quality requirements for finished natural health products natural health products directorate
TRANSCRIPT
Quality Requirements for Finished Natural Health Products
Natural Health Products Directorate
2
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?
3
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
4
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
5
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
6
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
7
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
8
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)
9
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
10
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)
11
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
12
Identity: Probiotics & Enzymes
• Probiotics: microscopic, phenotypic and genotypic methods
• Enzymes: gel electrophoresis, enzyme activity or substrate specificity assays, other verified methods
13
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)
14
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
15
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
16
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)
17
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
18
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
19
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
20
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.
21
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
22
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
23
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
24
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
25
Summary and Conclusions
• Relevant sections of NHP Regulations
• Safety Summary Report
• Evidence Summary Report
• Quality Summary Report
26
QUESTIONS AND ANSWERS
Please send further questions to the following:
Tel: 1-888-774-5555