|Year : 2015 | Volume
| Issue : 5 | Page : 2-10
Regulatory categories of probiotics across the globe: A review representing existing and recommended categorization
M Arora1, A Baldi2
1 Department of Quality Assurance, Indo Soviet Friendship College of Pharmacy, Moga, Punjab; Research Scholar, Life Sciences- Biotechnology, Punjab Technical University, Kapurthala, Punjab, India
2 Department of Quality Assurance, Indo Soviet Friendship College of Pharmacy, Moga, Punjab, India
|Date of Submission||21-Sep-2013|
|Date of Acceptance||19-Dec-2014|
|Date of Web Publication||6-Feb-2015|
Department of Quality Assurance, Indo Soviet Friendship College of Pharmacy, Moga, Punjab
Source of Support: None, Conflict of Interest: None
Probiotics are friendly live microorganisms (in most cases, bacteria) that are similar to beneficial micro-organisms found in the human gut, whenever consumed, have potential to confer benefit to the health of consumers by maintaining, or improving their intestinal microbial flora and are available to consumers mainly in the form of dietary supplements and foods. All-time high interest in the field of probiotics is due to emerging probiotic industry. Probiotics are available in foods and dietary supplements, even as pharmaceutical formulations (capsules, tablets and powders) and in some other forms as well, but their claims of health benefits may challenge the traditional border between food and medicine. A number of probiotic products have been already introduced into the international market as food supplements, dietary supplements, natural health products, functional foods and many more other categories; as a result, the position of regulatory system for probiotics within existing categories become vague and quite unclear. Common terminology for probiotic products has become a necessity to achieve adequate regulatory control for discussion of probiotic-related issues among government, producers and consumers. The lack of a consistent terminology across the globe leads to legal uncertainty and confusion instead of being a direct obstacle for development of a mature market. This article will explain differences in regulatory categorizations across the globe; discuss the terms like food and drugs with a close relationship to probiotics, the problems associated with unsatisfactorily approached categorization as well as suggestive consolidations for the new categorization which will demarcate probiotics into categories explaining their nutritive claims, health claims or both.
Keywords: Generally recognized as safe, probiotics, probiotic categories, regulatory bodies, therapeutic benefits
|How to cite this article:|
Arora M, Baldi A. Regulatory categories of probiotics across the globe: A review representing existing and recommended categorization. Indian J Med Microbiol 2015;33, Suppl S1:2-10
|How to cite this URL:|
Arora M, Baldi A. Regulatory categories of probiotics across the globe: A review representing existing and recommended categorization. Indian J Med Microbiol [serial online] 2015 [cited 2018 May 21];33, Suppl S1:2-10. Available from: http://www.ijmm.org/text.asp?2015/33/5/2/150868
| ~ Introduction|| |
Since past few years, demands of consumers for the food products have been changed considerably as it is believed that foods will directly contribute to health.  In today's era, as per consumer, food is not only to satisfy hunger rather changes have been incorporated to provide necessary nutrients for humans and to prevent nutrition-related diseases and improve physical and mental well-being of the humans. , In this regard, functional foods, dietary supplements, natural health products and other categories of food supplements play an outstanding role. Nowadays, ingestion of probiotic strains can be recommended as a preventative approach to maintaining the balance of the intestinal microflora and hence enhancing the 'well-being' of humans as well as animals.  Probiotics have been shown to exert a wide range of therapeutic effects which includes modulation of immunity,  lowering serum cholesterol, treating athereosclerosis and arteriosclerosis, treating rheumatoid arthritis, preventing cancer,  improving lactose intolerance and preventing or reducing the effects of atopic dermatitis, treating Helicobacter pylori infections, diarrhoea.  and constipation as well as candidiasis and urinary tract infections. , Increased commercial interest in exploiting the proposed health attributes of probiotics has contributed significantly to the erroneous growth and expansion of this market sector. The internationally endorsed definition of probiotics given by Food and Agricultural Organization/World Health Organization (FAO/WHO) is 'live micro-organisms that, when administered in adequate amounts, confer a health benefit on the host'.  Probiotic status is still not clear in health industry as they are used both as preventive and curative therapy. Since the awareness about the probiotic and its health benefits has grown tremendously among population, demand for probiotic foods has gained much popularity. Multinational companies are coming into the picture since they entered the food industry as well as major pharmaceuticals companies have become active and are trying to formulate newer drugs and products, and packaged products like probiotic-based nutritional supplements with special needs such as lactation, pregnancy, immunodeficiency, etc., and products especially for paediatric and geriatric patients. Probiotic formulations deal with a more complex pharmacology in comparison to the inert drugs and require detailed pharmacokinetic studies.  The development and maintenance of these products is complex, expensive and risky, as special requirements for manufacturing, labeling and safe delivery are required. Validation of probiotic category for commercial products is therefore needed to ensure consumer confidence. In different countries, these probiotics are sold under different categorical backgrounds, which create a major confusion in the legal regulations of these products.  Hence, internationally accepted categorization of probiotic products is required which will act as key to understand the type and scope of regulation. This paper offers a brief overview of the current categorization of probiotic products and some comments on future categorization on the basis of different factors having a major focus on acceptance of probiotic products by developing harmonized regulatory guidelines for global uniformity.
| ~ Probiotic categorization across the globe: Current state of art|| |
Probiotics have now become a commercial commodity because of its much widespread healthcare settings and global market for these functional foods is growing at a very fast pace.
Probiotics are categorized under different categories in different countries. They are named differently as natural health products in Canada, dietary supplements, drugs, medical food, live biotherapeutic agent, biological agent as per their intended use in USA, functional food in Japan, China, Malaysia, as food supplement in Sweden, Denmark and Finland, biotherapeutic/pharmaceuticals European countries like Belgium and Germany. Probiotics are not considered as single category rather subcategorized under different categories and are defined separately by different countries given in [Table 1]. The country wise regulatory status of probiotics along with their category is as follows:
Till date, Japan is acting as global market leader where probiotics are available as both foods and drugs. Japan was the very first global jurisdiction for implementing a regulatory system for functional foods and nutraceuticals in 1991. As per Japanese regulations, these probiotic products are in distinct category of foods and Foods for Specific Health Uses (FOSHU). For probiotic food products, efficacy claims are prohibited on the labeling and if to make claims about efficacy, one must obtain special permission from the Ministry of Health and Welfare (MHLW) for the product to be considered FOSHU, for which substantiation of efficacy and safety is a mandatory requirement.  FOSHU has divided food claims in various categories depending on the level of claim and scientific evidence and has allowed these claims depending on the strength of the supporting data.  A grade evidence is given to regular and disease risk reduction FOSHU, where evidences are both medically and nutritionally established from a scientific perspective. B grade evidence is allotted to standardised FOSHU, where evidences are confirmed at the level previously required for the approval of existing FOSHU. C level of evidence allows qualified FOSHU and is acceptable where evidences are not established but the efficacy is suggested.  The government has designated FOSHU health claims into different subcategories as per their health claims in gastrointestinal health, cholesterol moderation, hypertension moderation, lipid metabolism moderation, sugar absorption moderation, mineral absorption and bone and tooth health. As per Japenese regulations, new claims and combination of claims are approved on a regular basis.  MHLW approves the overseas applications directly. The calendar is divided into four quarters. The process of regular FOSHU registration depends upon the information which must include safety, efficacy, processing, formulation data, analytical method and chemical and physical analysis, as well as other specific information. This must be accompanied by product samples and proposed labels with proposed claims. This whole information must be in a Japanese scientific journal as it is also required. 
Europe was second for establishing definition of functional foods and implementing a regulatory commission on functional food science in Europe (FUFOSE) in 1995. Europe has a developed market for probiotics with rapid growth as functional foods, whose largest segment is composed of probiotic food products, especially dairy products such as yogurts and fermented milks.  As per European laws, even microbial cultures present in food needs to satisfy the legal requirements. European food safety authority introduced Qualified presumption of safety (QPS) for the first time for ensuring the premarket safety assessment in foods and food supplements.  European guidelines have been reviewed by various workers and coworkers and hence a thorough description of European guidelines has been outlined.  which ultimately conclude that probiotics are not having any legal definition and specific legislations rather they belong to the category of functional foods. 
European regulatory framework is still not harmonized as probiotics are regulated by the Food Products Directive and Regulation if to be marketed as food supplement (Regulation 178/2002/EC; Directive 2000/13/EU) and under Herbal Medicinal Products Directive (2004/24/EC) if marketed as traditional herbal products. For the use of probiotic product as herbal medicinal product, it is recommended to apply and obtain a drug registration, or they will be transferred to the category of food supplements. Finally, registered drugs are covered under the Drug Law (65/65/EC, amended). ,
China is known for its long traditional Chinese medicine history. Presently, China has a well-developed market for functional foods, which are based on traditional dietary culture and has rigorous standards of performance along with rapid economical growth.  Initially, China has adopted Food and Hygiene Law, which has defined food as 'any finished product or raw material intended for the people to eat and drink, as well as any product that has traditionally served as both food and medication'. But recently, State Food and Drug Administration (SFDA) are regulating all health foods which include all kind of functional foods and nutraceuticals in China. The functional foods are defined as a food that has special health functions or is able to supply vitamins or minerals. It is suitable for consumption by special groups of people and has the function of regulating human body functions. 
In American countries, Brazil is supposed to be first country to issue legislation regarding functional food. In Brazil, probiotics are considered as functional foods, and considered to be different from food. But legislation asks for safety and efficacy demonstration of food products and hence all these products must be registered and approved by health authority called National Health Surveillance Agency Brazil (ANVISA). 
New Zealand and Australia
New Zealand and Australia have joint framework agency named as Food Standards Australia and New Zealand (FSANZ).  Earlier by, functional foods were defined as the foods, which are similar in appearance to conventional foods and are intended to be consumed as part of a normal diet; but as per recent rules, these are supposed to serve physiological roles beyond the provision of simple nutrient requirements. ,
Currently USA is regulating probiotics as a variety of products as per their intended usage and dealing bodies are Dietary Supplement Health and Education Act (DSHEA) and Food and Drug administration (FDA). Such food products, i.e., dietary supplements are regulated by FDA's Center for Food Safety and Applied Nutrition.  and food ingredients do not need FDA approval before marketed. As per existing guidelines in USA,
- If a probiotic is used in the form of dietary supplement, then are considered as 'foods', and such products are regulated by DSHEA
- If a dietary supplement contains a new dietary ingredient and do not have a marketing history earlier, then the manufacturer is required to notify FDA 
- If the probiotics are considered to be the probiotic drugs for therapeutic purposes then probiotic drug must be proven safe and effective for its intended use before marketing and then it will be regulated by FDA 
- In case of biological product, one needs to have an approval via Biologic Licence Application (BLA). Determination of a biological product can be more complex because a biological product can be a virus, therapeutic serum, toxin, anti-toxin, vaccine, blood, blood component or derivative, allergenic product, or protein (except any chemically synthesized polypeptide) or analogous product applicable to the prevention, treatment, or cure of a disease condition. The definitions of drug, new drug and biological product are not different rather a product can be any of these categories, depending on its composition and intended use (s). FDA applies the current good manufacturing practices (cGMP) and investigational new drug (IND) approval process to new drugs as well as live biotherapeutic agents and biological products. 
Recently, probiotics are consumed as food and pharmaceutical as well in the country but because of varying categories, probiotics are regulated differently as per their intended use. In India, currently food and drugs are regulated by Prevention of Food Adulteration Act (PFA) and FDA, respectively. The Food Safety and Standards Act of 2005 (FSSA) defines the foods for special dietary uses or functional foods, nutraceuticals or health supplements (IMNA, 2010). Currently in India, probiotics are characterized as functional food rather than as pharmaceutical drugs and are regulated by food laws that regulate general food items. FSSA was passed by the Indian government with the purpose to regulate different varieties of eatables regulations covering nutraceuticals, foods and dietary supplements. According to FSSA, functional foods are defined legally but categorization of food categories, such as nutraceuticals, biotherapeutic agent is still unclear. Minimum standards related to quality and content for food products are set down by presently enforced PFA Rules. The PFA regulates labeling and packaging of food products in order that maximum information including the ingredients, nutritional information, date of expiry, manufacturer and manufacturing unit details and country of origin and importer (for imported food) with regard to the food product should be disclosed to the consumer. , In India, earlier there were no specific regulatory guidelines, so an approach was therefore needed for formulating guidelines and regulations for evaluating the safety and efficacy of probiotics and to prevent marketing of such products with false claims. Keeping in view the above, a Task Force was constituted by Indian Council of Medical Research (ICMR) along with the Department of Biotechnology (DBT), to frame regulatory guidelines for evaluation of probiotics in food in India. These guidelines have described set of parameters to define a product/strain as actual 'probiotic'. The guidelines deal with the use of probiotics in food and provide requirements for assessment of safety, health claims and labeling of probiotic strains which would be helpful to the consumers to safeguard their own interest. 
Currently functional food products are not having any official definition in Malaysia. Functional foods are classified as food and must comply with the food regulations. All food and drugs are regulated by a sophisticated legal system in Malaysia. The main regulatory bodies that implement and enforce regulations on food and drugs are the Food Safety and Quality Division (FSQD), the Drug Control Authority, the National Pharmaceutical Control Bureau (NPCB) and the Committee for the Classification of Food-Drug Interface Products. Malaysian regulations are locally developed with reference to CODEX, these are very complex regulatory guidelines for the functional foods but no separate guidelines are entitled for the probiotic category. 
Canadian functional food industry also has complex and unsatisfactory regulatory framework. As in Canada, probiotics are considered under the category of natural health products, approval and packaging of these products is mainly governed by Canadian Food and Drugs Act specifically under Natural Health Products Regulations. 
| ~ Problems of Current Categorization|| |
At present, the status of probiotic-based product is full of ambiguities because various regulatory agencies in different countries are defining and categorizing probiotics differently, due to this considerable confusion and skepticism exist amongst regulatory bodies, producers and consumers, for the associated claims of probiotic products. As the concept of probiotics is spreading widely throughout the world, it necessitates an in depth investigation of probiotic traits for vital reinforcement of probiotic concept and is a pre-requisite for their rational development.
Due to diverse categorization:
- Single definition of probiotics and consistent terminology is lacking, which should be framed and opted as soon as possible
- Difficult to enforce appropriate use of the term and/or difficult to know if someone is misusing it
- Regulatory framework in operation, proper standardization parameters and harmonization of guidelines are not established on international basis yet
- Posing a major threat to establish the credibility of health promoting functions of probiotics
- Posing challenges for regulators, consumers and producers
- Certain health effects or impact of probiotics on various diseases claimed by different companies of different countries cannot be proved whether the claims made by firms are true or not true as health effects will be given as per the ruling of the particular company
- Improper categorization of probiotic products in different categories has reduced the importance of the dose specificity and strain specificity which are the major issues of concern
- Local authorities handling probiotics are burdened as local manufacturers consult local authorities for labelling on probiotic product before launching a product to the market. Hence decision of local authorities may vary in the absence of harmonized regulations
- Consumers have trouble while understanding the difference between types of claims represented on the probiotic products
- No diagnostic tools to determine the appropriate probiotics to use in a particular situation
- Gaps in understanding of the interaction between the host, its genome and the microbiome in human beings, as well as the impact of probiotics on this balanced system.
'The good thing about the probiotics is that; no matter what probiotics are called, their name is ill defined, but still they are safe, natural and good for human and animal health and wellness'. So, probiotics-based facts must be regulated in a better manner to use them maximally for our personal interest. Otherwise, a serious area of concern, i.e., of probiotics is getting 'locked into' the categorization.
| ~ Future Recommendations for Categorization of Probiotics|| |
Recently probiotics is a major thrust area among clinicians to dissolve limitations associated with current probiotic status. Probiotics are being used since ancient times as fermented foods. Many consider them as complementary or alternative medicine. It has been already proved by many healthcare professionals that probiotics have a number of health benefits and probiotic therapy is being used for treatment of number of diseases. There is an urgent need to address the quality, safety and efficacy issues of probiotics by defining the limits of its categories. The adoption of definitions and standards is the major need of the hour as it will act as basic background to set a harmonized regulatory framework of guidelines which can be accepted internationally across the globe. Probiotics were earlier marketed as foods and were usually not manufactured to pharmaceutical-grade requirements; therefore, to fulfill their requirements as food and therapeutic probiotics, additional manufacturing and safety controls are required, to reduce batch variability.
The issues related to diverse categorization can be resolved by taking the following points into consideration which involves:
- A single and appropriate definition of probiotics should be opted as soon as possible. Till date, 'probiotics are defined as live microorganisms which when administered in adequate amounts confer a health benefit on the host' (FAO/WHO, 2002). But, probiotic products are not considered under single category across the globe and hence definition of the probiotic categories vary from country to country which is a major threatening force while drafting harmonized regulatory guidelines. In context to this, probiotics must be adequately defined, covering all the varying aspects of microorganism in single definition
- Clear regulatory categories for probiotics must be defined to reduce the confusions. Probiotics must not be treated as a single product-some have higher risks than others and they should be regulated differently. Probiotics that are genetically modified may need a higher level of regulatory scrutiny than non-modified probiotics as their potential risks need to be identified
- Continued vigilance for long term clinical trials of probiotics should be there
- Ongoing reporting of adverse effects of probiotic products of different recommended categories.
Taking above-said points into consideration, probiotics should be defined as viable micro-organisms/spores; reach the intestine in active state present either as mono or mixed cultures; which upon ingestion in animal or humans in certain numbers and adequate amount impart certain health/nutritional benefits.
- Probiotics should be categorized as an alternative framework that integrates a unique non-drug, non-food category for some of strains having probiotic potential along with two broad categories named as 'probiotics as food' and 'probiotics as pharmaceuticals'. This kind of new category might make sense which could be useful in future
- Beneficial microbes having probiotic potential must be categorized broadly as per their intended usage and safety parameters under different categories as follows.
Nutribiotics, i.e. Probiotics as food specifically having nutritive claim only
This category must include those probiotic microbes or products based on those microbes, which have general or any specified nutritive claim. This category of microbes must fullfill the regulatory requirements of particular regulatory authority responsible for food safety of that region/country.
Pharmabiotics, i.e. Probiotics as pharmaceuticals specifically having health claims
This category must include those probiotic microbes or products based on those microbes, which have general or any specified health claim against diseases. These may include the variety of microbes having general health claim, specified health claim, products for narrow use or products having both nutritive as well as health claims. Probiotics as pharmaceuticals must have further categorization as follows:
Beneficial and safe
This category must include those microbes which are used as starter culture as considered to be safe for internal use; possessing a role in fermenting food; but they do not qualify limits of probiotic potential. These types of microbes are unable to survive in stomach due to acid and bile salt sensitivity but still these can be used as probiotics as they are fit for diseases associated with oral cavity.
Beneficial and safe but not clinically proven to be probiotic
This category must include those microbes or products associated to those microbes which themselves have a safe history of their use but there clinically proven evidences supporting their probiotic potential do not exist. The only requirement of their safe use is that these strains must be genetically identified and meet safety standards of the regulatory authority before use.
Clinically proven potential probiotic strains
This category must include those microbes or products associated to those microbes whose beneficial health benefits are documented after experimentation in humans. These must include the microbes whose utilization via any of the target site, i. e., mouth, skin, vaginal and their delivery in any form, i.e., as dairy, powder, food, cream or other form confer a basic effect that benefits health, as per human studies. This category will further be bifurcated as follows.
Clinically proven potential probiotic strains with general health benefits
This category must include those microbes which possess general probiotic potential, which is generally conveyed by all other probiotic strains and can be given to a broad range of consumers.
Clinically proven potential probiotic strains with specific health benefits
This category must include those microbes which possess some additional probiotic potential, which are not conveyed by all other probiotic strains.
Clinically proven potential probiotic strains for narrow use only
This category must include those microbes which possess some additional probiotic potential, which is not conveyed by all other probiotic strains but only for narrow use or for a narrow range of consumers.
Still the regulatory framework of probiotics seems daunting, but yet there is hope for future victories. With time, there will be generation of new possible strategies targeting loopholes in the regulations regulating probiotics. Hence, understanding of the term probiotics is becoming a necessity to impose good regulatory decisions, to fully realize the exciting potential of probiotic products as foods, dietary supplements, as drugs. Suggestive categorization around the globe will bring:
- Internationally accepted consistent terminology
- Appropriate use of different terms related to probiotics on international basis
- Clear-cut demarcation of food based probiotics with nutritive claims and drug-based probiotic products with health claims
- Solution to ambiguities related to diverse categorization which involves categories like dietary supplements, medical food, functional food, natural health products, etc
- Development of methods and techniques (in vitro and in vivo) to evaluate the efficacy and safety on common basis
- Harmonized standards while drafting and promotion of suggestive guidelines in future for safety of consumers and better product acceptance
- Credibility of health promoting functions of probiotics
- Adequate regulatory control for discussion of probiotic-related issues among government, producers and consumers by using common terminology.
| ~ Conclusion|| |
Probiotic products have been commercialized and made their importance within past 50 years. Due to constant reporting of novel strains due to their novel health benefits, safety and efficacy issues of these products must be carefully resolved before their use into our own food. Improper use of the term probiotics should be rectified because lack of awareness and the credibility of health claims associated with probiotic products are posing a major threat to probiotic industry and its consumers. Till date, the rational usage, selection and design of probiotics remains an important challenge for the scientific community in concern with their safety factors. So, a careful risk assessment for patients and proper handling of the probiotic during administration need to be conducted before using probiotics as drugs. All the leading nations worldwide are now recognizing the importance of functional foods and their beneficial impact on human beings. Each country is in process of addressing the problematic issues and regulating proper regulatory structure for the functional foods but due to separate regulations in different countries, there are certain considerable confusions and challenges ahead for the regulatory bodies, food scientists, manufacturers and even consumers about the claims associated with probiotics, which needs to be addressed for the successful marketing and usage of functional foods. No doubt, the regulatory views are constantly changing as a result of ongoing developments in different countries and hence the global regulatory status of probiotics must be characterized by a certain degree of harmonization. To resolve all the issues related to probiotics, a common regulatory framework is required which will allow free exchange of products and will minimize confusion of different regulations. In context to these problematic issues, a step has been taken forward to bring recommended regulatory categorization explaining the demarcation of the probiotics in different levels and sublevels by keeping the problematic issues in mind, which will be later helpful to bring harmonized guidelines into consideration for future safe and efficacious use of probiotics.
| ~ Acknowledgement|| |
The authors are thankful to Sh. Parveen Garg, Chairman ISFCP for providing necessary facilities and support. The authors also acknowledge affiliation with Punjab Technical University, Kapurthala for Ph. D. degree.
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