Transcript Standards of Evidence

Quality Requirements for
Finished Natural Health Products
Natural Health Products Directorate
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/hpfbdgpsa/nhpddpsn/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, NonHuman 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
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•
•
•
•
•
•
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 for Microbial Contaminants
Schedule 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 nonhuman
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
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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
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
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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 Contaminants
Contaminants
Tolerance Limits
Arsenic
< 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-alphatocopheryl acetate providing 272 IU Vitamin E
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Tolerances for Quantity/Potency
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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 23
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
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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:
[email protected]
Tel: 1-888-774-5555
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