pregnancy, and in infants, or products or ingredients that, through their intended use, present a serious health risk^{Footnote 3}

For products used in pregnancy and infants, and other products or ingredients that, through their intended use, present a serious health risk^{Footnote 3 Footnote 11}: absent (USP General chapter <64>Probiotics tests)

All other products: as required^{Footnote 11}

Cronobacter sakazakii (formerly Enterobacter sakazakii)

Products containing live microorganisms (probiotics) and indicated for infant use or products or ingredients that, through their intended use, present a serious health risk^{Footnote 3}

For products used in infants and other products or ingredients that, through their intended use, present a serious health risk^{Footnote 3 Footnote 11}: absent (USP General chapter <64>Probiotics tests)

All other products: as required^{Footnote 11} (USP General chapter <64>Probiotics tests)

Clostridia spp.

Products containing live microorganisms (probiotics) and indicated for infant use or products or ingredients that, through their intended use, present a serious health risk^{Footnote 3}

For products used in infants and other products or ingredients that, through their intended use, present a serious health risk^{Footnote 3}: absent (USP General chapter <64>Probiotics tests, USP General chapter <62>Microbiological examination of nonsterile products: Tests for specified microorganisms)

All other products: as required (USP General chapter <64> Probiotics tests)

Candida albicans

Vaginal products containing live microorganisms (probiotics)

Absent (Ph.Eur. 11.0 LBP^{Footnote 10}, USP General chapter <62>Microbiological examination of nonsterile products: Tests for specified microorganisms)

Purity – Chemical

Total arsenic

All products (except topical)

< 0.214 µg/kg b.w./day

Topical

≤ 3.0 ppm for a daily dose of 10 g or less, PDE ≤ 30 µg/day

Organic arsenic

Only if total arsenic limit is exceeded

< 20.0 µg/kg b.w./day

Inorganic arsenic

Only if total arsenic limit is exceeded

< 0.214 µg/kg b.w./day

Cadmium

All products (except topical)

< 0.07 µg/kg b.w./day

Topical

≤ 2.0 ppm for a daily dose of 10 g or less, PDE ≤ 20 µg/day

Lead

All products (except topical)

< 5.0 µg/day

Topical

≤ 5.0 ppm for a daily dose of 10 g or less, PDE ≤ 50 µg/day

Total mercury

All products (except topical)

< 0.214 µg/kg b.w./day

Topical

< 3.0 ppm for a daily dose of 10 g or less, PDE ≤ 30 µg/day

Methylmercury^{Footnote 9}

Only if total mercury limit exceeds limit for methylmercury

< 0.029 µg/kg b.w./day

Chromium VI (when applicable)

All products (except topical)

< 0.29 µg/ kg b.w./day

Topical

≤ 1.0 ppm

Antimony (when applicable)

Topical

≤ 90 ppm for a daily dose of 10 g or less, PDE ≤ 900 µg/day

Solvent residues

Extracts, isolates, synthetic duplicates

ICH guideline Q3C or pharmacopoeial limits

Stability

For all products

Meets the requirements for stability as described in this guide and in the NHP GMP guide

Enumeration testing required for probiotics and activity testing required for enzymes

Products containing plants, plant material, fungi, algae, cyanobacteria, non-human animal material or their extracts

Pesticides

Limits from USP General chapter <561> Articles of botanical origin, USP General chapter <565> Botanical extracts, BP Appendix XI L Pesticide residues, or Ph.Eur. General chapter 2.8.13 Pesticide residues^{Footnote 1}; or MRLs established by the PRD

• Ashwagandha (Withania somnifera)
• Chinese salvia (Salvia miltiorrhiza) (also known as Danshen)
• Chinese skullcap (Scutellaria baicalensis) (also known as Radix Scutellariae)
• Peanuts (Arachis hypogaea)
• Radix saposhnikoviae (Saposhnikovia divaricate) (also known as Fang feng in Chinese)
• Rhodiola rosea (also known as Rhodiola and Roseroot)
• Tienchi ginseng (Panax notoginseng)
• other plants, plant materials, and their extracts when suspected

Aflatoxins

Aflatoxins B1+B2+G1+G2 < 20 µg/kg (ppb) of substance

Aflatoxin B1 <5 µg/kg (ppb) of substance

• Glycyrrhiza glabra
• Glycyrrhiza inflata
• Glycyrrhiza uralensis
• other plants, plant materials, and their extracts when suspected

Ochratoxin A

< 20 µg/kg (ppb) in liquorice root

< 80 µg/kg (ppb) in liquorice dry extract used for flavoring purposes

Plants, plant materials, algae and fungi, and their extracts when suspected

Fumonisins (FB1 + FB2 + FB3)

< 2 µg/kg b.w.

Cyanobacterial materials (blue-green algae, including Aphanizomenon flos-aquae)

Cyanobacterial toxins

≤ 0.02 µg MC-LR/kg b.w./day

Cannabis sativa (hemp products)

Total THC

≤ 10 ppm or a value lower than 10 ppm

Total CBD

Absent

Animal materials (for example, ovaries, hypothalamus, prostate gland, mammary gland, pituitary gland, adrenal gland and orchic gland)

Hormones (sex hormones that are regulated as prescription drugs under the Food and Drug Regulations, or as controlled substances as set out in Schedule IV of the Controlled Drugs and Substances Act)

Absent

Royal jelly and honey

Antibiotic residues (chloramphenicol, nitrofuran and their residues)

Absent

Ingredients sourced from an animal (when suspected)

• 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

Absent

Horsetail (Equisetum arvense)

Thiaminase activity (horsetail)

Free of thiaminase activity

Products containing extracts, isolates, synthetic duplicates

Related impurities

Product and/or process-related impurities, if applicable (for example, co-extracted substances, inactive isomers, degradation products, intermediate products, reagents, catalysts)

Pharmacopoeial limits when available or conforms to acceptable qualification of individual impurities^{Footnote 4 Footnote 5 Footnote 6}

Marine oils (for example, cod liver oil, fish oil, krill oil, seal oil, squid oil)

Sum of PCDFs, PCDDs and dioxin-like PCBs

≤ 10.0 pg TEQ TEF/g of oil

Sum of PCDFs and PCDDs

≤ 2.0 pg TEQ TEF/g of oil

PV

NMT 5.0 mEq active oxygen/kg of oil

Acid value

NMT 3.0 KOH/g

NMT 45.0 KOH/g (Krill oil and calcaneus oil)

AV

NMT 20.0 mEq/kg

TOTOX value

NMT 26.0

Oils containing non-marine unsaturated fatty acids

Oxidative stability:

Acid value, PV and/or AV as per pharmacopoeial monograph

Pharmacopoeial limits

Products that may have been in contact with radioactivity

Radioactivity (when suspected)

1 mSv/year

Glycerin (not including products where glycerin is only included as a capsule shell ingredient)

Diethylene glycol and related compounds

0.1% of any individual impurity, not more than 1.0% of total impurities

Label claims product is free of an allergen

Gluten

≤ 20 ppm

Sulphites

≤ 10 ppm

Other allergen

Absent

Products containing creatine monohydrate

Process-related impurities in the USP Creatine monograph

Pharmacopoeial limits

Nosodes (for homeopathic medicines containing nosodes)

Sterility technique in compliance with the sterility requirements in the HPUS or HAB

Complies with sterility requirements in the HPUS or HAB

Live microorganisms (probiotics)^{Footnote 3}

Antibiotic residues

Absent

Live microorganisms (probiotics)

Endotoxins

For products that, through their intended use, present a serious health risk^{Footnote 7}: Complies with USP General chapter <85> Bacterial endotoxins test or ICH guideline Q4B Annex 14: Bacterial endotoxins test general chapter

Products containing extracts, isolates, synthetic duplicates, vitamins, minerals, essential fatty acids, amino acids

Incidental impurities, related substances, process related impurities

Pharmacopoeial limits or absent

Ingredient- or product-specific

Adulterants (specify adulterant)

Pharmacopoeial limits if available^{Footnote 2}

Weight variation (WV), or Content uniformity (CU)

Discrete single-unit dosage forms, including:

• caplets
• lozenges
• chewable gels (commonly called gummies)
• hard- or soft-shell capsules
• plain coated, film coated or uncoated tablets

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

• USP General chapter <905> Uniformity of dosage unit
• USP General chapter <2091> Weight variation of dietary supplements
• Ph.Eur. General chapter 2.9.40. Uniformity of dosage units

Disintegration

Uncoated tablets

NMT 45 minutes

Immediate release

Plain coated tablets

NMT 60 minutes

Immediate release

Sublingual and buccal products such as tablets and films

Disintegrates in NMT 30 seconds

Claiming immediate release

Chewable gels (commonly called gummies)

NMT 15 minutes

Immediate release

Hard or soft shell capsules

NMT 30 minutes or conforms to pharmacopoeial limits

Immediate release

Sustained release – Buccal, sublingual or oromucosal products (such as cough lozenges)

Conforms to pharmacopoeial limits when available or in accordance with the intended release profile

Conforms to pharmacopoeial limits when available, or is in accordance with the intended release profile

Delayed release (enteric-coated dosage forms)

NLT 60 minutes in gastric fluid

NMT 60 minutes in simulated intestinal fluid

Two-stage testing (using different media in succession or in parallel, as appropriate)

Dissolution

Extended release

Meet individual product specifications for dissolution profile or conforms to pharmacopoeial limits

Multi-point sampling

Vitamin-mineral combination solid oral dosage forms (containing folic acid, vitamin A or water-soluble vitamins and minerals)

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

USP General Chapter <2040> Disintegration and dissolution of dietary supplements

Immediate release – Sublingual and buccal (such as tablets and films)

Conforms to pharmacopoeial limits when available

Dissolution test as applicable

Sustained release – Buccal, sublingual or oromucosal products (such as lozenges)

Conforms to pharmacopoeial limits when available

When no limits are available, pharmacopoeial limits should be determined in accordance with the intended rate of release

Dissolution test as applicable

Oromucosal products in pouches and chewing gums

Conforms to pharmacopoeial limits when available

Conforms to pharmacopoeial limits, or is in accordance with the intended release profile

Chewable gels (commonly called gummies)

Conforms to pharmacopoeial limits when available

Dissolution test as applicable

Dosage forms containing plants and plant materials and their extracts

More than 75% of the labelled content of the index or marker(s) or the extract (index or analytical) compound dissolved in 1 hour

When applicable

Rupture test

Soft shell capsules containing semisolid or liquid

NMT 15 minutes or conforms to pharmacopoeial limits

Immediate release

Antimicrobial content

Products containing preservative antimicrobials

Meets the content needed in accordance with the antimicrobial effectiveness test results

For example, potassium sorbate, sodium benzoate

Water activity^{Footnote 1}

Chewable gels (commonly called gummies)

NMT 0.75 or conforms to pharmacopoeial limits

Test for water activity as per the AOAC's Official Methods of Analysis, Official Method #978.18, or pharmacopoeial method

Live microorganisms (probiotics) that, through their intended use, present a serious health risk^{Footnote 2}

Conforms to pharmacopoeial limits

N/A

Dosage form-specific tests

Other dosage forms (see table 4 for common dosage forms)

Conforms to pharmacopoeial or internationally recognized limits when available

Refer to table 4