Probiotics

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Date: February 11, 2009

Background:

• This monograph is intended to serve as a guide to industry for the preparation of Product Licence Applications (PLAs) for natural health product (NHP) market authorization of probiotics. It is not intended to be a comprehensive review of all probiotic organisms and possible health claims associated with them.
• For the purpose of this monograph, probiotics are defined as "live microorganisms which when administered in adequate amounts confer a health benefit to the host" (Food and Agriculture Organization of the United Nations (FAO) and World Health Organization (WHO) 2006). One means through which probiotics might confer a health benefit in humans is through benefiting the microbiota indigenous to humans as described in the Natural Health Products Regulations (NHPR) (Justice Canada 2008a).
• PLAs for probiotic products that contain one or more of the bacterial or yeast species listed in the Proper and common name(s) section and meet the recommended conditions of use (e.g. use or purpose, route of administration, dose, etc.) set out in this monograph, can be submitted for NHP market authorization through the Natural Health Products Directorate's (NHPD) compendial application stream. PLAs for products that contain bacterial or yeast species not contained in the Proper and common name(s) section and/or do not meet the recommended conditions of use set out in this monograph can be submitted for NHP market authorization outside of the NHPD's compendial stream (when accompanied by adequate supporting evidence as per Section 5 of the NHPR) (Justice Canada 2008a). Detailed information on safety and efficacy requirements for non-compendial probiotic PLAs can be found in the NHPD's Evidence for Safety and Efficacy of Finished Natural Health Products guidance document (Health Canada 2006).
• This monograph is not intended to include NHPs in food formats such as beverages, cheeses or yogurts. PLAs for NHPs in food formats can be submitted for market authorization outside of the NHPD's compendial application stream (when accompanied by adequate supporting evidence as per Section 5 of the NHPR) (Justice Canada 2008a).
• Guidance regarding the use of probiotic health claims for foods (e.g. yogurt) is available in Health Canada's "The Use of Probiotic Microorganisms in Food" guidance document.
• This monograph does not cover probiotics containing bacteria or fungi created by recombinant DNA procedures as these are classified as biologics and are subject to the Food and Drug Regulations (Justice Canada 2008b), in accordance with Schedule 2 to the NHPR (Justice Canada 2008a) and Schedule D to the Food and Drugs Act (Justice Canada 2008c).

Proper and common name(s):^{1, 2}

• Bifidobacterium adolescentis Reuter
• Bifidobacterium animalis subsp. animalis (Mitsuoka) Scardovi and Trovatelli
• Bifidobacterium animalis subsp. lactis synonym: B. lactis Meile et al.
• Bifidobacterium bifidum (Tissier) Orla-Jensen
• Bifidobacterium breve Reuter
• Bifidobacterium infantis Reuter
• Bifidobacterium longum Reuter
• Lactobacillus acidophilus (Moro) Hansen and Mocquot
• Lactobacillus amylovorus Nakamura³
• Lactobacillus casei (Orla-Jensen) Hansen and Lessel
• Lactobacillus fermentum Beijerinck
• Lactobacillus gasseri Lauer and Kandler
• Lactobacillus johnsonii Fujisawa et al.
• Lactobacillus paracasei Collins et al.
• Lactobacillus plantarum (Orla-Jensen) Bergey et al.
• Lactobacillus reuteri Kandler et al.³
• Lactobacillus rhamnosus (Hansen) Collins et al.
• Lactobacillus salivarius Rogosa
• Saccharomyces boulardii Seguela, Bastide & Massot³

Source material(s):

Identity:

The NHPD defines probiotic source material as the strain identifier of the bacterial or yeast species (Health Canada 2006). Product licence applicants must identify the strain of each bacterial or yeast species in their product in both the PLA and on the product label.

As strain identity is necessary for post-market surveillance, product licence applicants must determine the strain of each bacterial or yeast species in their product unambiguously (e.g. by a combination of genotypic and phenotypic methods):

• Examples of genotypic methods include, but are not limited to, the following: Pulsed Field Gel Electrophoresis of the DNA sequence encoding 16S rRNA for Lactobacillus spp. or the DNA sequence encoding Heat Shock Protein HSP 60 for Bifidobacterium spp., polymerase chain reaction-based analyses, DNA-DNA hybridization (Holzapfel et al. 2001; Tannock 1999; Klein et al. 1998);
• Examples of phenotypic methods include, but are not limited to, the following: patterns generated from the fermentation of a range of sugars, final fermentation products obtained from glucose utilization (Holzapfel et al. 2001; Tannock 1999; Klein et al. 1998);
• All strains should be deposited in an internationally recognized culture collection (e.g. American Type Culture Collection) (FAO and WHO 2006; Salminen et al. 1998).

Probiotic activity:

Product licence applicants attesting to this monograph are not to submit the following data with their PLA forms. It is to be submitted to the NHPD upon request only (either directly or by authorized citation of an approved Master File).

Since some strains of bacterial or yeast species listed in this monograph do not have probiotic activity (either at all or under certain conditions of use), applicants attesting to this monograph must have data available to support the following criteria for the strain or strains that are identified as medicinal ingredients in their product (FAO and WHO 2006):

• In vitro data demonstrating the strain's resistance to gastric acid;
• In vitro data demonstrating the strain's resistance to bile acid;
• In vitro data demonstrating the strain's ability to hydrolyze bile salts;
• In vitro data demonstrating the strain's adherence to mucus and/or human epithelial cells;
• In vitro data determining the strain's antibiotic resistance pattern;
• In vitro data determining the strain's D-lactate production;
• Evidence from tests or scientific literature that the strain is not a significant risk with regard to transferable antibiotic resistance or other opportunistic virulence properties; and
• Evidence to support that the strain is safe for use in humans and can provide one or more of the health benefits in healthy or non-healthy humans listed in the Use or Purposesection (Note: evidence in non-healthy humans is acceptable only when the product indicates a specific use or purpose for a non-healthy population, e.g. patients with diarrhoea).

Alternatively, the applicant may have evidence available demonstrating that the strain is identical to a strain that meets all of the above criteria.

Route(s) of administration: Oral

Dosage form(s): Those pharmaceutical dosage forms suited to oral administration, including but not limited to chewable tablets, caplets, capsules, strips, lozenges, powders or liquids where the dose is measured in drops, teaspoons, or tablespoons are acceptable. This monograph is not intended to include foods or food-like dosage forms such as beverages, bars, yogurts or chewing gums. Further information regarding the use of probiotic health claims for foods is available in Health Canada's "The Use of Probiotic Microorganisms in Food" guidance document.

Use(s) or Purpose(s):

General:

The following general use or purpose statements can be used in reference to any single bacterial or yeast species or combination of bacterial and yeast species listed in the Proper and common name(s)section, provided that the information requirements on activity and identity listed under the Source material(s) section above have been satisfied. However, in order to state one of the first four use or purpose statements listed below, products must contain at least one bacterial species derived from the human intestinal microflora. See footnote 3 listed in the Proper and common name(s)section for species not derived from human intestinal microflora.

Statement(s) to the effect of:

• Probiotic that forms part of a natural healthy gut flora (Tappenden and Deutsch 2007; Reid et al. 2003; Isolauri 2001; Lu and Walker 2001; Saavedra 2001)
• Provides live microorganisms that form part of a natural healthy gut flora (Tappenden and Deutsch 2007; Reid et al. 2003; Isolauri 2001; Lu and Walker 2001; Saavedra 2001).
• Probiotic that contributes to a natural healthy gut flora (Tappenden and Deutsch 2007; Reid et al. 2003; Isolauri 2001; Lu and Walker 2001; Saavedra 2001)
• Provides live microorganisms that contribute to a natural healthy gut flora (Tappenden and Deutsch 2007; Reid et al. 2003; Isolauri 2001; Lu and Walker 2001; Saavedra 2001).
• Probiotic to benefit health and/or to confer a health benefit (Gill and Prasad 2008; Othman et al. 2008; Lenoir-Wijnkoop et al. 2007; O'Hara and Shanahan 2007; FAO and WHO 2006; Picard et al. 2005; Reid et al. 2003; Isolauri 2001; Saavedra 2001)
• Provides live microorganisms to benefit health and/or to confer a health benefit (Gill and Prasad 2008; Othman et al. 2008; Lenoir-Wijnkoop et al. 2007; O'Hara and Shanahan 2007; FAO and WHO 2006; Picard et al. 2005; Reid et al. 2003; Isolauri 2001; Saavedra 2001).

Specific:

In order to use a specific use or purpose statement, products must meet the minimum monograph dose for the species and strains listed below. One or more specific use or purpose statements can be used, as applicable.

Statement(s) to the effect of:

For Lactobacillus johnsonii La1 (synonym: L. johnsonii Lj1 (Reid 1999; Sanders 1999)):

• An adjunct to physician-supervised antibiotic therapy in patients with Helicobacter pylori infections (Cruchet et al. 2003; Pantoflickova et al. 2003; Felley et al. 2001)

For Lactobacillus rhamnosus GG:

• Helps to manage acute infectious diarrhoea (Canani et al. 2007; Guandalini et al. 2000; Guarino et al. 1997).
• Helps to manage antibiotic-associated diarrhoea (Cremonini et al. 2002; Armuzzi et al. 2001; Vanderhoof 1999).
• Helps to reduce the risk of antibiotic-associated diarrhoea (Cremonini et al. 2002; Armuzzi et al. 2001; Vanderhoof 1999).

For Saccharomyces boulardii:

• Helps to reduce the risk of antibiotic-associated diarrhoea (Cremonini et al. 2002; Armuzzi et al. 2001; Vanderhoof 1999).

Dose(s):

Subpopulation:

• Adults, adolescents, and children ≥ 1 year old

Quantity:

For general use or purpose statements:

• 1.0 x 10⁷ to 1.0 x 10¹¹ colony forming units (cfu) from one or more of the bacterial or yeast strains contained in this monograph, per day (Gill and Prasad 2008; Lenoir-Wijnkoop et al. 2007; Hawrelek 2006; Picard et al. 2005; Reid et al. 2003)

For patients with H. pylori infections:

• 1.25 x 10⁸ to 3.6 x 10⁹ cfu L. johnsonii Lj1, per day (Pantoflickova et al. 2003; Felley et al. 2001)

For management of acute infectious diarrhoea:

• 6.0 x 10⁹ to 1.2 x 10¹⁰ cfu L. rhamnosus GG, per day (Canani et al. 2007; Guarino et al. 1997)

For management of antibiotic-associated diarrhoea:

• 1.0 x 10¹⁰ to 2.0 x 10¹⁰ cfu L. rhamnosus GG, per day (Cremonini et al. 2002; Armuzzi et al. 2001; Vanderhoof 1999)

For risk reduction of antibiotic-associated diarrhoea:

• 1.0 x 10¹⁰ to 2.0 x 10¹⁰ cfu L. rhamnosus GG, per day (Cremonini et al. 2002; Armuzzi et al. 2001; Vanderhoof 1999)
• 1.0 x 10¹⁰ to 3.0 x 10¹⁰ cfu S boulardii, per day (Can et al. 2006; Kotowska et al. 2005; Cremonini et al. 2002; McFarland et al. 1995)

Duration of use: No statement required.

Risk information: Statement(s) to the effect of:

Caution(s) and warning(s):

• Discontinue use and consult a health care practitioner if symptoms of digestive upset (e.g. diarrhoea) occur, worsen, or persist beyond 3 days (WHO 2005; Berardi et al. 2002).

Contraindication(s):

• Do not use if you are experiencing nausea, fever, vomiting, bloody diarrhoea or severe abdominal pain (WHO 2005; Berardi et al. 2002; Canadian Pharmacists Association (CPA) 2002).
• Do not use if you have an immune-compromised condition (e.g. AIDS, lymphoma, patients undergoing long-term corticosteroid treatment) (Cukovic-Cavka et al. 2006; Ledoux et al. 2006; Riquelme et al. 2003; Lherm et al. 2002).

Known adverse reaction(s):

• No statement required.

Non-medicinal ingredients:

• Must be chosen from the current NHPD Natural Health Products Ingredients Database and must meet the limitations outlined in the database.
• Fermentable carbohydrates (e.g. transgalactooligosaccharides, lactulose and inulin-type fructans such as inulin and oligofructose) are acceptable non-medicinal ingredients.
• Lactobacillus delbrueckii (Leichmann) Beijerinck subsp. bulgaricus (Orla-Jensen) Weiss et al. (synonym: Lactobacillus bulgaricus (Orla-Jensen) Rogosa and Jensen), Lactobacillus helveticus (Orla-Jensen) Bergey et al. and Streptococcus thermophilus Orla-Jensen (synonym: Streptococcus salivarius Andrewes and Horder subsp. thermophilus comb. nov.) (Callanan et al. 2007; Senok et al. 2005) are acceptable non-medicinal ingredients.

Specifications:

• Must comply with the minimum specifications outlined in the current NHPD Compendium of Monographs.
• In addition to the requirements in the Compendium of Monographs, finished products must adhere to the following additional quality requirements:
  1. The identity of species and strain must be confirmed by both genotypic and phenotypic characterization at the master cell bank and/or the raw material and/or the finished product stage; and
  2. The quantity and dose frequency cited on the PLA and product label must reflect the total number of viable organisms, as measured by cfu, to which a consumer will be exposed within the shelf life period.
• Upon request only, product licence applicants will be required to submit the following information to the NHPD:
  1. Information on purity including details of the fermentation process such as culture medium(s), pH, temperature, isolation technique etc.;
  2. Appropriate finished product specifications including identity, purity and quantity along with corresponding tolerances and physicochemical tests (pH, specific gravity, viscosity etc.) appropriate to the dosage form; and
  3. Information on the source and history of the microorganism, confirmation of identity of the species, strain, etc.

References cited:

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Callanan M, Kaleta P, O'Callaghan J, O'Sullivan O, Jordan K, McAuliffe O, Sangrador-Vegas A, Slattery L, Fitzgerald GF, Beresford T, Ross RP. Genome sequence of Lactobacillus helveticus, an organism distinguished by selective gene loss and insertion sequence element expansion. Journal of Bacteriology 190(2):727-735.

Can M, Beşirbellioglu BA, Avci IY, Beker CM, Pahsa A. 2006. Prophylactic Saccharomyces boulardii in the prevention of antibiotic-associated diarrhea: a prospective study. Medical Medical Science Monitor: International Medical Journal of Experimental and Clinical Research 12(4):PI19-122.

Canani RB, Cirillo P, Terrin G, Cesarano L, Spagnuolo MI, De Vincenzo A, Albano F, Passariello A, De Marco G, Manguso F, Guarino A. 2007. Probiotics for treatment of acute diarrhoea in children: randomised clinical trial of five different preparations. British Medical Journal 335(7615):340.

CPA 2002: Canadian Pharmacists Association. 2002. Patient Self-Care: Helping Patients Make Therapeutic Choices. Ottawa (ON): Canadian Pharmacists Association.

Cremonini F, Di Caro S, Covino M, Armuzzi A, Gabrielli M, Santarelli L, Nista EC, Cammarota G, Gasbarrini G, Gasbarrini A. 2002. Effect of different probiotic preparations on anti-Helicobacter pylori therapy-related side effects: a parallel group, triple blind, placebo-controlled study. The American Journal of Gastroenterology 97(11):2744-2749.

Cruchet S, Obregon MC, Salazar G, Diaz E, Gotteland M. 2003. Effect of the ingestion of a dietary product containing Lactobacillus johnsonii La1 on helicobacter pylori colonization in children. Nutrition 19(9):716-721.

Cukovic-Cavka, Likic R, Francetic I, Rustemovic N, Opacic M, Vucelic B. 2006. Lactobacillus acidophilus as a cause of liver abscess in a NOD2/CARD15-positive patient with Crohn's disease. Digestion. 73(2-3):107-110.

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FAO and WHO 2006: Food and Agriculture Organization of the United Nations and World Health Organization. Probiotics in food: Health and nutritional properties and guidelines for evaluation. FAO Food and Nutrition Paper 85 [online]. Rome (I): Food and Agriculture Organization of the United Nations and World Health Organization. [Accessed 2008 May 28]. Available from: ftp://ftp.fao.org/docrep/fao/009/a0512e/a0512e00.pdf.

Felley CP, Corthésy-Theulaz I, Rivero JL, Sipponen P, Kaufmann M, Bauerfeind P, Wiesel PH, Brassart D, Pfeifer A, Blum AL, Michetti P. 2001. Favourable effect of an acidified milk (LC-1) on Helicobacter pylori gastritis in man. European Journal of Gastroenterology and Hepatology 13(1):25-29.

Gill H, Prasad J. 2008. Probiotics, immunomodulation, and health benefits. Advances in Experimental Medicine and Biology 606:423-454.

Gilliland SE. 2001. Technological & Commercial Applications of Lactic Acid Bacteria; Health & Nutritional Benefits in Dairy Products [online]. Background paper for the Joint FAO/WHO Expert Consultation on Evaluation of Health and Nutritional Properties of Probiotics in Food Including Powder Milk with Live Lactic Acid Bacteria. Rome (I): Food and Agriculture Organization of the United Nations (FAO). [Accessed 2008 May 28]. Available from: ftp://ftp.fao.org/es/esn/food/Gilli.pdf

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Guarino A, Canani RB, Spagnuolo MI, Albano F, Di Benedetto L. 1997. Oral bacterial therapy reduces the duration of symptoms and of viral excretion in children with mild diarrhea. Journal of Pediatric Gastroenterology and Nutrition 25(5):516-519.

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Ledoux D, Labombardi VJ, Karter D. 2006. Lactobacillus acidophilus bacteraemia after use of a probiotic in a patient with AIDS and Hodgkin's disease. International Journal of STD and AIDS 17(4):280-282.

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Arvola T, Laiho K, Torkkeli S, Mykkänen H, Salminen S, Maunula L, Isolauri E. 1999. Prophylactic Lactobacillus GG reduces antibiotic-associated diarrhea in children with respiratory infections: a randomized study. Pediatrics 104(5):e64.

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Azcarate-Peril MA, Altermann E, Hoover-Fitzula RL, Cano RJ, Klaenhammer TR. 2004. Identification and inactivation of genetic loci involved with Lactobacillus acidophilus acid tolerance. Applied and Environmental Microbiology 70(9):5315-5322.

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¹ The following references were reviewed for proper nomenclature: American Type Culture Collection (ATCC) 2008, Euzéby 2008, Skerman et al. 1989

² The following references were used to select the species included in this monograph: Reid 2001, Gilliland 2001

³ Not derived from human intestinal microflora