I. Introduction
Even though they may often resemble pharmaceutical products in appearance, under European Union (EU) law food supplements are classified as foodstuffs.Footnote 1 While legally defined as food products intended to supplement the normal diet, research shows that consumers often perceive these products as a low-risk means of maintaining or enhancing their health, rather than merely as sources of nutritional value.Footnote 2 This divergence gives rise to questions as to whether the existing regulatory framework is suitably designed to ensure effective oversight of the food supplement market, particularly with respect to market surveillance.Footnote 3 Given the credence nature of these products, consumers cannot independently ascertain whether food supplements possess the claimed nutritional and health-related properties, nor whether they are affected by potential deficiencies. One way of dealing with such shortcomings may be the introduction of more robust market surveillance mechanisms with the aim of empowering consumers to make informed choices and to realise the free movement provisions under EU primary law.
In EU food law, food quality and safety are distinct but interdependent concepts. Its horizontal legal framework constitutes a risk-based regulatory system, which defines the conditions for food safety under Article 14 of Regulation (EC) No 178/2002 (General Food Law), whereas the marketing of food which is injurious to human health or otherwise unfit for consumption is prohibited.Footnote 4 The General Food Law imposes an obligation on food business operators (FBOs) to ensure and verify that their products comply with the requirements of food law.Footnote 5 This regulatory framework applies by definition also to food supplements.Footnote 6 Several European food safety acts also relevant to food supplements, such as Regulation (EC) No 852/2004 (Food Hygiene Regulation), Regulation (EC) No 396/2005 (Food Pesticides Regulation), and Commission Regulation (EU) 2023/915 (Food Contamination Regulation), establish specific manufacturing standards and permissible limits.Footnote 7
The term of food quality is not uniformly defined by EU law, instead it is indirectly addressed through sectoral legislation, such as Directive 2002/46/EC (Food Supplements Directive), consumer information rules, or voluntary quality schemes. However, as quality defects may evolve into relevant safety aspects, such as contaminations or compositional inconsistency, establishing food quality serves a pivotal role in maintaining food safety and food supply chain integrity.
Implementing an effective quality control system is critical for performing robust product analyses and for the periodic assessment of results to identify and address quality defects, such as galenic inconsistencies or contamination.Footnote 8 However, the EU’s legal framework does not prescribe detailed quality control measures specific to the food supplement sector, leaving the development and implementation of such measures to individual FBOs. Since regulatory authorities typically evaluate the efficacy of quality control methods during inspections, this dynamic may, willingly or unwillingly, allow lower-quality products to enter the market.Footnote 9 This significance of this dynamic is further underscored by FBOs facing significant methodological challenges in developing effective quality control methods, particularly for complex products such as multi-herbal ingredient supplements.
Additionally, the range of enterprise sizes within the EU supplement market, from small and medium-sized enterprises (SMEs) to globally operating corporations, results in considerable disparities in financial and human resources. Although product quality is regarded as a key competitive factor among FBOs, the substantial effort required to develop and implement adequate quality control measures may place SMEs at a disadvantage compared to larger companies.Footnote 10 These variations affect FBOs’ ability to establish robust quality control systems, whether independently or through third-party contractors.Footnote 11 , Footnote 12 Addressing the resource allocation discrepancies between SMEs and larger enterprises in ensuring effective quality control could enhance consumer access to high-quality supplements across the EU, benefiting both public health and informed decision making.Footnote 13
The United States of America (USA) and Canada have adopted a more nuanced approach to regulating food supplements by explicitly considering their pharmaceutical properties. Both countries have updated their pharmacopoeial compendia for supplements, aiming to enhance their quality and safety. Building on these developments, this article explores whether utilising the European Pharmacopoeia (Ph. Eur.) as a platform for improving food supplement quality could strengthen quality control practices among FBOs and regulatory authorities.
This study seeks to examine the potential benefits and risks associated with introducing pharmacopoeial reference standards in the EU supplement market by comparing the EU’s legal framework, designed to support the production and sale of high-quality supplement products, with alternative regulatory approaches.
1. State of the art of the EU food supplements market regarding safety and quality control
The EU food supplements market has expanded from approximately €26 billion to nearly €32 billion between 2018 and 2020 and is projected to reach €48 billion by 2026.Footnote 14 This rapid growth highlights an increasing relevance of enhancing consumer access to safe and high-quality supplements.
Previous research has identified a range of persisting quality defects compromising the safe consumption of food supplements in the EU, with contamination being a primary concern. Among the most significant toxicological risks are the presence of heavy metals such as lead, arsenic, and chromium.Footnote 15 , Footnote 16 Pesticide residues and metabolites have also been detected in botanical food supplements, likely originating from the agricultural treatment of plants and raw materials.Footnote 17 Notably, substances such as piperonyl butoxide, cyromazine and chlorate, whose use is either strictly limited or prohibited in the EU due to safety concerns, have been found.Footnote 18 , Footnote 19 Microbiological contamination poses an additional threat, with potentially human-pathogenic bacteria such as Enterobacter spp., Salmonella spp., and Escherichia coli confirmed in food supplements.Footnote 20 Identification of harmful mycotoxins produced by fungi, including ochratoxins, aflatoxins, and fumonisins, further exacerbate microbiological risks.Footnote 21 Moreover, frequent consumption of herbal supplements containing naturally occurring toxic compounds such as hepatotoxic pyrrolizidine alkaloids may lead to acute or short-term toxicity, as highlighted by the European Food Safety Agency (EFSA) in 2016.Footnote 22
While the contamination issues documented in research may fall within the range of permitted daily doses and may not cause immediate toxic symptoms, the potential for frequent exposure to toxic substances and associated long-term health risks must be taken into account.Footnote 23 Beyond contamination, research has highlighted significant variability in ingredient quantities across supplements containing similar components, illustrating the broader problem of inconsistent galenic quality in EU food supplements.Footnote 24 Reflecting the prevalence of quality defects and their impact on product safety, food supplements have consistently ranked among the most frequently reported product categories in the European Commission’s (EC) annual Alert and Cooperation Network (ACN) reports, which track food product-related issues in the EU.Footnote 25 , Footnote 26
The increasing complexity and diversity of food supplements’ compositions present a major challenge for developing laboratory methods capable of verifying the purity, identity, and quality of new ingredients or individual substances in mixtures.Footnote 27 Accurate identification and labelling of ingredients are especially critical for botanical supplements due to their potential toxicological impacts.Footnote 28 , Footnote 29 However, developing effective quality control measures for singular ingredients within complex botanical mixtures is widely recognised as a difficult task.Footnote 30 , Footnote 31 Furthermore, these quality control measures are often not publicly disclosed, as they remain proprietary to FBOs or third-party contractors, limiting transparency and collaboration in addressing these challenges.Footnote 32
2. Consideration of pharmacopoeias as a remedy?
The current regulatory framework for food supplements in the EU places primary responsibility on FBOs, with a more limited role for competent authorities, to design and implement appropriate production and quality control procedures.Footnote 33 In contrast, jurisdictions outside the EU have adopted an alternative approach to enhancing the quality and safety of food supplements by providing the industry with scientifically validated production and quality control standards through pharmacopoeial codification.Footnote 34 In the USA, following debates over the regulatory status of certain botanical supplements and the subsequent enactment of the Dietary Supplements Health and Education Act (DSHEA) in 1994, the United States Pharmacopoeia (USP) was revised to incorporate supplement ingredients and preparations.Footnote 35 Additionally, the American Herbal Pharmacopoeia (AHP), which specialises in botanical supplements and ingredients, is accessible to supplement manufacturers.Footnote 36
In Canada, food supplements have been regulated as natural health products (NHPs), a category of over-the-counter (OTC) drugs, since 2004.Footnote 37 However, there is no specific Canadian pharmacopoeia dedicated to natural health products.Footnote 38 Instead, authorities actively encourage FBOs to utilise validated production and laboratory quality control methods outlined in recognised pharmacopoeias, such as the Ph. Eur. or the USP.Footnote 39 , Footnote 40
Traditionally associated with the pharmaceutical industry, pharmacopoeias constitute public collections of monographs containing standardised guidelines for defining, identifying, preparing, and storing ingredients, raw materials, and formulations. They also include suitable methods for determining the quantity, purity, and quality of listed ingredients or galenic preparations.Footnote 41 With contributions from stakeholders, including academics, regulatory authorities, and industry representatives, the development of pharmacopoeial monographs often achieves a high level of methodological validation.Footnote 42 In this context, the Ph. Eur. has long been established as a common reference standard for quality assurance programs across the European pharmaceutical market.Footnote 43 Given the challenges FBOs face in implementing effective quality control, pharmacopoeial standards applicable to supplements could offer a low-threshold solution by providing uniform, validated reference standards for FBOs in the EU.
II. Methodology
Through employing the functional method of comparative law, this study will examine the potential of the Ph. Eur. to serve as a platform for accelerating the development of quality control methods within the EU food supplement sector using the regulatory frameworks of the USA and Canada as case studies. The USA and Canada were selected as case studies as they already integrated pharmacopoeial standards into their regulatory systems, albeit to varying degrees, providing a broader perspective on the application of such standards in supplement regulation.Footnote 44 Moreover, the United States hosts the world’s largest supplement market, whereas Canada has adopted a distinct regulatory approach to supplements. As EU food law must balance progressing the EU’s internal market freedoms with ensuring a high level of consumer protection, this study also examines the legally binding nature of pharmacopoeias within these regulatory frameworks.Footnote 45 , Footnote 46
The functional method of comparative law provides an effective approach for identifying similarities and differences between legal frameworks governing a specific sector across different jurisdictions.Footnote 47 As described by previous research, comparative law can provide deep understanding and accelerate improvements of a legal system.Footnote 48 The functional method does not solely investigate the theoretical background of the studied legal frameworks provided by comprehensive law texts.Footnote 49 Instead, it also considers the effects created by these frameworks, thereby investigating different approaches to dealing with a comparable socio-legal problem.Footnote 50 Although there is no uniform definition of conducting functional legal comparison, it has been recognised as a suitable research method in the context of European law development.Footnote 51 In this study, we first examined and compared the corresponding legal frameworks defining and regulating the quality of food supplements in the observed countries. Second, we comparatively assessed the relevance of pharmacopoeial standards within the respective supplement markets. European legal texts were retrieved from N-Lex, US–American legal texts from the Federal Register. Canadian legislation was retrieved from the public Justice Laws Website maintained by the Canadian Department of Justice. To enhance the context of the studied legal texts, we included relevant grey literature, such as institutional statements, in the functional comparison.Footnote 52
The comparison between the European Roman law-based legal culture against the Anglo-Saxon legal cultures of the USA and Canada is not subject of this research as the assessment of different legal cultures primarily focuses on broad societal patterns and would exceed the scope of this study.Footnote 53 , Footnote 54
III. Results
1. Food supplement quality and safety framework conditions
a. Classification: Food or medicine
In the EU, supplements are regulated as foodstuff intended to supplement the regular diet with concentrates of vitamins, minerals and other micronutrients such as botanicals, amino acids, and other bioactive substances via the Food Supplements Directive.Footnote 55 Food supplements must also be marketed in pharmaceutical-like single-dosed forms intended for oral ingestion, such as capsules, tablets, powders or liquids.Footnote 56
In the USA, the Federal Food, Drug and Cosmetics Act (FD&C Act) stipulates comprehensive legal framework conditions for several product categories derived from the food and pharmaceuticals sector, defining basic terms and responsibilities.Footnote 57 In 1994, the FD&C Act was amended by the Supplements Act DSHEA.Footnote 58 Similarly to EU legislation, DSHEA Article 3 (21 United States Code (U.S.C.) Article 321(ff)) defines food supplements as foodstuff intended to supplement the diet, containing minerals, vitamins, botanicals, amino acids or other dietary ingredients and does not include a substance considered as a drug, antibiotic, biological or a substance under clinical investigation.Footnote 59
In Canada, food supplements are categorised as NHPs, a type of OTC self-care products containing naturally occurring substances designed for personal health maintenance.Footnote 60 Since 2004, around 120,000 products have been licensed, of which around half have been placed on the Canadian market.Footnote 61 Substantiated in a generally assumed level of risk derived from their consumption, although lesser than other pharmaceutical preparations, the corresponding regulatory framework provided by the Natural Health Products Regulation (NHPR) was adopted in 2004.Footnote 62 NHPR Article 1 defines NHPs as preparations containing Schedule 1 ingredients, meaning botanicals or their parts, algae, bacteria, fungi, animal materials or extracts and isolates derived from them.Footnote 63 NHPR Schedule 1 lists minerals, probiotics, enzymes, and certain vitamins as permitted ingredients.Footnote 64 Homoeopathic and traditional medicines, such as traditional Chinese medicine or ayurvedic medicines, and some cosmetics, such as certain sunscreens or toothpastes, also fall in the category of NHPs.Footnote 65 As of 2023, following the enactment of the Protecting Canadians from Unsafe Drugs Act (Vanessa’s Law), the definition of therapeutic products in the Canadian Food and Drug Act (F&D Act) was revised to include NHPs.Footnote 66
b. Baseline prerequisites for lawful market access
The eligibility of food supplements being placed on the market in the EU is generally regulated by the General Food Law and the Food Supplements Directive, stipulating that all foodstuff must be safe for human consumption, for which the FBO is responsible, and cannot be a medicinal product, cosmetic or medical device.Footnote 67 , Footnote 68 In the USA, by stating that food is considered adulterated if it is injurious to human health, FD&C Act Section 402(a)(1) (21 U.S.C. Article 342(a)(1)) also places the responsibility of ensuring food safety upon the FBO.Footnote 69 Section 402(g)(1) (21 U.S.C. Article 342(g)(1)) further requires FBO to manufacture their products in accordance with the applicable Good Manufacturing Practices (GMP) regulations.Footnote 70 DSHEA Article 4 (21 U.S.C. Article 343) requires supplements to be safe for consumption.Footnote 71 However, it places the burden of proof that a product or ingredient is unsafe for it being considered injurious upon the responsible authority, meaning the Food and Drug Administration (FDA).Footnote 72
Although NHPs are considered therapeutic products, the Canadian F&D Act only applies to them if specifically mentioned, as the NHPR is the primary legal act providing framework conditions.Footnote 73 However, the F&D Act stipulates that therapeutic products and foodstuffs must be safe for humans to consume (compare Section B.01.001, B.01.002., and C.01.016).
c. Technical regulations
While not directly aimed at supplements, horizontal technical specifications laid down in EU legislation concerning food quality and safety also apply to supplements as they fall under the definition of foodstuff.Footnote 74 Commission Regulation (EU) 2023/915 specifies maximum levels for food contaminants such as heavy metals, mycotoxins, pyrrolizidine alkaloids, polycyclic aromatic hydrocarbons (PAHs), dioxins or polychlorinated biphenyls (PCBs).Footnote 75 Regulation (EC) No 396/2005 further regulates maximum pesticide residue levels, while Regulation (EC) No 2073/2005 specifies microbiological criteria for foodstuff.Footnote 76 , Footnote 77 General requirements concerning product labelling, allergen declarations and advertisement claims are laid down by Regulation (EU) No 1169/2011 (Food Information Regulation) and Regulation (EC) No 1924/2006 (Health Claims Regulation).
Pursuant to Regulation (EC) No 1925/2006, the general use of ingredients or substances in food may be prohibited or limited in the EU if placed in the annexes of the regulation, such as ephedra or red yeast rice extracts.Footnote 78 Positive Union lists on ingredients approved for use in supplements exist only for vitamins and minerals, which are placed in the annexes of the Food Supplements Directive.Footnote 79 The creation of a list of approved ingredients other than nutrients, namely botanicals or other bioactive substances, was abolished by the EC in 2008.Footnote 80 Instead, it was anticipated that the principle of mutual recognition, where a product lawfully sold in a Member State cannot be restricted from entering the market in another Member State, would contribute to harmonising this supplement category.Footnote 81 As this particular mode of governance has not been widely established in the supplement sector, the use of botanicals in the EU remains mostly regulated at the national level.Footnote 82 While the applicable legal framework sets technical conditions that food supplement production has to meet, it remains the responsibility of the FBO to develop quality control methods suitable for process monitoring.Footnote 83 Since no uniform codex containing validated methods is available, FBOs must develop and implement these themselves or commission a third-party contractor.Footnote 84 The appropriateness of the implemented measures is regularly inspected by food safety authorities, as the assessment of production and quality control systems is mandated by Article 9(1) of the Official Controls Regulation (Regulation (EU) 2017/625).Footnote 85
Contrary, the quality of food supplements on the US market is further regulated by Chapter I, Subchapter B, Part 111 of Title 21 of the Code of Federal Regulation (21 CFR 111), which codifies current GMP (cGMP) rules applicable to manufacturing, packaging, labelling, and holding operations.Footnote 86 It contains detailed requirements that FBOs must meet regarding personnel and staff training, documentation, sanitary conditions, facility specifications and equipment.Footnote 87 Subpart E specifically mandates steps quality control systems should incorporate, emphasising the need for scientifically valid methods to continuously ensure defined identity, purity, composition and contamination limits.Footnote 88 However, manufacturers must only implement measures to identify reasonably expected contaminations and may rely on quality certificates provided by suppliers or third parties.Footnote 89
In Canada, the NHPR sets out a comprehensive framework governing the manufacturing, distribution and sale of NHPs. cGMP requirements are laid down in Part 3, and Article 43(1) makes compliance with them mandatory for selling, manufacturing and distribution. While cGMP requirements are more generally described, stipulating the need for business operators to implement sufficient measures to assess purity, identity, quantity and potency, describe testing methods and define their tolerance levels, emphasis is placed upon the responsibility of quality assurance staff Article 47 requires staff to be qualified for functional roles through sufficient training, education, or experience. Article 51 requires businesses to employ a trained quality assurance person responsible for approving every specification, material, method, procedure or activity before manufacturing and selling NHPs. To assist manufacturers in their legal obligations, the Natural and Non-prescription Health Products Directorate (NNHPD) has published a GMP guidance document, laying down specific steps ranging from sanitary conditions and formulation of standard operating procedures to effectively performing quality assurance activities.Footnote 90
d. The role of food safety authorities
EFSA, on behalf of the EC, is the EU’s authority responsible for safety assessments of food ingredients and providing guidance for FBOs. Following the adoption of the Food Supplements Directive, EFSA developed the list of minerals and vitamins and their chemical forms permitted for use in supplements.Footnote 91 Additionally, in the absence of respective legal statutes, EFSA published an overview of tolerable upper intake levels for nutrients.Footnote 92 Per Regulation (EC) No 1925/2006, EFSA carried out safety assessments for substances for which safety concerns were raised by Member States or the EC and subsequently banned or restricted, such as monacolins, ephedra or yohimbe.Footnote 93 However, following a decentralised approach, enforcing compliance of FBOs with EU food law to ensure safety and quality through inspections or sanctions remains the responsibility of national competent authorities.Footnote 94
Health Canada, being the Canadian Ministry of Health, and its subordinate NNHPD are the responsible authorities for regulating the use and sale of NHPs.Footnote 95 Via the introduction of Vanessa’s Law, Health Canada is entitled to order recalls, enclose confidential business information, or mandate healthcare institutions to report adverse reactions.Footnote 96 The act aims to strengthen regulatory oversight of NHPs in response to an audit by the Commissioner of the Environment and Sustainable Development in 2021.Footnote 97 , Footnote 98 Its report identified, among other issues, an inability of Health Canada to comprehensively enforce NHP safety and quality under the NHPR, e.g., successfully removing adulterated and contaminated products from the market.Footnote 99
In the USA, the FDA’s authority to regulate the sale and manufacturing of food supplements is limited by DSHEA to sole post-market enforcement.Footnote 100 Therefore, unlawfully marketed products can only be removed from the market upon individually establishing that they are misbranded, adulterated or hazardous.Footnote 101 In response to monitoring the sale of unlawfully sold or insufficiently produced supplements, the FDA has repeatedly issued warning letters to manufacturers.Footnote 102
e. Notification procedures
As NHPs are considered therapeutic products under Canadian law, the NHPR prohibits their manufacturing, sale and importing without a respective license.Footnote 103 Business operators are mandated by NHPR Part 1 to apply with the NNHPD for a product license prior to selling (compare Article 4(1)). Application requirements are also specified, whereas the names of ingredients and excipients and their potency, quantity, and purpose must be stated. After issuing a license, every NHP is assigned a number, which must be presented on the label. Amendments or changes to the permit needs approval from the authority or must be notified 60 days prior. NNHPD retains the authority to remove a product from the market upon the reasonable belief of unsafety and the business operator’s inability to prove its safety sufficiently.Footnote 104 As of 2023, Canadian authorities receive around 10,000 product applications annually.Footnote 105 NHPR Part 2 also mandates that every production site or storage site, in the case of imported NHPs, must be licensed by the NNHPD before manufacturing, packaging, labelling, or storing NHPs.Footnote 106 Site licence applications further require the statement of an assigned quality assurance person that all used buildings, equipment, practices and procedures comply with cGMP requirements. If a licence is obtained by an FBO, it must be renewed periodically.
In the EU, FBOs intending to place a new product on the market are required by the Food Supplements Directive to notify the responsible national authority.Footnote 107 However, the design of the notification procedures is left to the individual European Member States and may range from a simple notification form to authorisation-like procedures.Footnote 108 As many botanical ingredients, extracts or preparations may be found in food or medicine, EU legislation allows the marketing of a majority of them as herbal medicinal products (HMPs) or food supplements.Footnote 109 , Footnote 110 HMPs are defined as pharmaceuticals containing a botanical active ingredient by Directive 2001/83/EC (Medicinal Products Directive), thereby being regulated by medicinal products law in terms of efficacy, quality and safety.Footnote 111 Botanical ingredients used in medical indications for at least 30 years can also be registered as Traditional Herbal Medicinal Products (THMPs) under the provisions of Article 16(a)(1) of the Medicinal Products Directive, which includes a simplified authorisation procedure, requiring proof of quality and safety, but not of efficacy.Footnote 112 Depending on commercial interests, such as authorisation procedures, development costs or permitted advertisement claims, FBO may choose under which legal framework they register their product.Footnote 113 , Footnote 114 The European Court of Justice (ECJ) established in its case Commission v Germany (C-319/05) that supplements containing botanical ingredients, which may be found in both food or pharmaceuticals, should be considered a supplement if their physiological effect and dosage are comparable to regular dietary consumption of this ingredient.Footnote 115
f. New dietary ingredients
Following a debate on the legal status of botanical supplement ingredients, comparable to the EU borderline product issue, all supplement ingredients legally marketed in the USA before 1994 are considered safe without the need for pre-marketing approval from the FDA since the adoption of DSHEA.Footnote 116 Since then, only so-called new dietary ingredients (NDI), which were placed on the market after DSHEA was adopted, require pre-market approval from the FDA.Footnote 117 FBO intending to sell NDI supplements must notify the authority 75 days before market entry, during which the agency shall issue a decision based upon an individual safety assessment.Footnote 118 However, as stated by the FDA, the growing number of available supplements and FBOs pose a great regulatory challenge.Footnote 119 As estimated by the authority, several thousand NDI were not notified correctly prior to market entry, circumventing pre-market authorisation procedures.Footnote 120
Comparable to the US-American regulation of NDI, the EU Regulation (EU) 2015/2283 (Novel Food Regulation) defines substances which have not significantly been consumed in the EU before 1997, are newly developed and innovative food products, or are foodstuff produced by using new technologies as novel foods.Footnote 121 Regarding supplements, these mainly concern new botanicals, certain bioactive micronutrients or new analogues of permitted nutrients. Comparable to the USA, novel foods in the EU also require pre-market authorisation by the EC, contingent upon individual safety assessments by EFSA.Footnote 122 FBOs must detail scalable and reliable production procedures and provide a proof of safety in their application file.Footnote 123 EFSA published several guidance documents aimed at FBOs, detailing the required product information necessary for a sufficient safety assessment. Besides toxicological data, emphasis is placed on the description of production procedures and the provision of compositional data and stability. In its Guidance on the scientific requirements for an application for authorisation of a novel food in the context of Regulation (EU) 2015/2283 from 2024, EFSA explicitly states a preference for internationally recognised and validated methods such as provided by the Ph. Eur.Footnote 124 Another example of the use of Ph. Eur. quality control methods relevant to novel food safety assessment is the mention of Ph. Eur. methods for conducting dissociation studies.Footnote 125 Further, in its scientific opinion on assessing the safety of botanical ingredients in food supplements, EFSA advises FBOs to follow the Ph. Eur. nomenclature for the identification of botanicals.Footnote 126 To standardise manufacturing procedures of botanical supplements and set analytical specifications for characterising one or multiple ingredients, EFSA also recommends leveraging on validated Ph. Eur. methods.Footnote 127 However, the use of these methods is focused on the proof of safety of an ingredient or product, albeit there might be an overlap in determining a product’s quality to demonstrate its safety. Therefore, supervising production procedures and quality control methods for food supplements containing novel food ingredients remain with the responsible national food safety authorities.
2. Pharmacopoeias: Ph. Eur., USP-NF, AHP, compendium of monographs
a. Pharmacopoeial compendia
The Ph. Eur. is the EU pharmacopoeia, codifying definitions of active pharmaceutical ingredients (APIs) and preparations thereof and validated analytical or production methods.Footnote 128 The European Directorate for the Quality of Medicines & Health Care (EDQM), a directorate of the Council of Europe, is the responsible agency for developing the Ph. Eur. and its monographs. In cooperation with the European Medicines Agency (EMA), national safety authorities, academic experts, and stakeholders from the pharmaceutical industries, the EDQM’s Ph. Eur. Commission aims to continuously update and revise the Ph. Eur. monographs and general chapters.
In the USA, USP develops and publishes standards for ensuring the identity, purity and strength of APIs, pharmaceutical preparations, excipients and food supplements, published as monographs in the USP-National Formulary (USP-NF).Footnote 129 Unlike EDQM, USP is a scientific non-profit organisation aiming to improve the quality of pharmaceuticals and food supplements and strengthen its supply chains by developing public reference standards.Footnote 130 It is governed by the USP Convention, which consists of 455 primarily US–American member organisations, ranging from healthcare professional associations, consumer organisations, manufacturer and trade associations, and academic or governmental entities.Footnote 131 The development of monographs is conducted by voluntary USP Expert Committees working together with FDA experts representing governmental liaisons.Footnote 132 The life cycle of monographs is also continuously updated by incorporating public comments from academia, industry, healthcare professionals or governmental entities.Footnote 133 Additionally, the AHP non-profit organisation was founded in 1995, shortly after DSHEA was adopted. AHP provides several public monographs on botanical ingredients intended for use in herbal medicines or food supplements.
Unlike the EU and the USA, the quality of NHPs and other types of therapeutic products are not defined by a national pharmacopoeia in Canada.Footnote 134 Instead, the NNHPD provides the Compendium of Monographs, explicitly pertaining to single or multiple NHP ingredients and specific so-called product monographs.Footnote 135 Compendial monographs set out the proper common and scientific name, administration route, recommended use, dosage, preparation method, current risk information and duration of use.Footnote 136 However, unlike the Ph. Eur. or USP, they do not detail methods for verification of quality, purity or identity. All monographs are publicly available through the Natural Health Products Ingredient Database and may function as references for which efficacy, quality and safety have been demonstrated during licence application procedures.Footnote 137 , Footnote 138 , Footnote 139
b. Monographs
The Ph. Eur.’s general part contains detailed information on analytical methods for physicochemical and microbiological testing, standard procedures for assays involving biological materials, and descriptions of preparing, using and calibrating reference standards for these methods.Footnote 140 An additional list of reagents for use in analytical methods and assays, detailing their preparation and standardisation, is also provided.Footnote 141 A chapter on pharmaceutical technology describes preparation and testing methods, including guidelines on their respective performance and specifications for primary contact materials and dosage forms such as tablets, capsules or injections.Footnote 142 The specific part contains a collection of monographs which define and characterise natural, synthetic, semi-synthetic, biological or microbiological API.Footnote 143 Each API monograph contains information and reference values for analytical identification, purity and stability methods.Footnote 144 Monographs on excipients and bulking agents for pharmaceutical use can be found in the general part.Footnote 145
Like the Ph. Eur. monographs, USP–NF monographs define quality aspects of a substance or preparation, such as identity, purity, strength, composition or pharmacodynamic aspects and provide validated testing methods and acceptance levels for these criteria.Footnote 146 Besides monographs, the USP–NF also contains general chapters, which provide manufacturers with information on validated production and testing procedures.Footnote 147 Additionally, USP–NF provides material references as standards for reagents and apparatus to be used in conjunction with the general chapters and monographs.Footnote 148 AHP monographs outline quality control methods required to assess the identity, purity and quality solely of botanical preparations and raw ingredients. Additionally, they also encompass reviews on traditional use and current scientific-based knowledge.
As quality assurance methods are not described by NHP monographs, the NNHPD provides an additional quality control guideline to FBOs, detailing validated control procedures, analytical methods and corresponding specifications.Footnote 149 Moreover, the NNHPD specifically references methods and procedures described by other international pharmacopoeias such as USP–NF or Ph. Eur.Footnote 150 Against the background of a Canadian national pharmacopoeia being unavailable, the NNHPD generally accepts and supports FBOs in leveraging specifications and methods published in certain other international pharmacopoeias to effectively ensure the quality of NHPs and food supplements.Footnote 151
c. Compendial legal character
As the legal framework conditions for pharmaceuticals are more restrictive, based on a generally higher assumed risk for consumers arising from consumption thereof, Article 8(3)(h) of the European Medicinal Products Directive stipulates that APIs and preparations thereof must comply with specifications laid down in the Ph. Eur. to obtain a marketing authorisation.Footnote 152 , Footnote 153 , Footnote 154 Mandating the summary of product characteristics and the production process to comply with the pharmacopoeia, the legally binding character of the Ph. Eur. in the EU pharmaceutical sector is further strengthened by Article 11 and 23.Footnote 155 Although pharmacopoeial monographs may concern ingredients or formulations identically used in food supplements, such as minerals, vitamins, botanical preparations, or essential oils, the Ph. Eur. exclusively applies to medicinal products.Footnote 156 , Footnote 157 FBOs manufacturing supplements containing ingredients also referenced in the Ph. Eur. could choose to adhere to pharmacopoeial reference standards voluntarily. However, previous research has identified great differences in quality between herbal medicinal products and food supplements containing similar ingredients on the EU market.Footnote 158
The USP–NF is legally recognised as the official compendium of the USA by Section 201(j) of the FD&C Act (21 U.S.C. Article 321(j)).Footnote 159 Section 501(b) FD&C Act (21 U.S.C. Article 351(b)) stipulates that pharmaceuticals which do not comply with USP standards are deemed to be adulterated, thereby making adherence mandatory for business operators.Footnote 160 Regarding food supplements, the USP–NF is also recognised by Section 403(s) FD&C Act (21 U.S.C. Article 343(s)) as an official compendium, but only deeming them misbranded if they state to comply with a compendial standard but fail to do so.Footnote 161 , Footnote 162 Therefore, compliance with the USP–NF remains voluntary in the supplement sector.Footnote 163 However, cGMP rules applicable to food supplement production laid down in 21 CFR 111 emphasise the implementation of scientifically valid methods.Footnote 164 To clarify the term of validation, the FDA stated in their final rule on the cGMP code in 2007 that while the authority recognises the significance of compendial standards such as USP or AHP, a specific compendium shall not be listed as a source of validated methods.Footnote 165 Instead, it should remain the responsibility of the FBO to validate applied production and quality control methods, regardless of whether they are compendial or not.Footnote 166
d. Limitations of pharmacopoeial methods in quality assurance
Despite methods and procedures described by the Ph. Eur. are considered validated and sufficient for meeting their analytical purposes, previous research identified cases in which they could not deliver desired analytical results compared to other non-pharmacopoeial methods.Footnote 167 This was partly attributed to Ph. Eur. materials not always corresponding with the latest materials practically in use. Additionally, research has identified a shortcoming of Ph. Eur. development regarding the adoption of innovative laboratory methods, such as the characterisation of different nanoparticles or DNA-based analytical methods pertaining to identifying herbal ingredients individually or in multi-ingredient compositions.Footnote 168 , Footnote 169
In the USA, where FBOs are voluntarily subjected to USP standards, only few seek official USP verification. Compared to around 80,000 supplements available on the US market, as of 2024, only a small number of around 100 products are certified with the USP label.Footnote 170 , Footnote 171 Additionally, despite issuing warning letters from the FDA to FBOs regarding the detection of insufficient food supplement quality, research has identified an increasing trend of supplements adulterated with pharmaceuticals sold in the USA.Footnote 172 In Canada, the regulatory requirements to manufacture and sell food supplements are higher than in the EU and USA due to them being considered a subset of therapeutic products. However, in the 2021 audit report, the Commissioner of the Environment and Sustainable Development also emphasised that Health Canada failed to enforce compliance with NHPR and GMP regulations due to a lack of routine inspections of production sites between 2017 and 2020.Footnote 173 The limited monitoring of license holders led to non-compliance of FBOs, e.g., selling of unlicensed products, unauthorised manufacturing activities, or product mislabeling.Footnote 174 This was partly found to be due to the high numbers of registered products on the market and pending licence applications affecting Health Canada’s ability to enforce NHP regulations.Footnote 175
IV. Discussion
The EU’s regulatory framework governing food supplements faces multiple challenges to ensure access to products of sufficient quality and safety.Footnote 176 Previous research has identified a wide range of quality issues impairing the safe consumption of food supplements available in the EU.Footnote 177 Additionally, the extent to which they are present in food supplements remains uncertain, and it has been estimated that only 1 % of adverse effects are reported.Footnote 178 Consumers cannot generally assess and differentiate the quality of supplements nominally containing the same ingredients.Footnote 179 Instead, they have to rely on efficacy and quality claims made by FBOs and trust that the stated quality complies with technical specifications in EU regulations.Footnote 180 , Footnote 181 However, as product quality can be considered a factor driving competition in a free market, the lack of opportunity for consumers to independently assess supplement quality could represent a distorting factor for the EU internal market.Footnote 182 Furthermore, against the background of the continuously expanding supplement market, it could be considered an incentive to reduce adequate quality assurance due to financial or other interests despite the risk of punitive actions or sanctions from regulatory authorities.Footnote 183
The regulation of the EU supplement market has been described as fragmented by previous research due to missing harmonisation in certain aspects, such as permission of herbal and bioactive ingredients or dosages, resulting in differing national regulatory approaches.Footnote 184 Additionally, the enforcement practices of responsible safety authorities vary greatly between Member States. These have not been fully mitigated despite certain Union-level governance efforts, e.g., via mutual recognition procedures.Footnote 185 , Footnote 186 Since harmonisation efforts in the EU aim to strengthen consumer protection and establish the internal market, a single set of quality rules generally recognised for reference purposes may reduce regulatory fragmentation. The Ph. Eur. has long been established in the pharmaceutical sector, and its uniform quality standards benefit the industry and consumers alike. Manufacturers and third-party contractors gained public access to effective, validated methods for analytical testing to ensure reliable product quality management in accordance with the requirements set by the applicable legislation. Despite singular incidents, patients generally benefit from the exclusion of low-quality therapeutic products from the EU market via the mandatory adherence to Ph. Eur. standards. As food supplements and pharmaceuticals share galenic forms and properties, the Ph. Eur. could potentially offer comparable opportunities for the supplement market.Footnote 187 , Footnote 188
The American and Canadian regulatory systems illustrate that it is possible to include pharmacopoeial compendia in food supplement regulation to improve the quality and safety by strengthening quality control practices.Footnote 189 , Footnote 190 Additionally, the factual implementation of the Ph. Eur. in the Canadian NHP sector could be considered as an example of the Brussels effect, whereas EU legislation is adopted or impacts comparable legal frameworks in third countries outside the EU.Footnote 191 Despite not being recognised as an official supplement compendium in the EU, EFSA already references the Ph. Eur. in its ingredient safety assessments and encourages FBOs to leverage validated pharmacopoeial methods.Footnote 192
However, the results of this study demonstrate obstacles encountered by Canadian and USA authorities in implementing pharmacopoeial reference standards in the respective supplement markets, illustrated by the emergence of quality issues comparable to those identified in the EU.Footnote 193 , Footnote 194 In the USA, the adulteration of supplements with APIs, usually found in prescription drugs or doping substances, remains a persisting issue in particular.Footnote 195 , Footnote 196 This has primarily been attributed to DSHEA placing the burden of proof of a product hazard or manufacturing sites and procedures not being cGMP-compliant upon the FDA.Footnote 197 , Footnote 198 Regarding NDI, for which pre-market approval is required, the FDA has stated that thousands of unapproved supplements containing such ingredients are available on the market.Footnote 199 This, further illustrated by the FDA repeatedly issuing warning letters to manufacturers, could highlight that manufacturers tend not to comply with the applicable legal provisions of DSHEA.Footnote 200 , Footnote 201 Against the background of a legal framework considered to shield the private sector from extensive regulatory oversight, FBOs manufacturing supplements generally seem to refrain from adopting pharmacopoeial standards.Footnote 202 Although the low number of USP-verified food supplements does not necessarily indicate that FBOs do not apply these standards, there appears to be little incentive to seek compliance with the USP–NF officially.Footnote 203
In contrast, the Canadian legal framework conditions governing supplements impose a stricter regime on FBOs for manufacturing and selling NHPs.Footnote 204 However, authorities allow for a flexible approach while keeping high-quality validated reference standards, whereas FBOs may choose their preferred pharmacopoeia or develop a comparable method or procedure by themselves.Footnote 205 , Footnote 206 Previous research found that the Canadian NHP industry has welcomed the approach, as although some FBOs followed this approach before the introduction of the NHPR in 2004, its introduction advanced equal conditions in the NHP market regarding efforts for implementing comprehensive quality assurance programs.Footnote 207 The acceptance of the introduction of higher quality and safety requirements via NHPR has been described as being promoted through close communication of Canadian authorities with stakeholders such as industry associations or healthcare professionals during its development.Footnote 208 Despite its introduction is generally being considered an improvement of food supplement regulation in Canada, it also increased the regulatory and financial burden on FBOs.Footnote 209 , Footnote 210 Aligning with observations from other food categories such as the EU novel food sector, streamlining the NHP regulatory conditions has been found to increase the risk of lowering innovation in this sector.Footnote 211 , Footnote 212 SMEs could be especially affected, as they require more resources to market innovative or niche products lawfully.Footnote 213 For Canadian authorities, the regulatory burden to enforce safety and quality provisions of the NHPR has also increased.Footnote 214 In this regard, previous research has identified a lack of regulatory oversight by provincial health ministries due to unmet personnel requirements.Footnote 215 Additionally, the reliance on the NHP industry to provide correct testing methods and results for products and manufacturing sites has also been found to be a potential weak point of the Canadian NHP regulation.Footnote 216 This seems to be acknowledged by Canadian authorities, as Health Canada’s ability to supervise and enforce applicable NHP regulations appears to be challenged by a high number of products, licence applications and manufacturing sites.Footnote 217 Additionally, while Canadian sellers, importers and distributors are obligated to comply with the NHPR, selling and importing non-compliant supplements via internet trade has been identified as a possibility to circumvent implemented higher regulatory requirements.Footnote 218 Therefore, amending the Ph. Eur. to include food supplements and the extent of its legally binding character in this sector must be considered carefully.
EU primary law mandates that interventions with the EU’s free movement of goods, including foodstuff, should not be more restrictive than necessary and justified in balancing other fundamental rights such as the protection of consumer health. Within the EU’s risk-based legal framework governing products intended for use in humans, food supplements being considered as food nominally constitute a lower risk as compared to pharmaceuticals. Mandating FBOs and adherence to Ph. Eur. quality standards, originally intended to ensure safety and quality of a product category for which a higher risk has been established, could conflict with EU law. However, leaving it to the FBOs’ discretion to adhere to pharmacopoeial standards could lead to a comparable situation like in the USA, where FBOs are reluctant to apply them to their manufacturing operations to decrease production costs and increase profit margins.Footnote 219 , Footnote 220 Contrary, as discussed by previous research and observed from our study on the Canadian NHP regulatory framework, mandatory compliance to augmented safety legislation could increase the regulatory burden of administrative procedures for authorities and industry in the EU.Footnote 221 As the adoption of Vanessa’s Law in Canada demonstrated, food safety authorities require sufficient resources and a robust legal mandate to enforce such regulations. The decentralised enforcement landscape across the Union may form another obstacle to effectively implementing this approach.
Another aspect that should be considered is the development of pharmacopoeial validated methods, as the development of analytical methods suitable for ingredient or product quality control is rapidly advancing. Although pharmacopoeias such as the Ph. Eur. or USP–NF are constantly reevaluated by the responsible committees, concerns have been raised by research whether new and innovative methods, e.g., genetic fingerprinting of herbal ingredients or identification of nano-particles, are insufficiently integrated.Footnote 222 , Footnote 223 Missing suitable reference standards despite a potential mandatory adherence could lead to a regulatory gap, creating legal uncertainty, especially in the field of innovative products, underscoring the effect of additional regulatory burden on consumers’ access to new products. However, in this regard, the Canadian NHP framework, providing the opportunity for FBO to leverage non-pharmacopoeial methods if they are considered a suitable quality control method nonetheless, could be considered.
In conclusion, the Ph. Eur. could serve as a platform to generally improve quality control practices of food supplement FBOs, based on its already existing overlap with this product category. Additionally, while EFSA promotes the use of pharmacopoeial validated methods in the supplement and novel food sector, Canada has officially encouraged the use of the Ph. Eur. for supplement quality standards. However, if considered in the EU, careful considerations such as the extent of legal adherence by FBO, an increased need for resources for both industry and authorities, and the potential effects on innovations on the market must be made.
This study is subject to several limitations considering the methodological approach of functional comparative legal analysis. While extensive literature research was performed, insights derived from empirical research, such as expert interviews, are missing. As empirical methods can contribute to support findings derived from comparative legal analysis, data on stakeholders, such as FBOs or authorities illustrating their perception of pharmacopoeial references to supplements, could have been a valuable addition. However, it would have exceeded the scope of this research. Additionally, the studied legal systems differ significantly, as the EU is governed by a multi-leveled structure consisting of horizontal technical regulations and different food law enforcement structures on national levels. Canada and the USA have implemented national regulatory systems, independent from an additional comparable supra-national legal framework. Further, while supplements are considered foodstuff in the EU and the USA, they are regulated as therapeutic products in Canada. This has major implications for legal quality and safety requirements, which cannot necessarily be met by EU and US food law.
V. Conclusion
Pharmacopoeial reference standards and monographs offer considerable potential to strengthen food supplement quality control practices. Although traditionally applied in the pharmaceutical sector, pharmacopoeial standards have long been extended to food supplements in major markets outside the EU. This study demonstrates, however, that both the scope of their application and the degree of industry adherence vary substantially.
Integrating food supplements into the Ph. Eur. could enhance consumer access to high-quality products while reducing barriers for SMEs to implement effective product quality control measures. Nonetheless, legislators should appropriately calibrate the extent to which the use of pharmacopoeial references is mandated. Minimal mandatory requirements risk discouraging the private sector from adoption for economic reasons. Conversely, overly stringent requirements could impose additional regulatory burdens on both the industry and authorities, potentially hindering the entry of innovative food products into the EU market.
Future research should therefore focus on empirical research to highlight the perspectives of the EU industry on proportionate strategies, that enhance the safety and quality control practices in the food supplement sector without impeding innovation or market access.
Declarations
The authors declare that no funding was received for conducting this study.
Competing interests
The authors declare none.
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