Digestive Enzymes

What is it used for?

All products

• Digestive enzyme(s).

• Digestive aid.

Products containing proteases (Table 2)

• Helps digest proteins [Source note 1].

Products containing pancreatic enzymes

• Digestive aid to help decrease bloating after high caloric, high fat meals [Source note 2].

• Helps to decrease bloating after high caloric, high fat meals [Source note 3].

Products containing alpha-galactosidase

• Helps prevent gastrointestinal intolerance of oligosaccharides/fermentable carbohydrates [Source note 4].

• Helps reduce gas production/flatulence following a meal rich in oligosaccharides/fermentable carbohydrates (such as vegetables, pulses/legumes/beans and whole grains) [Source note 5].

Products containing bromelain

• Used in Herbal Medicine to help relieve minor pain, swelling and inflammation [Source note 6].

Products containing lactase

• Assist in the digestion of foods containing lactose (e.g., dairy foods, milk, etc.) [Source note 7].

• Helps prevent symptoms of lactose intolerance (including gas, bloating, cramping, and diarrhea) [Source note 8].

What this guide covers

• Any ingredient in Tables 1 to 3 may be formulated as single ingredient products, or two or more ingredients may be combined to form multi-ingredient products.

• The enzyme nomenclature identification number (IUBMB No.) is not required but may be provided as additional information on the cover letter.

• The

Rules when this reference is combined with other references (source review category II and III):

• Liquid and liquid-containing dosage forms (e.g., capsule, soft; spray) are not acceptable as source review category II when an enzyme is combined with non-enzymatic ingredients as this may impact the enzyme activity. These products may be submitted as a source review category III.

• However, this restriction does not apply if the enzymes are microencapsulated (i.e., Capsule, enteric-coated pellets and Tablet, enteric-coated granules).

Who does this guide cover?

Adults 18 years and older

How is it taken?

Oral

Which forms are covered?

this reference excludes foods or food-like dosage forms as indicated in the Compendium of references Guidance Document.

It includes the dosage forms listed below for pancreatic enzymes.

Pancreatic enzymes; pancreatic extract; pancreatin; pancrelipase:

The only acceptable dosage forms are: Capsule, enteric-coated; Capsule, soft, enteric-coated; Capsule, enteric-coated pellets; Granule enteric-coated; Tablet, enteric-coated; Tablets, enteric-coated granules.

Quantities

References: alpha-Amylase: FCC 2024; Glade et al. 2001; alpha-Galactosidase: FCC 2024; Di Stefano et al. 1999; Domínguez-Muñoz et al. 1997; Other enzymes: source authority 2012.

¹When multiple enzymes are combined, the total activity of each enzyme in the finished product must not exceed the maximum single and daily activities listed in Table 4. ²Other recognized enzymatic activity units may be listed on the product label as long as equivalent to the ones indicated on this reference and product documentation form. ³Pharmacopoeial units other than USP may be represented on the label as additional information. The following approximate conversion factors can be used to convert the activities of pancreatic enzymes (including pancreatic extract, pancreatin, pancrelipase) into USP units [Source note 10]:

• Amylase: 1 Ph. Eur. unit = 1 BP unit = 1 FIP unit ~ 4.15 USP units

• Lipase: 1 Ph. Eur. unit = 1 BP unit = 1 FIP unit ~ 1 USP unit

• Protease: 1 Ph. Eur. unit = 1 BP unit = 1 FIP unit ~ 62.5 USP units

Note: The quantity per dosage unit must be the enzymatic activity. The quantity of the enzymatic preparation in mg or ml may also be included as additional quantity.

How is it used?

All products; Optional for bromelain used for minor pain, swelling, and inflammation relief

Take with (or immediately before) a meal/food.¹

¹Note: This directions for use statement can be adjusted on the product label to provide clear instructions to consumers. If the product contains multiple digestive enzymes and associated claims, the directions should be linked to each claim and may be modified to include additional details (e.g., "For lactose intolerance, take with each meal containing lactose"). Additional information, such as “Do not exceed (X capsules per single dose and) Y capsules per day” may replace the dosing information when there is no established minimum dose associated with a claim.

Products containing pancreatic enzymes; pancreatic extract; pancreatin; pancrelipase

Use the smallest effective dose which controls symptoms [Source note 11].

Capsule, enteric-coated; Capsule, soft, enteric-coated; Capsule, enteric-coated pellets; Granule enteric-coated; Tablet, enteric-coated; Tablets, enteric-coated granules

Swallow whole. Do not crush or chew [Source note 12].

Capsule, enteric-coated pellets; Tablets, enteric-coated granules

(For individuals who experience difficulties swallowing) Capsules/Tablets may be opened and the content may be mixed with soft food or fluid. Use immediately after mixing [Source note 13].

How long is it used?

Products providing 60,000,000 FCC PU or less bromelain, per day

Ask a healthcare professional for use beyond 16 weeks [Source note 14].

Products providing more than 60,000,000 FCC PU bromelain, per day and products containing pancreatic enzymes; pancreatic extract; pancreatin; pancrelipase

Ask a healthcare professional for use beyond 4 weeks.

Products containing any other enzyme from Tables 1, 2 and 3

Ask a healthcare professional for use beyond 4 to 8 weeks¹.

¹Note: The term ‘prolonged use ’used in previous version of the reference has been further defined to avoid confusion.

Warnings and precautions

All products

Ask a healthcare professional before use if you are pregnant or breastfeeding.

Products containing one or more carbohydrases (Table 1); cellulase; lactase; pancreatic enzymes; pancreatic extract; pancreatin; pancrelipase

Ask a healthcare professional before use if you have diabetes.

Products containing one or more proteases (Table 2); chymotrypsin; bromelain; papain; trypsin

• Ask a healthcare professional before use if you have gastrointestinal lesions/ulcers or are having surgery.

• Ask a healthcare professional before use if you are taking blood thinners or anti-inflammatory medications.

Products containing papain

Ask a healthcare professional before use if you have an allergy to latex or fruits (such as avocado, banana, chestnut, passion fruit, fig, melon, mango, kiwi, pineapple, peach, and tomato) [Source note 15].

Products containing pancreatic enzymes; pancreatic extract; pancreatin; pancrelipase

Ask a healthcare professional before use if you have pancreatitis, pancreatic exocrine insufficiency or cystic fibrosis [Source note 16].

Prevention of gastrointestinal intolerance/Reduction of flatulence/Minor pain, swelling, and inflammation relief/Lactose digestion/Symptoms of lactose intolerance/Digestive aid/Decrease bloating

Ask a healthcare professional if symptoms persist or worsen.

When should it be avoided?

Products containing pancreatic enzymes; pancreatic extract; pancreatin; pancrelipase

Do not use if you are sensitive to pancreatic enzymes [Source note 17].

Products sourced from Sus scrofa pancreas

Do not use if you are sensitive to pork proteins [Source note 18].

Possible side effects

All products

Stop use if hypersensitivity/allergy occurs [Source note 19].

Products containing lactase

Stop use if gastrointestinal discomfort/disturbances occur [Source note 20].

Products containing pancreatic enzymes; pancreatic extract; pancreatin; pancrelipase

Stop use and ask a healthcare professional if nausea, vomiting, abdominal pain/epigastric pain, and/or heartburn occur [Source note 21].

Products containing bromelain

When using this product you may experience gastrointestinal discomfort/disturbances [Source note 22].

Storage

Must be established in accordance with the requirements described in the applicable product regulations.

Conditions for combined preparations

• For multi-ingredient products containing bromelain and papain, the maximum enzymatic activity from both enzymes combined cannot exceed the maximum proteolytic activity of 130,000,000 FCC PU per day and 45,000,000 FCC PU per single dose.

• For multi-ingredient products containing diastase and malt diastase, the maximum enzymatic activity from both enzymes combined cannot exceed 6,000 FCC DP per day.

Appendix I

Definitions of the activity units listed in 4:

• ALU: One lactase unit (ALU) is defined as the quantity of enzyme that will liberate o-nitrophenol at a rate of 1 μmol/minute under the conditions of the assay.

• BGU: One β-glucanase unit (BGU) is defined as the quantity of enzyme that will liberate reducing sugar (as glucose equivalence) at a rate of 1 μmol/minute under the conditions of the assay.

• BU: One Baker unit is defined as the amount of catalase that will decompose 264 mg of hydrogen peroxide under the conditions of the assay.

• ChyU: One USP chymotrypsin unit (ChyU) is defined as the activity causing a change in absorbance at the rate of 0.0075/minute under the conditions of the assay.

• CU: One cellulase unit (CU) is defined as the amount of activity that will produce a relative fluidity change of 1 in 5 minutes in a defined carboxymethyl cellulose substrate under the conditions of the assay.

• DP (or DDPU): One unit of diastase activity, expressed as degrees diastatic power (DP°), is defined as the 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 hour at 20°C.

• DU: One α-amylase dextrinizing unit (DU) is defined as the quantity of α-amylase that will dextrinize soluble starch in the presence of an excess of β-amylase at the rate of 1 g/hour at 30°C.

• endo-PG: One endo-polygalacturonase unit (endo-PG) is the amount of enzyme required to release 1 µmol/minute of galacturonic acid from polygalacturonic acid under the conditions of the assay.

• FTU: One phytase unit (FTU) is the amount of enzyme that liberates inorganic phosphate at 1 μmol/minute from 0.0051 mol/L of sodium phytate at 37ºC and pH 5.50 under the conditions of the test.

• GaIU: One galactosidase activity unit (GalU) is defined as the quantity of the enzyme that will liberate p-nitrophenol at the rate of 1 μmol/minute under the conditions of the assay.

• GU: One glucoamylase unit (GU) is defined as the amount of glucoamylase that will liberate 0.1 μmol/minute of p-nitrophenol from the p-nitrophenyl-α-d-glucopyranoside solution under the conditions of the assay.

• HCU: One hemicellulase unit (HCU) is defined as the activity that will produce a relative fluidity change of 1 over a period of 5 minutes in a locust bean gum substrate under the conditions specified.

• HUT: One hemoglobin units on the tyrosine basis (HUT) is defined as the amount of enzyme that produces, in 1 minute under the specified conditions, a hydrolysate whose absorbance at 275 nm is the same as that of a solution containing 1.10 μg/mL of tyrosine in 0.006 N hydrochloric acid.

• SAP: One spectrophotometric acid protease unit (SAP) is that activity that will liberate 1 μmol of tyrosine per minute under the conditions specified.

• INVU: One invertase unit (INVU) is defined as the amount of enzyme that hydrolyzes 1.0 microµmol of sucrose to invert sugar per minute at 55ºC and pH 4.5.

• LU: One lipase unit (LU) is defined as the quantity of enzyme that will liberate 1 μmol of butyric acid per minute under the conditions of the test.

• PC: One bacterial protease unit (PC) 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.

• PepU: One pepsin unit (PepU) is defined as the quantity of enzyme that produces the equivalent of 1 µmol of tyrosine per minute under the conditions of the assay.

• PU: One papain unit (PU) is defined as the quantity of enzyme that liberates the equivalent of 1 μg of tyrosine per hour under the conditions of the assay. One gelatin digestion unit (GDU) is approximately equivalent to 15,000 FCC papain units (1 GDU ≈ 15,000 FCC PU).

• SU: One Sumner unit (SU) is the quantity of enzyme which, under the conditions of the assay, will convert 1 mg of sucrose to glucose and fructose in 5 minutes.

• TrypU: One USP trypsin unit (TrypU) is the activity causing a change in the absorbance of 0.003 per minute under the conditions of the assay.

• XU: One xylanase unit (XU) is defined as the amount of enzyme that releases 1 µmol of reducing sugar, equivalent to xylose, per minute under specific conditions. These standard conditions include a pH of 5.3 and a temperature of 50°C.

Appendix II

Amylase, lipase and protease activity units per milligram of pancreas preparation according to the British, European and United States pharmacopoeias

¹Minimum amounts. ²Cross-referenced within the respective pharmacopoeias. The proper and common name ‘Pancreatic extract’ should be used for both BP 2025 and Ph.Eur 2025.