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Drugs and Health Products

Digestive Enzymes

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This monograph is intended to serve as a guide to industry for the preparation of Product Licence Applications (PLAs) and labels for natural health product market authorization. It is not intended to be a comprehensive review of the medicinal ingredients.

Notes
  • Any ingredient in Tables 1, 2 or 3 may be formulated as single ingredient products, or two or more ingredients may be combined to form multi-ingredient products. In addition, multi-ingredient products may be formulated from the one or more ingredients from these tables with ingredients from any one or more of the following single ingredient monographs: Alpha-amylase, alpha-galactosidase, Cellulase, Chymotrypsin, Fruit bromelain, Fungal protease, Lactase, Lipase, Pancreatic enzymes, Papain, Stem bromelain, Trypsin.
  • Text in parentheses is additional optional information which can be included on the PLA and product label at the applicant's discretion.
  • The solidus (/) indicates that the terms and/or the statements are synonymous. Either term or statement may be selected by the applicant.
  • The International Union of Biochemistry and Molecular Biology (IUBMB) enzyme nomenclature identification number (IUBMB No.) is not required on the PLA form but may be provided as additional information.

Date

August 20, 2012

Proper name(s), Common name(s), and Source material(s)

Table 1 Carbohydrases
IUBMB No. Proper name(s)Table 1 footnote 1 Common name(s)Table 1 Footnote 1 Source material(s)See Table 1 Footnote 2

Table 1 footnotes

Table 1 footnote 1

Return to Table 1 footnote 1 referrer

Proper and common names are supported by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (IUBMB) unless otherwise specified.

Table 1 footnote 2

Return to table 1 footnote 2 referrer

Source materials supported by FCC 8 unless otherwise specified

Table 1 footnote 3

Return to table 1 footnote 3 referrer

FCC 8

Table 1 footnote 4

Return to table 1 footnote 4 referrer

No reference available.

Table 1 footnote 5

Return to table 1 footnote 5 referrer

Justice Canada 2012

Table 1 footnote 6

Return to table 1 footnote 6 referrer

Enzyme Technical Association [no date].

3.2.1.6 3-(1→ 3;1→ 4)-beta-D-glucan 3(4)-glucanohydrolase beta-glucanase
beta-1,4-glucanase
Aspergillus niger
Trichoderma longibrachiatum
Trichoderma reesei
3.2.1.3 1,4-alpha-D-glucan glucohydrolase Glucoamylase
Amyloglucosidase
acid maltase
Aspergillus niger
Aspergillus oryzae
Rhizopus niveus
Rhizopus oryzae
3.2.1.55 alpha-L-arabinofuranoside arabinofuranohydrolase hemicellulaseSee Table 1 Footnote 2 Aspergillus niger
Aspergillus oryzaeSee Table 1 Footnote 3
Trichoderma longibrachiatum
Trichoderma reesei
3.2.1.78 1,4-beta-D-mannan mannanohydrolase
3.2.1.32 1,3-beta-D-xylan xylanohydrolase
3.2.1.99 1,5-alpha-L-arabinan arabinanohydrolase
3.2.1.26 beta-D-fructofuranoside fructohydrolase invertase
sucrase
Aspergillus nigerSee Table 1 Footnote 4
Saccharomyces cerevisiae
N/A diastase diastaseSee Table 1 Footnote 4 Aspergillus nigerSee Table 1 Footnote 4
Aspergillus oryzae
See Table 1 Footnote 4
N/A malt diastaseSee Table 1 Footnote 3 malt diastaseSee Table 1 Footnote 4
maltaseSee Table 1 Footnote 4
Hordeum vulgareSee Table 1 Footnote 4
3.2.1.15 poly(1,4-alpha-Dgalacturonide)glycanohydrolase pectinase Aspergillus niger
Aspergillus oryzaeSee Table 1 Footnote 5 See Table 1 Footnote 6
Trichoderma longibrachiatumSee Table 1 Footnote 4
Trichoderma reesei
See Table 1 Footnote 4
3.1.1.11 pectin pectylhydrolase
4.2.2.2 poly(1,4-alpha-Dgalacturonide)lyase
4.2.2.10 poly(methoxyl-Lgalacturonide)lyase
3.2.1.32 1,3-beta-D-xylan xylanohydrolase See Table 1 Footnote 5 xylanase
beta-1,3-xylanase
Trichoderma longibrachiatum See Table 1 Footnote 6
Trichoderma reesei
See Table 1 Footnote 6
3.2.1.8 1,4-beta-D-xylan xylanohydrolase See Table 1 Footnote 5 xylanase
beta-1,4-xylanase
Trichoderma reesei(taxonomical syn. Trichoderma longibrachiatum) See Table 1 Footnote 6
Table 2 Proteases
IUBMB No. Proper name(s)Table 2 footnote 1 Common name(s)Table 1 Footnote 1 Source material(s)See Table 2 Footnote 2

Table 2 footnotes

Table 2 footnote 1

Return to Table 2 footnote 1 referrer

Proper and common names are supported by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (IUBMB) unless otherwise specified

Table 2 footnote 2

Return to table 2 footnote 2 referrer

Source materials are supported by FCC 8 unless otherwise specified

Table 2 footnote 3

Return to table 2 footnote 3 referrer

Proper and common names are derived from the general class of proteases which are described in FCC 8

Table 2 footnote 4

Return to table 2 footnote 4 referrer

No reference available.

N/A bacterial protease See Table 2 Footnote 3 bacterial protease See Table 2 Footnote 3
neutral protease See Table 2 Footnote 4
Bacillus subtilis
3.4.23.1 pepsin A pepsin Sus scrofa, stomach
3.4.23.2 pepsin B pepsin Sus scrofa, stomach
Table 3 Other enzymes
IUBMB No. Proper name(s)Table3 footnote 1 Common name(s)Table3 footnote 1 Source material(s)Table 3 Footnote 2

Table 3 footnotes

Table 3 footnote 1

Return to Table 3 footnote 1 referrer

Proper and common names are supported by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (IUBMB)

Table 3 footnote 2

Return to table 3 footnote 2 referrer

Source materials supported by FCC 8 unless otherwise specified

Table 3 footnote 3

Return to table 3 footnote 3 referrer

No reference available.

1.11.1.6 hydrogen peroxide: hydrogen peroxide oxidoreductase catalase Aspergillus niger
Saccharomyces cerevisiae
Table3 footnote 3
3.1.3.2 orthophosphoric-mono ester phosphohydrolase phytaseTable3 footnote 3 Aspergillus niger
3.1.3.8 myo-inositol-hexakisphosphate-3-phosphohydrolase phytase
1-phytase
3-phytase
Aspergillus niger
3.1.3.26 myo-inositol-hexakisphosphate-4-phosphohydrolase phytase
4-phytase
6-phytase
Aspergillus niger

Route of administration

Oral

Dosage form(s)

  • The acceptable pharmaceutical dosage forms include, but are not limited to capsules, chewables (e.g. gummies, tablets), liquids, powders, strips or tablets.
  • This monograph is not intended to include foods or food-like dosage forms such as bars, chewing gums or beverages.

Use or Purpose

Statement(s) to the effect of

Digestive enzyme(s)

Dose(s)

Notes

  • Dose unit information must include the quantities of both the enzyme preparation and its enzymatic activity.
  • Enzyme activity units are defined in Appendix 1

Subpopulation(s)

Adults (≥ 19 years)

Quantity(ies)

Table 4 Carbohydrases
Enzyme Daily maximum (activity unit/day)

Table 4 footnotes

Table 4 footnote 1

For the FCC Glucoamylase Activity (Amylogucosidase Activity) assay, the Abbreviation “FCC AGU” will be recognized as acceptable.

Return to Table 4 footnote 1 referrer

diastase Not to exceed 6.0 x 103 FCC DP
beta-glucanase Not to exceed 210 FCC BGU
glucoamylase (amyloglucosidase) Not to exceed 300 FCC AGUSee Table 4 Footnote 1
hemicellulase Not to exceed 4.5 x 104 FCC HCU
invertase Not to exceed 3.0 x 103 FCC INVU
or
Not to exceed 4.2 x 103 FCC SU
malt diastase Not to exceed 6.0 x 103 FCC DP
pectinase Not to exceed 180 Endo-PG
xylanase Not to exceed 3.3 x 103 XU
Table 5 Proteases
Enzyme Daily maximum (activity unit/day)
bacterial protease Not to exceed 4.9 x 105 FCC PC
pepsin Not to exceed 1.9 x 106 FCC Pepsin
Table 6 Other enzymes
Enzyme Daily maximum (activity unit/day)
catalase Not to exceed 3.2 x 103 FCC Baker
phytase Not to exceed 75 FCC FTU

Directions for use

Statement(s) to the effect of

Take with food/meal

Duration of use

For prolonged use, consult a health care practitioner.

Risk information

Caution(s) and warning(s)

For all medicinal ingredients and ingredient combinations
If you are pregnant or breastfeeding, consult a health care practitioner prior to use

For products containing one or more carbohydrases
If you have diabetes, consult a health care practitioner prior to use.

For products containing one or more proteases
If you have gastrointestinal lesions/ulcers, are taking anticoagulant agents or anti-inflammatory agents, or are having surgery, consult a health care practitioner prior to use.

Contraindication(s)

No statement required

Known adverse reaction(s)

For all medicinal ingredients and ingredient combinations

Hypersensitivity/allergy has been known to occur; in such a case, discontinue use.

Non-medicinal ingredients

Must be chosen from the current NHPD Natural Health Products Ingredients Database and must meet the limitations outlined in the database.

Storage conditions

No statement is required.

Specifications

  • The finished product must comply with the minimum specifications outlined in the current NHPD Compendium of Monographs.
  • Details of the manufacturing of the enzyme at the raw material stage should include fermentation medium and the isolation process of the medicinal ingredient.
  • The specifications must include testing for enzymatic activity of the medicinal ingredient at appropriate stages of formulation and manufacturing using the assay outlined in the current Food Chemicals Codex (FCC):
    • beta-GLUCANASE ACTIVITY
    • GLUCOAMYLASE ACTIVITY (AMYLOGLUCOSIDASE ACTIVITY)
    • HEMICELLULASE ACTIVITY
    • INVERTASE SUMNER UNIT ACTIVITY
    • DIASTASE ACTIVITY
    • PROTEOLYTIC ACTIVITY, BATERIAL (PC)
    • PEPSIN ACTIVITY
    • CATALASE ACTIVITY
    • PHYTASE ACTIVITY
  • Testing for enzymatic activity of the medicinal ingredient must be done at the appropriate stages of formulation and manufacturing using the assay outlined in the Food Chemicals Codex (FCC 5) : INVERTASE ACTIVITY
  • Testing for Endo-Polygalacturonase Activity must be done at the appropriate stages of formulation and manufacturing as outlined in Blandino et al. (2002).
  • Testing for Xylanase Activity must be done at the appropriate stages of formulation and manufacturing as outlined in Ghose and Bisaria (1987).
  • Manufacturers are responsible for ensuring that activity assays that are used outside the conditions specified in the FCC have been sufficiently validated for their intended use in accordance with the requirements of good manufacturing practices.
  • Where published assays are not suitable for use, manufacturers will use due diligence to ensure that the enzymes remain active to the end of the shelf life indicated on the product label.

References cited

  • Blandino A, Iqbalsyah T, Pandiella SS, Cantero D, Webb C. Polygalacturonase production by Aspergillus awamori on wheat in solid-state fermentation. Applied Microbiology and Technology 2002;58:164-169.
  • Ghose TK, Bisaria VS. Measurement of hemicellulase activities part 1: Xylanases. Pure and Applied Chemistry 1987;59(12):1739-1752.
  • ETA: Enzyme Technical Association. Next link will take you to another Web site Enzyme Preparations used in Food Processing (as compiled by the ETA members) [Internet]. [Accessed 2012 March 21].
  • FCC 8: Food Chemicals Codex. Eighth edition. Rockville (MD): The United States Pharmacopeial Convention; 2012.
  • FCC 5: Food Chemical Codex, Fifth edition. Washington (DC): The National Academy of Sciences; 2001.
  • IUBMB 2012: International Union of Pure and Applied Chemistry and International Union of Biochemistry (IUPAC) and Molecular Biology (IUBMB).
  • IUPAC-IUBMB Next link will take you to another Web site Joint Commission on Biochemical Nomenclature (JCBN) [Internet]. [Accessed 2012 March 21].
  • Justice Canada. Next link will take you to another Web site Food and Drug Regulations (C.R.C., c. 870); B.16.100; Table 5 [Internet]. Ottawa (ON): Justice Canada. [Regulations are current to 2012-07-08 and last amended on 2012-06-01; Accessed 2012 August 20].

References reviewed

  • United States Food and Drug Administration. Next link will take you to another Web site GRAS Notice Inventory [Internet]. [Accessed 2012 March 21].
  • EFSA Panel on Biological Hazards. Scientific Opinion on the maintenance of the list of QPS microorganisms intentionally added to food or feed (2009 update). EFSA Journal 2009;7(12):1431.

Appendix 1 Definition of units

Table 7 Enzymatic Units
Enzymatic Unit Definition
Endo-Polygalacturonase (Endo-PG) One unit is defined as the amount of enzyme that reduces the viscosity of the pectin solution by 50% per minute under the conditions of the assay. Blandino et al. 2002)
FCC Bacterial Protease (FCC PC) One unit is defined as the quantity of enzyme that produces the equivalent of 1.5 μg/mL of L-tyrosine per minute under the conditions of the assay (FCC 8)
FCC Baker One unit is defined as the amount of catalase that will decompose 264 mg of hydrogen peroxide under the conditions of the assay (FCC 8).
FCC Beta-Glucanase (FCC BGU) One unit is defined as the quantity of enzyme that will liberate reducing sugar (as glucose equivalence) at a rate of 1 μmol per minute under the conditions of the assay (FCC 8)
FCC Degrees of Diastatic Power (FCC DP°) One unit is defined as amount of enzyme contained in 0.1 mL of a 5% solution of the sample enzyme preparation that will produce sufficient reducing sugars to reduce 5 mL of Fehling's solution when the sample is incubated with 100 mL of the substrate for 1 h at 20° (FCC 8)
FCC Glucoamylae Activity (Amyloglucosidase Activity) (FCC AGU ) One unit is defined as the amount of glucoamylase that will liberate 0.1 μmol per minute of p-nitrophenol from the PNPG Solution under the conditions of the assay (FCC 8)
FCC Hemicellulase (FCC HCU) One unit is defined as the activity that will produce a relative fluidity change of 1 over a period of 5 minute in a locust bean gum substrate under the conditions specified (FCC 8)
FCC Invertase (FCC INVU) One unit is defined as the quantity of enzyme that will hydrolyze 1.142 μmol of sucrose per minute under the conditions of the assay (FCC 5)
FCC Pepsin One unit is defined as the quantity of enzyme that digests 3000 times it weight of coagulated egg albumen under the conditions of the assay (FCC 8)
FCC Phytase (fytase) (FCC PU/ FCC FTU) One unit is defined as the amount of enzyme that liberates inorganic phosphate at 1 μmol/min from sodium phytate 0.0051 mol/L at 37.00 at pH 5.50 under the conditions of the test (FCC 8)
FCC Sumner (FCC SU) One unit is defined as that quantity of enzyme which, under the conditions of the assay, will convert 1 mg of sucrose to glucose and fructose in 5 minutes (FCC 8)
Xylanase Activity (XU) One unit is expressed as the number of μmoles of reducing sugars produced per minute of hydrolysis per ml of enzyme used; i.e., the number of international units per ml. (Ghose and Bisaria 1987)