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 ReportTo 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 ContaminantsSchedule 1 List Item

Yeast and Mould Contamin.

Total Aerobic Count

E. coli Salmonella spp.

S. aureus Enterobacter spp.

P.

aeruginosa

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

< 1 x 104 for infusion, decoction, topical forms

<1 x 103 for other internal use

< 1 x 107 

for infusion, decoction, topical forms

<1 x 105 for other internal use

< 1 x 102

for infusion, decoction, topical dosage forms

Absent for other internal use

Absent < 1 x 104 for infusion, decoction, topical forms

<1 x 102 for other internal use

< 1 x 102

Applicable only to bacterial products e.g. cyanobacteria

N/A

Extracts or isolates

< 1 x 103 < 1 x 105 Absent Absent Absent < 1 x 102

Applicable only to bacteria-derived enzymes

Absent

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

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

Essential Fatty Acids

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

Synthetic duplicates

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

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

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

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 ContaminantsContaminants Tolerance LimitsArsenic < 0.14 g / kg b.w./day

Cadmium < 0.09 g / kg b.w./day

Lead < 0.29 g / kg b.w./day

Total mercury < 0.29 g / kg b.w./day

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

Solvent residues (when applicable) ICH limits

Impurities (when applicable) No undeclared impurity

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

Specific toxins (when applicable) Dioxins < 2 pg/kg/b.w./day

PCBs < 0.13 g/kg/b.w./day

Radioactivity (if suspected) 600 Becquerels / kg of substance

Antibacterial activity

(for microbial derived enzymes)

Absent

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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