Biologically active additives: what they should be
Modern approaches to ensuring the quality and safety of biologically active food additivesViktor A. Tutelyan, Director of the State Research Institute of Nutrition of the Russian Academy of Medical Sciences, Academician, Professor, MD.
Sukhanov Boris Petrovich, Professor of the Department of Food Hygiene and Toxicology of the I.M. Sechenov MMA, MD.
Newspaper "Moscow pharmacies", April 2008 No. 4 (170)
MA: What is the value of dietary supplements for the consumer?The development of the pharmaceutical industry, biotechnology, chemistry, the introduction of state-of-the-art technologies for processing plant and other raw materials to obtain high-purity biologically active compounds and their complexes made it possible to produce biologically active and minor components of food necessary to improve the quality of nutrition in unlimited quantities.
It remained to find forms in which it would be convenient to introduce these compounds into food. And pharmaceutical forms were quite justifiably chosen for this: tablets, capsules, powders, pills, etc. The use of biologically active substances (BAS) in these forms made it possible to strictly dose them in accordance with the needs of a person depending on gender, age, health status, professional activity and other factors.
The coincidence of these three components, on the one hand, created a high interest and demand for natural biologically active substances by the population to improve the quality of nutrition and life, prevention of many diseases, on the other hand, opened up prospects and opportunities for their production in the required quantity and real practical application.
The scientific component of the need for additional use of biologically active and minor components of food in the form of pharmaceutical forms was obtained on the basis of large–scale epidemiological studies, on the one hand, evidence of their important role in ensuring the vital activity of the human body, on the other - the detection of their deficiency in the diet of modern man.
For the majority of the population of economically developed countries, as well as for the population of Russia, currently, due to the above reasons, diets are deficient in polyunsaturated fatty acids (omega-3 and omega-6), soluble and insoluble dietary fibers (pectin, mucus gum, cellulose, etc.), vitamins (group B, E, etc.), a wide range of vitamin-like substances of natural origin (L-carnitine, ubiquinone, choline, methylmethionine sulfonium, lipoic acid, etc.), macronutrients (calcium, etc.), trace elements (iodine, iron, selenium, zinc, etc.).
Based on the principles of evidence-based medicine, fundamentally new data have been obtained regarding the biological role of natural minor biologically active substances for humans. This primarily applies to compounds such as
– various groups of flavanoids (flavanols and their glycosides – quercetin, kemferol, rutin, etc.; flavones – luteolin, apigenin, etc.; flavonones – naringenin, hesperidin, etc.; dihydroflavanols, protocyanidins, catechins, etc.), whose physiological functions are extremely diverse and important for reducing the risk of developing many widespread human diseases, including cardiovascular and oncological;
– indoles, one of the most important functions of which is the regulation of the activity of enzymes of the first and second phases of metabolism and the neutralization of foreign substances;
– exogenous peptides and individual amino acids and their mixtures, whose participation in the regulation of organ and system functions has been proven by numerous studies (for example, peptides provide specific intermolecular interaction with promoter regions of genes, are present as fragments in a number of polypeptides – interleukins, cytostatin, thyroglobulin, etc.).
The important role of both nutrition components and substances such as organic acids, phenolic compounds, beta-sitosterols, isoflavones, isothiocyanates, glucomannans, polypructans, inulin, chlorophyll, caffeine, hypericin, glucosamines, chondriotin sulfate, chitosan and many others has been proven.
The deficiency of biologically active compounds in the diets of the population leads to a decrease in the body's resistance to adverse environmental factors (maladaptation), the formation of immunodeficiency states, disruption of the function of antioxidant defense systems, chronization of diseases, increased risk of diseases, a decrease in the quality of life and the effectiveness of therapeutic measures.
We have identified more than 120 biologically active compounds of plant, animal, and biotechnological origin belonging to minor components of food, the mechanism of action of which has been deciphered, and thereby provided the possibility of their use as part of dietary supplements for individualizing nutrition, filling their deficiency in the diet and reducing the risk of developing many diseases.
Medicinal plants, non-traditional marine food products, biotechnological and less often chemical synthesis products and other natural sources (bee products, mummies, etc.) can be used as sources identical to compounds found in food. The use of such sources is more than justified both from an economic and scientific point of view, since the content of BAS in them tens and hundreds of times higher than in traditional food products.
MA: What laws regulate legal relations in the field of dietary supplements turnover? What regulatory documents are designed to ensure their quality and safety? What parameters and characteristics of dietary supplements are being investigated by the Research Institute of Nutrition?Legal relations in the field of dietary supplements turnover are regulated by the laws of the Russian Federation "On Sanitary and epidemiological welfare of the population" (No. 52-FZ of March 30, 1999; the first version of the Law was adopted in 1991), "On the quality and safety of food Products" (No. 29-FZ of January 02, 2000), "On the Protection of Consumer Rights" (No. 196-FZ of December 30, 2001), "On Advertising" (No. 38-FZ of March 13, 2006), resolutions of the Government of the Russian Federation, the National Standard of the Russian Federation "Food products.
Information for the consumer. General requirements" (GOST R No. 51074-2003), as well as a number of other documents of the federal level of action, which include sanitary rules and regulations (SanPiN), methodological guidelines (MUK) and methodological recommendations (MR), which reflect various aspects of turnover control, quality assurance, safety and effectiveness of this new for the country product type. Orders of the Ministry of Health, Rospotrebnadzor, resolutions of the Chief State Sanitary Doctor of the Russian Federation and other departmental documents have an important place in the system of ensuring the control of dietary supplements turnover.
In accordance with the above laws of the Russian Federation, the manufacturer of products is responsible for its quality, safety, efficiency, reliability and completeness of the information provided about the products.
To date, the legislative, regulatory and methodological framework has been formed in the Russian Federation to ensure the safety of the use of dietary supplements. It is much tougher than in Europe, the USA or Asia. The beginning of the formation of this database dates back to 1997, when almost the first document concerning the regulation of dietary supplements turnover in Russia appeared. It was in 1997 that the Ministry of Health of Russia issued an order "On the procedure for the examination and hygienic certification of biologically active food additives".
In accordance with the sanitary legislation of the Russian Federation, dietary supplements in Russia are subject to state registration, which is carried out at the federal level by Rospotrebnadzor. The state registration of dietary supplements is a confirmation of compliance of the quality and safety of dietary supplements with the sanitary legislation of the Russian Federation in this area. Data on the state registration of dietary supplements are entered in the Federal Register of Dietary Supplements, which can be found on the website of Rospotrebnadzor.
The Law of the Russian Federation "On the quality and safety of food products" refers dietary supplements to a group of food products and gives them the following definition: Dietary supplements are "natural (identical to natural) biologically active substances intended for use simultaneously with food or introduction into the composition of food products." Thus, dietary supplements are not medicines intended for the treatment or diagnosis of human diseases. Referring to food products, they serve as an additional source in the human diet of necessary, nutritionally deficient nutrients (amino acids, vitamins, macro- and microelements, polyunsaturated fatty acids, vitamin-like, etc. compounds) and a source of biologically active substances, and control over their production and turnover is within the competence of the state sanitary and epidemiological supervision (Rospotrebnadzor).In accordance with the sanitary legislation of the Russian Federation, dietary supplements can be produced in the form of various pharmaceutical forms in accordance with technical documents.
Unlike medicines that include biologically active substances for medicinal purposes and doses that are usually tens or hundreds of times higher than the physiological need of a healthy person, and injected into the body both per os and parenterally, dietary supplements are used to compensate for the deficiency of these substances in diets in quantities that are in the daily dose of dietary supplements in within the limits of a person's physiological needs, and are applied only per os with food during meals.
The effects of dietary supplements, as a rule, are realized primarily by initiating universal mechanisms of adaptive reactions of the body to the effects of external and internal factors of a very different nature. At the same time, quantitative changes in the parameters of the functioning of the body systems are within their physiological boundaries.
Dietary supplements can also be used for various diseases, but necessarily along with the use of specific therapy and only as an element of a therapeutic diet (dietary or therapeutic nutrition), but in no case as a drug, which they are not by definition. In this case, dietary supplements help to shorten the duration of the disease, accelerate the recovery of patients, avoid some complications and chronization of the disease, quickly reduce the volume of specific chemotherapy, the length of stay of patients in hospitals. However, it is necessary to take into account the compatibility of the composition of dietary supplements with medicines during their joint use in order to avoid possible mutually negative effects on each other or on the processes of realization of the activity of each of them.
In accordance with the sanitary legislation of Russia, dietary supplements can be considered as an additional source of proteins, fats or carbohydrates only if their amount in a single serving of dietary supplements is at least 2% of the recommended daily intake of these components; with respect to vitamins, macro- and microelements and biologically active substances, this the value should not be lower than 10%.
At the same time, the content of vitamins in the daily dosage of dietary supplements, as is customary in international practice, should not exceed the recommended daily intake (an adequate level of daily intake) by more than 3 times (the upper permissible level of consumption) for vitamins A, D, K, B 1, B 2, B 6, 12, niacin, folic and pantothenic acids, biotin and no more than 10 times – for vitamins E and C. Moreover, when recommending vitamin intake above an adequate level, the manufacturer must provide a convincing evidence base. It can be obtained both as a result of analysis and generalization of literature data, and as a result of specially conducted experimental studies or clinical observations. These documents are submitted at the state registration of dietary supplements in Russia.
The amount of minerals (macro- and microelements) in the composition of dietary supplements is allowed at levels that most often do not exceed the daily (adequate) need for them by 2 times (the upper permissible level). Recommendations for an increased level of mineral intake (above 100% of the adequate level), as well as vitamins, should have a convincing documented evidence base.
In the daily dose of dietary supplements, the content of vitamins and mineral salts should be 10-100% of the recommended daily (adequate) consumption level.
The sanitary and epidemiological examination of dietary supplements precedes its state registration, is carried out by organizations authorized by Rospotrebnadzor, is carried out to identify compliance of products with current legislative acts and regulatory requirements for quality and safety and includes the following procedures (Guidelines "Determining the safety and effectiveness of biologically active food additives", Ministry of Health of Russia. M., 1999, 88 p.):
– initial expert evaluation of the application, documents and materials characterizing these products;
– determination of the need and scope of the necessary dietary supplements research;
– carrying out the necessary complex of sanitary-chemical, sanitary-microbiological and other types of studies and evaluating their results in order to confirm the safety, authenticity of the components of the product formulation, the quantitative content of active components;
– experimental studies of toxicological, physiological and metabolic effects to confirm the safety of dietary supplements and the claimed effectiveness (if necessary);
– clinical evaluation (if necessary);
– evaluation of the results of experimental and clinical trials and observations (if any);
– evaluation of the results of studies of the content of the main ingredients and the authenticity of dietary supplements;
– preparation and execution of an expert opinion, including a draft label for products; their approval in an organization conducting a sanitary and epidemiological examination, followed by sending an expert opinion and a draft label to Rospotrebnadzor for registration in accordance with the established procedure.
All documentation for the sanitary and epidemiological examination is provided in the original and/or in the form of notarized copies and translated into Russian.
Any studies of dietary supplements are carried out in institutions and laboratories accredited for specific types of work in accordance with the established procedure.
MA: How is the effectiveness and safety of dietary supplements determined? How is the permissible content of biologically active substances in dietary supplements determined? What biologically active substances are prohibited in the manufacture of dietary supplements due to their possible harmful effects on human health?The widespread use of medicinal plants as part of dietary supplements has caused the need to develop a regulatory and methodological framework that allows for effective control of the safety and quality of this type of product.
And if the safety problems of such products according to generally accepted indicators in world practice (toxic elements, pesticides, mycotoxins, sanitary significant microorganisms, radionuclides, etc.) have now been generally solved both abroad and in Russia, then the safety problem of dietary supplements with the inclusion of medicinal plants or their extracts in methodological and methodological terms is not only in Russia, but in general in the world practice until 2004, it remained practically open (control of the amount of pharmacologically active substances and the establishment of their permissible level in the composition of dietary supplements, indicators of the authenticity of dietary supplements components).
In solving this complex problem, it was important to provide that "golden mean" when a product based on medicinal plants, on the one hand, would be a source of biologically active substances (BAS), on the other – would remain in the group of food products (dietary supplements).
Having started work in this direction, we drew attention to the fact that many BAS of medicinal plants are also characteristic of food products of plant origin. For example, anthraquinones are characteristic of such daily used food plants, which include rhubarb, sorrel, legumes, and medicinal plants – Cassia tora, Aloe vera, Polygonum bistoria; isoflavones are found in both legumes and medicinal plants – Trifolium pretense, Sophora jaropis. Coming with food in small quantities, pharmacologically active substances have a regulating effect on the functional activity of human systems and organs within the physiological boundaries of their activity. In higher doses, these substances already have a significantly more pronounced effect on human organs and systems, which is beyond the parameters of the physiological boundaries of the functional activity of human organs and systems. In the latter case, the sources of BAS should already be considered as medicines of natural origin, used as prescribed and under the supervision of a doctor.
Taking into account the importance of biologically active and minor compounds in maintaining the functional activity of human systems and organs, and at the same time their real deficiency in the diet of the population due to limited, monotonous, refined nutrition, as well as the impossibility of increasing their intake due to traditional nutrition, we made an attempt first from a large number of BAS of medicinal plants, the most frequently used in the composition of dietary supplements presented on the Russian market, highlight the most common. By analyzing the literature data, generalizing our own experience, as well as joint consideration of this problem with pharmacologists, clinicians, toxicologists, pharmacognosists and other interested specialists, based on the structure of the population's nutrition and calculating the possible content of specific BAS in the daily diet, we obtained calculated data on their approximate intake with the daily diet and through this, they reached the recommended values of their daily intake. The results of this work were the scientific justification for the use of medicinal plants in dietary supplements as sources of biologically active compounds important for human nutrition. However, this path is long, extremely difficult, and requires significant resource and material costs.
The second approach to calculating the permissible values of the content of medicinal plants in dietary supplements, which we have applied, is much simpler and more accessible. Together with the above-mentioned group of specialists, we made a decision: as part of a daily portion of dietary supplements, the content of pharmacologically active compounds of a medicinal plant should be no more than 50-60% of the single therapeutic dose when using this plant as a medicinal product. At the same time, the lower limit of the content of these compounds in dietary supplements should not be less than 10% of the single therapeutic dose. Such an approach, on the one hand, ensured the presence of compounds important for the vital activity of the body in dietary supplements, on the other hand, it did not assume the presence of medicinal properties in it, and, finally, thirdly, it ensured safety by the criterion of the content of specific pharmacologically active components. This criterion is the most important guideline when deciding on the dose of a specific BAS in the composition of dietary supplements.
Traditional sources of food and biologically active substances are sources of food and biologically active compounds of animal, plant and microbiological (biotechnological) origin, certainly and traditionally related to food (food) raw materials and food products.
Alternative, identical to natural, sources of food and biologically active substances are sources, in accordance with the established procedure, permitted for food and medical use, not related unconditionally to traditional food raw materials and food products (medicinal plants; substances obtained as a result of biotechnological or chemical synthesis, natural mineral raw materials, bee products, mummies, etc.).
It is impossible to ensure the safety of dietary supplements during their turnover on the market without reliable methods of monitoring the content of active substances in them and confirming the authenticity of the components claimed in the product. These are the main criteria for the quality and effectiveness of dietary supplements. In the Russian Federation, a methodological framework has been developed that allows for the quantitative determination of more than 120 active components in the composition of these products (Manual 4.1.1672-03 "Guidelines for quality control and safety of biologically active food additives").
In 2000, Russia approved a positive list of components that can be used in the production of dietary supplements (SanPiN 2.3.2.1078-01 "Hygienic requirements for the safety and nutritional value of food products"). It includes more than 190 titles. In the same document there is also a negative list (prohibited components). The first among them are components containing potent, narcotic, psychotropic and toxic substances. In accordance with this list , the use of dietary supplements in the Russian Federation is also not allowed:
– substances not peculiar to food, food and medicinal plants;
– non-natural synthetic substances – analogues of active principles of medicinal plants (which are not essential nutrition factors);
– antibiotics;
– hormones;
– potentially dangerous animal tissues, their extracts and products of their processing, including specific risk materials for transmission of agents of prion diseases (transmissible spongiform encephalopathy): skull, including brain and eyes, palatine tonsils; vertebral column, spinal cord and dorsal ganglia; intestines; spleen of ruminants, as well as mechanically deboned meat, melted fat, gelatin, collagen and calcium diphosphate produced from them; organs and tissues of livestock and commercial wild animals older than 30 months; organs and tissues livestock from third countries without a certificate of removal of specific risk materials.
When importing dietary supplements to the Russian Federation (raw materials for dietary supplements) made using raw materials of animal origin, the epizootological situation of transmissible spongiform encephalopathy (including bovine spongiform encephalopathy) in the country of the manufacturer of these components should be taken into account (EU Commission Decision 2000/418/EC "Prohibition of the use of SRM" dated 29.06.2000 and Resolution 999/2001 of 22.05.2002 "Prevention, control and eradication of certain TSE").
Prohibited for use as part of dietary supplements:– representatives of genera and species of microorganisms, among which variants that cause human diseases or can serve as vectors of antibiotic resistance genes are common;
– spore–forming aerobic microorganisms - representatives of the genus Bacillus: B.polimyxa, B.cereus, B.megatherium, B.thuringiensis, B.coagulans, B.subtilis, B.licheniformis and other representatives of this genus;
– representatives of genera and species of bacteria, among which conditionally pathogenic strains are common (Enterococcus spp., Escherichia, etc.);
– microorganisms with hemolytic activity;
– viable yeast and yeast-like fungi;
– all kinds of microscopic mold fungi belonging to the genera Aspergillus, Alternaria, Candida, Chaetomium, Cladosporium, Fusarium, Geotrichum, Pseudollescheria, Misog, etc.;
– undisputed microorganisms isolated from the body of animals and birds and not characteristic of the normal protective human microflora, including representatives of the genus Lactobacillus;
– human tissues and organs.
In addition, it is forbidden to use scorpion, all types of Spanish fly, seven-point ladybug, as well as any other objects that may pose a danger to human health from objects of animal origin as part of dietary supplements.
MA: Are there any special conditions for the registration of dietary supplements intended for children?Dietary supplements for children of various age groups are most often a source of micronutrients (vitamins, minerals, certain types of polyunsaturated fatty acids, etc.). Products with this composition do not meet objections to its use in children's practice, since children of all age groups also have exceptionally frequent nutritional deficiencies of these components.
However, in the last few years, the developers of these products have begun to include various medicinal plants in the composition of dietary supplements for children, including those with a pronounced pharmacological effect of action. How reasonable and necessary is this? After all, children under the age of 14 are particularly sensitive to non-traditional, including food influences. Their metabolic systems are not yet sufficiently formed and are not always able to effectively resist and adequately respond to increased loads. At the same time, dietary supplements are used without the participation of a doctor for a long time. This poses a high potential threat to children's health.Therefore, in Russia, only a very limited number of food, spicy and medicinal plants are allowed to be used as part of dietary supplements for children under 14 years of age (Appendix 3).
Vitamins and minerals are used in accordance with the positive list published in SanPiN 2.3.3.1940-05 "Organization of baby food" (Appendix 4). Components with pre- and probiotic effects are also allowed for use in this product group.
The components used in dietary supplements for children must comply with special hygienic standards of safety and nutritional value established by sanitary and epidemiological rules and regulations (SanPiN 2.3.2.1078-01 "Hygienic requirements for safety and nutritional value of food products").
As part of dietary supplements and herbal "teas" for children under 3 years of age, it is prohibited to use flavorings, dyes, stabilizers, preservatives, food additives, except for those approved for the production of baby food, which is reflected in SanPiN 2.3.2.1293-03 "Hygienic requirements for the use of food additives". The use of artificial sweeteners (sweeteners) is also not allowed.
In 2006 Rospotrebnadzor has introduced a non-governmental system of voluntary certification of dietary supplements, which has the right, after reviewing the results of clinical trials of dietary supplements, to issue its registration document on voluntary certification of dietary supplements. In this document, in the column "Indications for use", the expected medical effects from the use of dietary supplements can also be noted. At the same time, the sanitary legislation of the Russian Federation (SanPiN 2.3.2.1290-03 "Hygienic requirements for the organization of production and turnover of biologically active food additives (dietary supplements)") allows the following formulations on the effectiveness of dietary supplements: to optimize carbohydrate, fat, vitamin or other metabolism in various functional states; to normalize and/ or improve the functional state of organs and systems of the human body, including through products that have a restorative, mild tonic, soothing or other types of action in various functional conditions; to reduce the risk of diseases; to normalize the microflora of the gastrointestinal tract; as enterosorbents. Other formulations for use in dietary supplement labels are prohibited. These formulations generally coincide with the practice of labeling dietary supplements adopted in many countries. Although it should be noted that this problem in the world is still far from being completely solved and is constantly being discussed both at the international level and at the level of individual interested States.
MA: What are the current requirements in dietary supplement advertising?Advertising of dietary supplements should not contradict the materials agreed upon during state registration; advertising of dietary supplements that have not passed state registration is not allowed; as a unique, most effective and safe means in terms of side effects; advertising should not mislead the consumer about the composition of dietary supplements and its effectiveness; it is unacceptable in advertising to create the impression that the natural origin of raw materials, used in the composition of dietary supplements, is a guarantee of its safety; advertising dietary supplements should not undermine consumers' faith in the effectiveness of other means; should not give the impression that the participation of a doctor in the use of dietary supplements is unnecessary, especially for plant-based dietary supplements.