Quality Requirements for Finished Natural Health Products

Natural Health Products Directorate

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Mandate of NHPD

• Consumers need to know:–Is this product safe?–Does it do what it says it will do

on the label?–Is it of good quality?

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Assessing Product Quality• All finished Natural Health Products

must meet the minimum specification requirements for identity, purity, quantity, and potency (if applicable)

• Details are provided in the “Evidence for Quality of Finished Natural Health Products Guidance Document” at URL: http://www.hc-sc.gc.ca/hpfb-dgpsa/nhpd-dpsn/evidence_for_quality_nhp_e.html

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Relevant Sections of NHP Regulations• Should be read in conjunction with Part

3 of the NHP Regulations, i.e., Good Manufacturing Practices (GMP), and the GMP guidance document

• S. 5 (i) states that a copy of the NHP specifications must be submitted when applying for a product licence

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Relevant Sections of NHP Regulations• S. 44 states that the specifications shall

contain the following information:(a) Purity & its tolerances(b) Identity, quantity & their tolerances(c) Potency (if applicable) & its tolerances(d) Description of test methods used

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Relevant Sections of NHP Regulations• S. 98 deals with labelling & advertising

of an NHP in oral dosage form with respect to the site, rate, extent of release or availability of the medicinal ingredient

• S. 103 deals with disintegration times of an uncoated, plain coated tablet, enteric coating or similar coating and other related information including labelling & advertising

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Quality Summary Report

To be submitted with Product Licence Application:

• Description of manufacturing process• Sterilization or irradiation of NHP if

applicable• Analytical procedures• Justification of specifications including

exceptions to testing• Summary template for specifications

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Identity: Plant, Plant Material, Alga, Bacterium, Fungus, Non-Human Animal Material

• Macroscopic, e.g. comparison with text book and herbarium specimens

• Microscopic, e.g. special glandular hairs• Chemical fingerprinting, e.g. high

performance liquid chromatography (HPLC)

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Identity: Extract or Isolate of Plant, Plant Material, Alga, Bacterium, Fungus, Non-Human Animal Material

• Chemical fingerprinting of extracts and/or other chemical analytical methods for extract marker constituents and pure isolates– e.g. HPLC, gas chromatography with

mass spectrometry

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Identity: Vitamins, Amino Acids, Essential Fatty Acids, Synthetic Duplicates & Minerals

• Tests appropriate to the substance, that may include:– Physical description, molecular

weight, infrared absorption– Specific rotation (isomers)– Refractive index (liquid)

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Identity: Vitamins, Amino Acids, Essential Fatty Acids, Synthetic Duplicates & Minerals

– Pharmacopoeial methods e.g., United States Pharmacopeia (USP)

– Other verified methods, e.g. by the Association of Analytical Communities (AOAC) International

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Identity: Probiotics & Enzymes

• Probiotics: microscopic, phenotypic and genotypic methods

• Enzymes: gel electrophoresis, enzyme activity or substrate specificity assays, other verified methods

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Purity: Microbial Contaminants

• Yeast and mould contaminants• Total aerobic count• Escherichia coli• Salmonella spp.• Staphylococcus aureus• Enterobacter spp.• Pseudomonas aeruginosa (only in liquid

products with water or less than 50% ethanol)

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Tolerances Tolerances for Microbial Contaminantsfor Microbial Contaminants

N/A < 1 x 102 Absent Absent Absent N/A< 1 x 104 Probiotics

Absent N/A Absent Absent Absent < 3 x 103 < 3 x 102 Minerals

Absent N/A Absent Absent Absent < 3 x 103 < 3 x 102 Synthetic duplicates

Absent N/A Absent Absent Absent < 1 x 105< 1 x 103 Essential Fatty Acids

Absent N/A Absent Absent Absent < 1 x 105 < 1 x 103 Amino Acids

Absent N/A Absent Absent Absent < 3 x 103 < 3 x 102 Vitamins

Absent < 1 x 102

Applicable only to bacteria-derived enzymes

Absent Absent Absent < 1 x 105< 1 x 103 Extracts or isolates

N/A < 1 x 102

Applicable only to bacterial products e.g. cyanobacteria

< 1 x 104 for infusion, decoction, topical forms

<1 x 102 for other internal use

Absent < 1 x 102

for infusion, decoction, topical dosage forms

Absent for other internal use

< 1 x 107

for infusion, decoction, topical forms

<1 x 105 for other internal use

< 1 x 104 for infusion, decoction, topical forms

<1 x 103 for other internal use

Plant, alga, fungus, bacterium and non-human animal materials

P.

aeruginosa

Enterobacter spp.

S. aureus Salmonella spp.

E. coli Total Aerobic Count

Yeast and Mould Contamin.

Schedule 1 List Item

1 Units are in Colony Forming Units per gram or per milliliter; 2 Absent means < 1 x 101 CFU/g or 1 x 101 CFU/ml

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Microbial Reduction or Sterilization

• Irradiation may be used for microbial reduction or sterilizing procedure except for vitamins and probiotics

• Sterility test must be included in the specifications for all ophthalmic products and other sterile products

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Purity: Chemical Contaminants• Arsenic, cadmium, lead, total mercury• PCBs, PCDDs, PCDFs (e.g., fish oils)• Toxins (e.g., cyanobacterial)• Mycotoxins (e.g., aflatoxins), where

necessary• Pesticides (not for certified organic NHP)• Other impurities e.g., solvent residues,

radioactivity (if suspected)

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Tolerancess for Chemical ContaminantsTolerancess for Chemical Contaminants

AbsentAntibacterial activity

(for microbial derived enzymes)

600 Becquerels / kg of substance Radioactivity (if suspected)

Dioxins < 2 pg/kg/b.w./day

PCBs < 0.13 µg/kg/b.w./day

Specific toxins (when applicable)

Pharmacopoeial limits (USP, BP, Eur. Ph)Pesticides (when applicable)

No undeclared impurity Impurities (when applicable)

ICH limits Solvent residues (when applicable)

Aflatoxins: < 0.02 µg/kg of substance Mycotoxins (when applicable)

< 0.29 µg / kg b.w./day Total mercury

< 0.29 µg / kg b.w./day Lead

< 0.09 µg / kg b.w./dayCadmium

< 0.14 µg / kg b.w./day Arsenic

Tolerance LimitsContaminants

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Quantity & Potency• Quantitative tests: apply to all NHPs

– Amount of each medicinal ingredient per dosage unit, e.g. 500 mg vitamin C per tablet

• Potency tests: apply to standardized NHPs, e.g. herbs, extracts, isolates, enzymes, essential fatty acids, vitamins– Percentage of an identity marker compound, e.g.

1.5% echinacoside in Echinacea angustifolia root– Percentage of an active ingredient in extract, e.g.

7% GLA in evening primrose oil– Units of activity of vitamin, e.g. 200 mg of d-alpha-

tocopheryl acetate providing 272 IU Vitamin E

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Tolerances for Quantity/Potency

• 80 to 120% of label claim for most NHPs• 80 to 150% of label claim for enzymes• 80 to 300% of label claim for probiotics• Established standards for vitamins,

minerals, amino acids & synthetic duplicates e.g. USP

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Standardization

• The preparation of a consistent product from batch to batch using a master formula that specifies standard operating procedures, materials and manufacturing steps such the extraction ratio and solvent composition.

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Standardization• Acceptable methods include mixing

batches of raw material (best practice), normalization by adjusting the extraction process or amount of excipients, and pharmacological standardization with a bioassay

• Spiking with an isolate or synthetic substance gives a product that is fortified/enriched but not standardized

• Provide rationale with respect to standardization and methods used

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Manufacturing Information• Required for all non-compendial

applications except:– Traditional methods of preparation

(e.g. powdered herb, tea, tincture)– Vitamins & minerals– Item 1 of Schedule 1: plant or plant

material, alga, bacterium, fungus or non-human animal material

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Type of Manufacturing Information• A flow diagram including a description of:

– Raw materials, solvents, catalysts, reagents

– Yield ranges• The description should reflect:

– Representative batch scale for commercial production

– Critical steps, process controls, equipment and operating conditions such as temperature, pressure, pH and time

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Other Tests

• Disintegration time test is required• Tests below are not required but

recommended for certain NHPs:– Dissolution– Leak rate and leachability– Uniformity of dosage units– Water (moisture) content

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Summary and Conclusions

• Relevant sections of NHP Regulations• Safety Summary Report• Evidence Summary Report• Quality Summary Report

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QUESTIONS AND ANSWERS

Please send further questions to the following:

nhpd_dpsn@hc-sc.gc.ca

Tel: 1-888-774-5555