Guidelines for marketing authorisation for vitamin and mineral products
Table of contents
1. General
1.1 Background
1.2 What is covered by these guidelines?
2. Definitions
2.1 Exemption from the limits for maximum contents in food supplements
2.2 Can products which have already been authorised continue as strong vitamin and mineral products?
2.3 Only for human use and only for oral ingestion
3. How do you apply for a marketing authorisation, and how long will it take?
3.1 Four stages in the processing of applications
4. Application layout
Module 1: Administrative data
Module 2: Summaries
Module 3: Quality
Module 4: Non-clinical reports
Module 5: Reports on clinical studies
5. Requirements for manufacturing and wholesale
5.1 Manufacturing of active substances
5.2 Manufacturing, import and wholesale of the finished product
5.3 Manufacturers in Denmark
5.4 Manufacturers abroad
5.5 Importers in Denmark
5.6 Wholesalers in Denmark
8. Changes in authorised products
Annex 1. Table of contents
Annex 2. Four stages in the processing of applications
Annex 3. Examples of conversion factors
Annex 4. List of frequently used abbreviations
Annex 5. References to laws, Executive Orders etc.
Chapter 1. General
These guidelines have primarily been prepared as information and help for companies wishing to market a product in Denmark which is covered by Danish Executive Order no. 752 of 1 July 2008 on vitamin and mineral products, which companies must therefore apply to the Danish Medicines Agency for a marketing authorisation in advance.
These guidelines replace guidelines no. 157 of 20 October 1999.
1.1 Background
Products which
- contain vitamins and/or minerals,
- are in dosage form,
- are intended for humans and
- are designed for oral ingestion,
may be marketed as either food supplements covered by the Danish food legislation or as vitamin/mineral products covered by the Danish Medicines Act (see Annex 5, item 1 for reference). In addition, vitamin/mineral products intended for specific illnesses may be marketed as medicinal products which are covered by the general provisions of the Danish Medicines Act on medicinal products.
Whether a specific product should be marketed according to one or the other type of legislation depends on several factors and is based, among other things, on a specific assessment of the desired marketing of the product as well as the actual contents of vitamins and minerals.
These guidelines are concerned with the particular group of medicinal products which contain larger amounts of vitamins or minerals and which are exclusively marketed as products for the “prevention and treatment of deficiency conditions”. This group of vitamin/mineral products is often called “strong vitamin and mineral products”.
Food supplements are foods which in dosage form (tablets, capsules etc.) are intended to supplement a normal diet and which are concentrated sources of nutrients or other substances with a nutritional or physiological effect. Food supplements are defined and described in the Danish Executive Order on food supplements (see Annex 5, item 3 for reference). Information about this and about the associated guidelines is available from the Danish Veterinary and Food Administration.
Products, in which the active substances are exclusively vitamins and minerals in amounts which significantly exceed the normal daily requirements of adults, are covered by the Danish Executive Order on vitamin and mineral products.
The Executive Order establishes the particular requirements which must be met in order to obtain a marketing authorisation as medicinal products for this type of product. In addition, vitamin and mineral products are covered by the Danish Executive Order on marketing authorisation (see Annex 5, item 8 for reference) with the modifications which apply to vitamin and mineral products.
1.2 What is covered by these guidelines?
These guidelines elaborate the provisions of the Danish Executive Order on vitamin and mineral products (see Annex 5, item 2 for reference) – which includes a description of the distinction made for this type of product between medicinal products and food supplements. Furthermore, the requirements for manufacture, quality, safety, labelling etc. are elaborated. Annex 5 of the guidelines lists the most relevant executive orders and guidelines. Please note that these are revised continuously.
Chapter 2. Definitions
The assessment of whether a vitamin and/or mineral product is a medicinal product is performed in the same way as for all other types of products, i.e. as a specific assessment of whether the product is covered by the definition of medicinal products in Section 2 of the Danish Medicines Act.
According to Section 2 of the Danish Medicines Act, medicinal products are defined as any product that:
- is presented as a suitable product for the treatment or prevention of disease in human beings or animals, or
- may be used in or administered to human beings or animals in order to restore, change or modify physiological functions by having a pharmacological, immunological or metabolic effect, or to make a medical diagnosis.
A product can thus be a medicinal product if it is either stated as being able to prevent or treat diseases (the so-called presentation criterion) and/or if the product modifies physiological functions through a pharmacological, immunological or metabolic effect (the so-called functional criterion).
The Danish Medicines Agency website, www.dkma.dk, contains elaborative descriptions of the parameters which the Danish Medicines Agency includes in the assessment of whether a product is a medicinal product, either on the basis of the presentation used and/or on the basis of the effect of the product. If you are in doubt whether a product you want to market is a medicinal product and thus needs approval through a marketing authorisation before it can be sold, you can contact the Danish Medicines Agency to obtain a guiding statement on the classification of the product.
Only a few important elements should be emphasised here, which companies should take into consideration in the classification of vitamin and/or mineral products. For further elaboration, see the Danish Medicines Agency website.
In relation to the presentation criterion, a vitamin and/or mineral product will be considered a medicinal product if it is stated in connection with its marketing that the product is able to prevent or treat illnesses. In this regard, not only packaging information will be considered, but also information available on e.g. the company’s website, information leaflets, advertisements etc.
Vitamin and/or mineral products which are designed for ingestion in very large quantities may be considered to be covered by the functional criterion, cf. Section 2, para 2 of the Danish Medicines Act. There is no fixed limit to decide when a vitamin and/or mineral product is considered to be covered by the functional criterion. This is evaluated through a specific assessment which takes into consideration such factors as the type of vitamin/mineral, dosage, formulation form etc.
If you want to market vitamin and/or mineral products, it is important to note that the Danish Veterinary and Food Administration has established limits for the daily doses of vitamins and minerals that a food supplement is allowed to contain seen from a safety point of view. The maximum limits for food supplement which apply today are listed in the Danish Executive Order on food supplements and are available there. In addition, the Danish Veterinary and Food Administration has issued general exemptions for larger daily doses for several vitamins than those specified in the Executive Order on food supplements. These exemptions can be seen on the Danish Veterinary and Food Administration website, www.foedevarestyrelsen.dk.
Products which are marketed in such a way that they are covered by the Danish Medicines Act are medicinal products, regardless of whether the contents of vitamins and minerals exceed the maximum limit for allowed contents in food supplements.
2.1 Exemption from the limits for maximum contents in food supplements
It is possible to apply for an exemption from the maximum limits listed in the Danish Executive Order on food supplement, Annex 1, until such time as common EU maximum limits are introduced. Applications must be sent to the Division for Nutrition, Danish Veterinary and Food Administration, Mørkhøj Bygade 19, 2860 Søborg, Denmark. Until now, general exemptions have been granted for most vitamins, whereas no exemptions have been granted for minerals. Common EU maximum limits for the contents of vitamins and minerals in food supplement are expected to be established in 2009, after which time those limits will apply.
The possibility of exemption until then means that a wide variety of products which could previously not be marketed as food supplement, but required authorisation as medicinal products in accordance with the provisions on strong vitamin and mineral products, can be notified as food supplements. The general exemption limits that have been established are available on the Danish Veterinary and Food Administration website.
2.2 Can products which have already been authorised continue as strong vitamin and mineral products?
The possibility of applying for an exemption from the maximum allowed contents in food supplements raises some questions about existing and new products:
- Strong vitamin and mineral products with an existing marketing authorisation from the Danish Medicines Agency will be able to continue under the Danish Medicines Act if so desired by the company, even though the possibility of exemption from the Danish Veterinary and Food Administration provides an opportunity of marketing the product as a food supplement. If the owner of the marketing authorisation so desires, it is possible to apply for a notification of the composition of the product as a food supplement instead and subsequently withdraw the marketing authorisation as a medicinal product. The company can then market a new product with the same composition as the product which was previously sold as an authorised medicinal product.
- For vitamin and/or mineral products which do not have a marketing authorisation, it will not be possible to apply for an authorisation as a strong vitamin and mineral products with the Danish Medicines Agency, if the limits of exemption, or the future common EU limits, provide the opportunity of applying for authorisation of the product as a food supplement.
- For strong vitamin and mineral products containing active substances in amounts exceeding the limits of exemption, it will still be possible to apply for authorisation with the Danish Medicines Agency in accordance with the provisions of the Executive Order before marketing.
2.3 Only for human use and only for oral ingestion
The Danish Executive Order on vitamin and mineral products only covers products for human and not for veterinary consumption. Therefore, vitamin and mineral products for animals cannot be authorised according to these rules and are not covered by these guidelines. Applications in this regard should be submitted to the Danish Plant Directorate.
Only vitamin and mineral products for oral ingestion may be granted marketing authorisation in accordance with this Executive Order. Therefore, vitamin or mineral products, e.g. for external use or local use on mucosa, cannot be authorised as strong vitamin and mineral products.
Chapter 3. How do you apply for a marketing authorisation, and how long will it take?
Vitamin and mineral products covered by the Executive Order can only be marketed in Denmark if a marketing authorisation has been issued by the Danish Medicines Agency in advance.
For vitamin and mineral products covered by the Executive Order, it is possible to apply for authorisation by national application in accordance with the provisions for so-called bibliographical applications, cf. Directive 2001/83, Article 10a and Section 18 of the Danish Executive Order on marketing authorisation.
Applications must be compiled in accordance with the common EU application form, which is available on the European Commission website or can be downloaded from the Danish Medicines Agency website. The application form is available under Notice to Applicants (NtA) Volume 2B in both PDF and Word version.
3.1 Four stages in the processing of applications
The processing of new national applications for authorisation of medicinal products consists of four stages, which are described in Annex 1.
Applications for marketing authorisation must be submitted according to Guidelines for submission and technical validation of applications.
Language: draft of summary of product characteristics, package leaflet and labelling must be in Danish. Other documentation, including references to literature, may be in either Danish or English.
Fees for the authorisation of medicinal products cannot be paid in advance. The Danish Medicines Agency will send an invoice with one month of credit.
Chapter 4. Application layout
The application must be in the CTD (Common Technical Document) format in accordance with the guideline described in the EU guideline Notice to Applicants, Volume 2B. CTD is an international format for the layout of applications for marketing authorisation submitted to a medicines agency in Europe, the USA or Japan. The application must be compiled in modules, of which the most important ones are listed below. See also NtA, where all points are described in further detail.
Module 1: Administrative data
- Module 1.0: Accompanying letter with information about the type of application.
- Module 1.1: Table of contents with overview of the entire application.
- Module 1.2: Application form, including proposal for product name, component overview and annexes with information about manufacturing authorisations (Annex 6.6), any TSE certificates etc.
- Module 1.3: Product data, including draft of summary of product characteristics, package leaflet and labelling as well as information about user testing.
Vitamin and mineral products are covered by the Danish Executive Order on labelling (see Annex 5, item 7 for reference) which, among other things, contains requirements to the information which must be available from the outer and immediate packing material, including product name, pharmaceutical form, package size, declaration etc. It is also apparent from the Executive Order on labelling that the designation “Strong vitamin product”, “Strong mineral product” or “Strong vitamin/mineral product” must be listed in connection with the indication for medicinal products covered by the Danish Executive Order on vitamin and mineral products.
Products containing beta-carotene must be labelled: “Contains beta-carotene. Should not be ingested by smokers”.
Applications for marketing authorisation must contain a summary of product characteristics draft, which the Danish Medicines Agency will assess together with the application. If the application for marketing authorisation is approved, the Danish Medicines Agency will include the approved summary of product characteristics as an annex to the marketing authorisation.
No unauthorised changes must be made to the approved summary of product characteristics. Detailed guidance is available in the Danish Medicines Agency’s guidelines for the preparation of summary of product characteristics for pharmaceutical specialties for human consumption of 24 January 2003, revised 19 January 2006. These guidelines including template are available on the Danish Medicines Agency website.
Module 1.3 is also used to present the result of the user testing of the labelling and the package leaflet made by patient groups, or to state a reason why such testing has not been made. Finally, it must be described how the requirement that the name of the medicinal product must be written in Braille (embossed printing for the blind) is going to be met. - Module 1.4: Data about the experts cf. modules 3, 4 and 5.
The overview must contain a critical assessment of the data and references which form part of the safety documentation. The report must be prepared by a person with sufficient qualifications and experience. It must be signed and dated by the expert and accompanied by a short overview of the expert’s background, education and experience as well professional relationship with the applicant company. - Module 1.5: Justification for the application being a bibliographical application.
- Module 1.8: Description of the company’s pharmacovigilance. It must also be described whether a risk management programme exists – alternatively a reason why risk management is not deemed necessary.
Module 2: Summaries
The purpose of this module is to give a summary of the chemical, pharmaceutical, biological, non-clinical and clinical data contained in modules 3, 4 and 5 of the application for marketing authorisation.
The data in module 2 must also be presented in accordance with the format, contents and numbering system described in Notice to Applicants, Volume 2B.
- Module 2.1: Table of contents.
- Module 2.2: Introduction (less relevant for this type of applications).
- Module 2.3: Quality overall summary. A summary of module 3, in which special conditions, deviations from guidelines etc. can be described. Constructed according to the guidelines in NtA.
- Module 2.4: Non-clinical overview in which the literature references submitted are compared and discussed.
- Module 2.5: Clinical overview in which the literature references submitted are compared and discussed. For this type of application, where the indication has been determined in advance as “prevention and treatment of deficiency symptoms”, clinical documentation is usually not required.
- Module 2.6: Non-clinical summary including summary of references submitted.
- Module 2.7: Clinical summary including summary of any references. Usually not required for well-known substances.
Module 3: Quality
P harmaceutical-chemical and biological data for medicinal products containing chemical, active substances
Introduction
The requirements for quality are generally set out in the Danish Executive Order on vitamin and mineral products, in which it is indicated that the products “must be of a satisfactory quality”, and in the Executive Order of the Danish Medicines Agency on the quality of medicinal products (see Annex 5, item 4 for reference).
The documentation containing chemical, microbiological and pharmaceutical technical data must, in addition to securing a satisfactory quality of the product, ensure against batch-to-batch variations.
In order to approve the quality of a strong vitamin and mineral product, the following items will be assessed in an application:
- The active substance(s) (module 3.2.S)
- The finished product (module 3.2.P)
The active substances are the substances which determine the therapeutic effect of the medicinal product, i.e. in this connection the vitamins and minerals, as raw materials.
The documentation in module 3 is, as mentioned previously, summarised in the quality overall summary (module 2.3).
The pharmaceutical form must be listed (e.g. film-coated tablets), the relevant determination of pharmaceutical form being chosen as defined in the applicable edition of the Danish Drug Standards (DLS).
Strength: The declaration of the product must be constructed in such a way that the name and quantity of the vitamin proper (normally the base)/mineral for each added vitamin/mineral is listed, e.g. “X mg vitamin B2 (riboflavin)”. In cases where the vitamin/mineral is added in the form of a salt/derivative, the name of that salt/derivative must also be listed, e.g. “Riboflavin sodium phosphate corresponding to X mg vitamin B2 (riboflavin)”. This means that volumes must be stated in mass units (mg or µg) and not, as was previously the case, in international units (IU or EU). For vitamins/minerals adopted in the European Pharmacopoeia (Ph.Eur.), the associated Danish names adopted in the applicable edition of the DLS must be used.
Module 3.1 Table of contents
The overall table of contents for module 3 must be listed here.
Module 3.2.S Documentation for the active substances – raw materials
Sources: As vitamin and mineral sources, the bases and salts/derivatives allowed for food supplements may be used, cf. Annex 2 of the Danish Executive Order on food supplements. The naming of the sources must be in accordance with the DLS.
Any application for the use of other vitamin and mineral sources must contain full pharmaceutical-chemical documentation as well as, in bibliographical form, clinical and toxicological documentation, including data on bioavailability, pharmacokinetics and any interactions with foods and other medicinal products.
In the food area, the requirements of the EU guidelines for the use of other sources in food supplements, “Guidance on Submissions for Safety Evaluation of Sources of Nutrients or of Other Ingredients Proposed for Use in the Manufacture of Foods” apply.
Documentation: The documentation for a vitamin/mineral as a raw material can either be presented in the form of a CEP, an EDMF or full documentation:
- For substances adopted in the Ph.Eur., for which the raw material supplier has obtained a CEP, Certificate of Suitability (issued by EDQM) for their raw material quality, this constitutes the documentation. It can therefore be considered to be the easiest solution from a regulatory point of view.
- If the supplier does not have a valid CEP (applies to substances which have been adopted – as well as all substances which have not been – adopted in the Ph.Eur.), the documentation for the substance can be submitted in the form of an EDMF (European Drug Master File) from that supplier, cf. the EU “Guideline on Active Master File Procedure”.
- Alternatively, the documentation for the quality of the raw material can be presented in the form of full documentation, i.e. the applicant’s own documentation, inserted directly into module 3.2.S.
In all the above cases, there must be additional documentation for the finished product manufacturer’s control of the raw materials.
If the product contains several different active substances, documentation for each substance must be available. If the manufacturer wants to use several suppliers for an active substance, separate documentation must be prepared for each supplier. Similarly, in the cases where a vitamin/mineral is supplied in “diluted” form (typically as a trituration or a granulate), separate documentation must be available for the pure substance and the dilution, respectively. For dilutions, the method of manufacture and the composition must therefore also be described, including information about the qualitative and quantitative composition of excipients (fillers) used.
The scope of control of the raw materials must be determined in a specification in which test parameters, limits and references to methods of analysis are specified. If the substance has a monograph adopted in the Ph.Eur., the requirements thereof must be met. To this end, the suitability of the monograph in the Ph.Eur. must be assessed, and there may also be a need for additional tests in the specification. If the substance has not been adopted in the Ph.Eur., the company must set up a specification itself containing requirements for identification, quantitative contents and purity tests, including residual solvents, heavy metals, possibly impurities and possibly microbial purity, depending on what is relevant for the raw material from the supplier in question.
The description of the analytical methods must be so detailed that it is possible for the authorities to perform analytical control. Analytical methods which do not originate from recognised pharmacopoeias must be validated.
In addition to information about supplier, manufacturing (of dilutions), specification and methods of analysis, batch analysis results must be presented for the assessment of the proposed limits as well as documentation for reference substances and packaging.
If there is a wish for determining a retest time and storage conditions for the raw materials from the supplier in question, documentation is required for stability testing performed for the raw material stored in the desired packaging. The requirements for stability testing are detailed in the EU “Guideline on Stability Testing: Stability Testing of Existing Active Substances and Related Finished Products”. If no such determination is desired, it is expected that a given raw material batch is reanalysed – and shown to fulfil the specification – immediately before being used to manufacture a batch of finished product.
Module 3.2.P Documentation for the finished product
Composition: The qualitative and quantitative composition of the finished product must be listed in a composition chart. This means that every active substance and excipient (including any excipients in raw materials) must be listed with name, quality, mass and function in the product. For every active substance, listing must include both the mass and the composition of any dilution (e.g. granulate), the expected mass of salt/derivative, the equivalent (de clared) mass of the base/mineral and the size of production and stability overage, respectively, if such items have been added.
Conversion factors (equivalents): Annex 3 contains a number of examples of vitamin sources, and for each source is indicated the amount (mass) equivalent to 1 part base. For instance, 1.12 mg sodium ascorbate corresponds to 1.00 mg L-ascorbic acid. For vitamins A, D and E is also listed the previously accepted equivalents in IU in relation to 1.00 mg of the base.
Other documentation: In addition to the composition chart, the following documentation must generally be submitted for the finished product:
- The pharmaceutical development work: For fixed-dosed medicinal products, dissolution profiles must be documented as part of the development work. For liquid/semi-solid medicinal products, compatibility with the packaging must be documented. If a manufacture and/or stability overage (of vitamins) is added, the need for and scope of this must be justified by documenting losses during production and storage, respectively.
- Manufacturing of the finished product: The manufacturing method for the finished product and any intermediate products must be described and validated.
- Excipients: Excipients, including preservatives, colorants and flavouring agents, which are used in the manufacture of medicinal products, and which do not determine the therapeutic effect of the medicinal product. The excipients used must fulfil the requirements of the European Pharmacopoeia (or the national pharmacopoeia of an EU member state). If, however, the substances do not have a monograph description, full documentation is required for the substance. For “novel excipients”, see module 3.2.A. If an excipient of animal origin is included, e.g. gelatine or lactose, documentation for the absence of TSE must be available.
- Control of the finished product: Specifications must be determined for release and during storage (shelf life), respectively. As it is the case for the raw material, the finished product specification must contain requirements for identification, quantitative contents and purity tests, including degradation products, microbial purity and any residual solvents, depending on what is relevant for the finished product in question. In addition, pharmaceutical-technical tests related to the pharmaceutical form.
Multivitamin/mineral products are exempt from the general requirement for dose variation (Uniformity of Content of Single-Dose Preparations, Ph.Eur. 2.9.6 and dose variation in the monograph Uniformity of Dosage Units, Ph.Eur. 2.9.40).
Furthermore, methods of analysis, validations thereof, batch analysis results for the assessment of the suggested limits and data on reference substances must be submitted. The description of the analytical methods must be so detailed that it is possible for the authorities to perform analytical control.
- Packaging: The packaging in which the finished product is to be marketed, must be described, and specifications must be included. Reference is made to the quality requirements in relevant monographs in Ph.Eur.
- Shelf life: Before a vitamin/mineral product can be authorised, stability tests must have been performed for the finished product in the consumer packaging applied for; documenting that the product fulfils the specification for the entire storage period stated under the established storage conditions. To ensure the stability of the entire product, it is thus necessary to investigate all the relevant chemical, physical and microbiological parameters that are included in the finished product specification. This includes investigation of the content of any degradation products (from the vitamins or any interactions with the packaging) during storage. The requirements for stability testing are detailed in the EU “Guideline on Stability Testing: Stability Testing of Existing Active Substances and Related Finished Products”.
On the basis of the results submitted, the Danish Medicines Agency will determine a storage life and storage conditions, e.g. “Do not store above 25°C, keep in original packaging”, as defined in the applicable edition of the DLS. The maximum storage time that can be approved for the finished product, is five years.
Module 3.2.A Annexes
This module is reserved for information on any excipients which have not been used previously (novel excipients). The documentation for such substances must include data on quality, safety and efficacy.
It is thus the intention that other annexes pertaining to the quality of the product are placed here. These must be inserted directly under the relevant sections in modules 3.2.S and 3.2.P.
Module 3.2.R Regional data
This module is reserved for information about the risk of TSE.
If the manufacturing method for the finished product has not been validated for production batches, a validation protocol in this regard must also be included.
Module 3.3 Literature references
Normally not relevant.
Module 4: Non-clinical reports
In the Danish Executive Order on vitamin and mineral products, it is stated that the safety requirement is that under normal use, the product must be harmless. Applications for marketing authorisations must therefore contain documentation for the safety of the product.
Applications for marketing authorisation for a vitamin and mineral product according to the Executive Order will be considered, as indicated above, as applications on the basis of bibliographic documentation as described in Section 18 (1) of the Danish Executive Order on marketing authorisation. This means that the documentation on the product’s safety must be prepared on the basis of detailed references to published scientific literature. As stated in Annex 1 of the Danish Executive Order on marketing authorisation, the documentation must cover all the points included in an application for authorisation of a medicinal product. If data is not submitted on all points, this must be indicated in the expert’s report, and there must be a discussion about the significance of this on the overall assessment of safety.
Module 5: Reports on clinical studies
Vitamin and mineral products can be approved for deficiency conditions only, e.g. “Prevention and treatment of vitamin C deficiency”.
In the Danish Executive Order on vitamin and mineral products, it is stated that the Executive Order covers products “which are exclusively designed to prevent or treat vitamin and mineral deficiency or deficiency of other substances with similar properties”.
Therefore, only indications such as “prevention and treatment of vitamin B deficiency” can be approved. The indication applied for must be briefly discussed in the expert’s report, and documentation must also be submitted that the deficiency condition applied for is described in literature.
Chapter 5. Requirements for manufacturing and wholesale
5.1 Manufacturing of active substances
The active substances (also called active pharmaceutical ingredients) are the responsibility of the medicinal product manufacturer. This means that every pharmaceutical manufacturer must ensure that the purchased active substance which is used as a raw material in the manufacture of medicinal products is in accordance with good manufacturing practice for active substances. The principles of good manufacturing practice are described in the Rules Governing Medicinal Products in the European Union, Volume 4, Medicinal Products for Human and Veterinary Use, Part II. The pharmaceutical manufacturer must ensure this by performing an audit of every manufacturer of pharmaceutical substances.
5.2 Manufacturing, import and wholesale of the finished product
The Danish Executive Order on vitamin and mineral products states that the products “must be manufactured in a company which possesses the required professional knowledge, and the design and operation of which is considered to ensure safe manufacturing of medicinal products”.
This means that the vitamin and mineral product must be manufactured in a company which is authorised by the Danish Medicines Agency in accordance with Section 39 (1) of the Danish Medicines Act to manufacture the product.
Companies handling medicinal products must have an authorisation from the Danish Medicines Agency in accordance with Section 39 (1) of the Danish Medicines Act. Companies manufacturing, importing, storing and wholesaling vitamin and mineral products must therefore obtain the authorisation for these activities from the Danish Medicines Agency before such activities are commenced. More detailed information is available in the guidelines of the Danish Medicines Agency on manufacturing and importing and on wholesaling, respectively:
- Guidelines on submission of applications for company authorisations (s. 39) – Manufacture and import of human and veterinary medicinal products and intermediates) (see Annex 5, item 16 for reference).
- Guidelines on submission of applications for company authorisations (s. 39) – wholesale distribution of medicinal products) (see Annex 5, item 17 for reference).
Both guidelines are available on the Danish Medicines Agency website, from where application forms can also be downloaded.
Please note that no authorisation is required for retailing of vitamin and mineral products.
Application fees and annual fees for authorisation to manufacture, import and wholesale vitamin and mineral products have been determined in the applicable Danish Executive Order on fees (see Annex 5, item 9 for reference).
The requirements for companies handling medicinal products are described in the Executive Order on GMP (see Annex 5, item 6 for reference) and the Executive Order on GDP (see Annex 5, item 5 for reference).
Furthermore, the requirements are described in more detail in the Rules Governing Medicinal Products in the European Union, Volume 4, Medicinal Products for Human and Veterinary Use: Good Manufacturing Practice.
5.3 Manufacturers in Denmark
If the company already has a Section 39 (1) authorisation from the Danish Medicines Agency covering what is applied for, it is sufficient to refer to said authorisation. If such authorisation does not exist, it must be applied for.
5.4 Manufacturers abroad
The application must be accompanied by a recent official document stating that the company is authorised to handle medicinal products in its country of origin as well as the product types in question. An original document or a certified copy issued and submitted 1-2 years previously will normally be acceptable if reference is made thereto or a copy thereof is enclosed.
5.5 Importers in Denmark
If the company already has a Section 39 (1) authorisation from the Danish Medicines Agency covering what is applied for, it is sufficient to refer to said authorisation. If such authorisation does not exist, application must be made for it.
5.6 Wholesalers in Denmark
If the company already has a Section 39 (1) authorisation from the Danish Medicines Agency covering what is applied for, it is sufficient to refer to said authorisation. If such authorisation does not exist, application must be made for it.
Application form etc. in connection with authorisation to manufacture, import or wholesale vitamin and mineral products is available on the Danish Medicines Agency, Inspection & Laboratories, or via the Danish Medicines Agency website, www.dkma.dk.
Chapter 6. Advertising
As it is the case for other medicinal products, vitamin and mineral products are covered by the advertising provisions of the Danish Medicines Act, i.e. Chapter 7, and the Danish Executive Order on advertising (see Annex 5, item 10 for reference). Advertising for strong vitamin and mineral products must comply with the general provisions for pharmaceutical advertising. Information and advertising to the public must be adequate and objective and in accordance with the approved summary of product characteristics. It must also contain the general compulsory information – name and generic name, package sizes, prices, effect, adverse effect, dosage, an express request to read the information on the package leaflet or on the packaging as well as other information which is necessary with a view to correct and appropriate use of the medicinal product, e.g. warnings and interactions. The Executive Order contains specific provisions on compulsory information for advertising outdoors, in films and on the radio, on television and in advertisements towards health care staff. See also guidelines no. 29 of 24 May 2007 from the Danish Medicines Agency on advertising etc. for medicinal products.
Chapter 7. Fees
Application fees and annual fees for vitamin and mineral products have been determined in the Danish Executive Order on fees. The application fee for applications for marketing authorisation is currently set at DKK 13,165.00.
Chapter 8. Changes in authorised products
According to Section 26 of the Danish Medicines Act, any changes in marketing authorisations issued must be presented by application to the Danish Medicines Agency. This means that no changes are allowed in e.g. raw material supplier, limits, methods of analysis, packaging, shelf life, composition or summary of product characteristics without prior approval. Contrary to other medicinal products, it is not necessary to report changes in package sizes to the Danish Medicines Agency in regard to “Medicine Prices”, as vitamin and mineral products are not entered there; such changes must be reported by letter or e-mail to Medicines Licensing, Regulatory Project Management.
Further information see Application for variations.
The application must be must be submitted according to Guidelines for submission and technical validation of applications.
If the composition and specifications for a product need to be changed significantly, this requires a new application, e.g. in the case of the addition or removal of one or more active substances to/from multivitamin and mineral products.
It is possible to apply for changes in the pharmaceutical form or replacements of salt or complex for the vitamin or mineral source used as an extension of an already approved product.
Chapter 9. Safety update reports
A periodic safety update report is a report describing the safety status of a medicinal product for a certain period. In accordance with the Danish Executive Order on requirements for the layout of adverse effect reports and periodic safety updates etc. (see Annex 5, item 11 for reference), the report must contain, among other things:
- an overview of the adverse effects of which the company has knowledge
- an estimate of the number of patients who have been treated with the medicinal product
- an overall assessment of the safety profile of the medicinal product
- proposals for new safety initiatives, if relevant.
Also pharmaceutical companies with a marketing authorisation for a strong vitamin and mineral product must submit periodic safety update reports.
In accordance with the Danish Executive Order on adverse effects (see Annex 5, item 12 for reference), pharmaceutical companies must submit periodic safety update reports to the Danish Medicines Agency at the following frequency:
- every six months after the issue of the marketing authorisation in Denmark and until marketing commences
- every six months for the first two years after initial placing on the market of the product
- once a year for the following two years
- every third year after that, and
- when applying for a renewal of the marketing authorisation.
For the preparation of periodic safety update reports, reference is made to the Rules Governing Medicinal Products in the European Union, Volume 9A.
Chapter 10. Renewal of marketing authorisations
In accordance with Section 27 of the Danish Medicines Act, a marketing authorisation must be renewed after five years. Applications for the renewal of a marketing authorisation must be submitted to the Danish Medicines Agency by the holder of the marketing authorisation no later than six months prior to the expiry of the authorisation. An authorisation which has been renewed earlier, will then have unlimited validity. However, if indicated by the benefit-risk balance, the Danish Medicines Agency may decide that the marketing authorisation should only be renewed for a new five-year period.
For further information on applications form, deadlines, processing and requirements for documentation see Application for renewal of marketing authorisation.
The fee for processing of the application for a five-year extension of the marketing authorisation will be invoiced.
The renewal of the marketing authorisation will be valid for five years from the expiry of the previous marketing authorisation.
The Danish Medicines Agency, 22 July 2008
Annex 1. Table of contents
Chapter 1
General
1.1 Background
1.2. What is covered by the guidelines?
Chapter 2
Definitions
2.1 Exemption from the limits for maximum contents in food supplements
2.2 Can products which have already been authorised continue as strong vitamin and mineral products?
2.3 Only for human use and only for oral ingestion
Chapter 3
How do you apply for a marketing authorisation, and how long will it take?
3.1 Four stages in the processing of applications
Chapter 4
Application layout
Chapter 5
Requirements for manufacturing and wholesale
5.1 Manufacturing of active substances
5.2 Manufacturing, import and wholesale of the finished product
5.3 Manufacturers in Denmark
5.4 Manufacturers abroad
5.5 Importers in Denmark
5.6 Wholesalers in Denmark
Chapter 6
Advertising
Chapter 7
Fees
Chapter 8
Changes in authorised products
Chapter 9
Safety update reports
Chapter 10
Extension of marketing authorisations
Annex 2. Four stages in the processing of applications
|
Processing stage |
Description |
Deadline |
|
Start-up |
Validation of application and placement in order book until start of assessment |
60 days |
|
Assessment |
First assessment of the application, resulting in Day 120 Assessment Rapport |
120 days |
|
Company reply |
The company replies to questions and prepares any additional documentation |
6 months |
|
Follow-up |
Assessment of replies to questions and application or substantiated rejection |
60 days (abridged applications) |
|
Company reply |
The company prepares replies to any additional questions |
30 days |
|
Conclusion |
Assessment of additional replies and authorisation or final rejection |
30 days |
Annex 3. Examples of conversion factors
Vitamin A must be indicated as the content of all–(E)-retinol
- Previous IU 3-333
- all-(E)-retinol 1.00
- all-(E)-retinyl acetate 1.15
- all-(E)-retinyl propionate 1.20
- all-(E)-retinyl palmitate 1.83
- Beta-carotene 2.00
Vitamin B1 must be indicated as the content of thiamine hydrochloride
- Thiamine hydrochloride 1.00
- Thiamine nitrate 0.97
Vitamin B2 must be indicated as the content of riboflavin
- Riboflavin 1.00
- Riboflavin sodium phosphate 1.27
Pantothenic acid must be indicated as the content of D-pantothenic acid
- D-pantothenic acid 1.00
- Calcium pantothenate 1.09
Vitamin B6 must be indicated as the content of pyridoxine hydrochloride
- Pyridoxine hydrochloride 1.00
Vitamin C must be indicated as the content of L-ascorbic acid
- L-ascorbic acid 1.00
- Sodium ascorbate 1.12
- Calcium ascorbate (dihydrate, Ph. Eur.) 1.21
Vitamin D must be indicated as the content of cholecalciferol
- Previous IU 40,000
- Cholecalciferol (D3) 1.00
- Ergocalciferol (D2) 1.00
Vitamin E must be indicated as the content of d-alpha-tocopherol
- Previous IU 1.49
- d-alpha-tocopherol (= RRR-alpha-tocopherol, Ph.Eur.) 1.00
- d,l-alpha-tocopherol (= all-rac-alpha-tocopherol, Ph.Eur.) 1.35
- d-alpha-tocopheryl acetate (= RRR-alpha-tocopheryl acetate, Ph.Eur.) 1.10
- d,l-alpha-tocopheryl acetate (= all-rac-alpha-tocopheryl acetate, Ph.Eur.) 1.49
- d-alpha-tocopheryl hydrogen succinate (= RRR-alpha-tocopheryl hydrogen succinate, Ph.Eur.) 1.23
- d,l-alpha-tocopheryl hydrogen succinate (= DL-alpha-tocopheryl hydrogen succinate, Ph.Eur.) 1.67
Annex 4. List of frequently used abbreviations
CTD: Common Technical Document. Format for the layout of applications in the EU, the USA and Japan.
DLS: Danske Lægemiddelstandarder (Danish Drug Standards). Document prepared by the Danish Medicines Agency, giving requirements and standards from the Ph.Eur. effect in Denmark. Additionally includes standards which have not been determined in the Ph.Eur.
EDQM: European Directorate of Quality of Medicine. Organisation under the Council of Europe, determining requirements and standards for the quality of medicinal products etc.
EMA: European Medicines Agency. The European Medicines Agency in London.
GDP: Good Distribution Practice.
GMP: Good Manufacturing Practice.
ICH: International Conference on Harmonisation. Cooperation between medicines agencies in the EU, the USA and Japan for mutual requirements for medicinal products.
NtA: Notice to Applicants. EU guideline available to companies applying for a marketing authorisation for medicinal products.
Ph.Eur.: European Pharmacopeia.
TSE: Transmissible Spongiform Encephalopathies. Common designation for the BSE-related diseases occurring in other veterinary species than cattle.
Annex 5. References to laws, Executive Orders etc.
- Lægemiddelloven (Danish Medicines Act) Danish Act no. 1180 of 12 December 2005, latest amended by Act no. 534 of 17 June 2008, on medicinal products.
- Bekendtgørelse om vitamin- og mineralpræparater (Danish Executive Order on vitamin and mineral products) Danish Executive Order no. 752 of 1 July 2008 on vitamin and mineral products.
- Kosttilskudsbekendtgørelsen (Danish Executive Order on food supplements) Danish law no. 683 of 21 July 2003, as amended by Danish Executive Order no. 1478 of 14 December 2006, on food supplements.
- Bekendtgørelse om lægemidlers kvalitet (Danish Executive Order on the quality of medicinal products) Danish Executive Order no. 1211 of 7 December 2005 on the quality of medicinal products.
- GDP-bekendtgørelsen (Danish Executive Order on GDP) Danish Executive Order no. 1243 of 12 December 2005, as amended by Danish Executive Order no. 186 of 22 February 2007, on the distribution of medicinal products.
- GMP-bekendtgørelsen (Danish Executive Order on GMP) Danish Executive Order no. 1242 of 12 December 2005 on the manufacture and import of medicinal products and intermediate products.
- Mærkningsbekendtgørelsen (Danish Executive Order on labelling) Danish Executive Order no. 869 of 21 July 2011 on the labelling etc. of medicinal products.
- Bekendtgørelse om markedsføringstilladelse (Danish Executive Order on marketing authorisation) Danish Executive Order no. 1239 of 12 December 2005, as amended by Danish Executive Order no. 782 of 29 June 2007, on marketing authorisations for medicinal products etc.
- Afgiftsbekendtgørelsen (Danish Executive Order on fees) Danish Executive Order no. 1416 of 13 December 2006, as amended by Danish Executive Order no. 267 of 21 March 2007, on fees for medicinal products and manufacturers of medicinal products, intermediate products and raw materials.
- Reklamebekendtgørelsen (Danish Executive Order on advertising) Danish Executive Order no. 272 of 21 March 2007, as amended by Danish Executive Order no. 393 of 27 April 2007, on advertising etc. for medicinal products.
- Bekendtgørelse om krav til udformning af bivirkningsindberetninger og periodiske sikkerhedsopdateringer m.v. (Danish Executive Order on requirements for the layout of adverse effect reports and periodic safety updates etc.) Danish Executive Order no. 1214 of 7 December 2005 on requirements for the layout of adverse effect reports and periodic safety updates etc.
- Bivirkningsovervågningsbekendtgørelsen (Danish Executive Order on the monitoring of adverse effects) Danish Executive Order no. 1238 of 12 December 2005 on the monitoring of adverse effects for medicinal products.
- Danske Lægemiddelstandarder (Danish Drug Standards) (DLS) Applicable edition.
- Vejledning om ansøgning af variationer (Guidelines for the application for variations) Guidelines for the application for changes (variations) of national and mutually recognised (MRP) marketing authorisation for medicinal products. The Danish Medicines Agency, 16 July 2007
- Vejledning til ansøgning om forlængelse af markedsføringstilladelse (Guidelines for the application for extension of marketing authorisation) Guidelines for the application for extension of marketing authorisation for nationally approved medicinal product for human use. The Danish Medicines Agency, 15 April 2008
- Vejledning om tilladelse til fremstilling og indførelse af lægemidler (Guidelines for application to manufacture and import medicinal products) Guidelines for the application for company authorisation (Section 39) – Manufacturing and importing medicinal products and intermediate products for human and veterinary use.
The Danish Medicines Agency, 7 June 07 - Vejledning om tilladelse til engrosforhandling af lægemidler (Guidelines for application to wholesale medicinal products)
- Guidelines for the application for company authorisation (Section 39) – Wholesale of medicinal products. The Danish Medicines Agency The Rules Governing Medicinal Products In The European Union
Volume 1: Pharmaceutical Legislation: Medicinal products for human use
Volume 2A: Pharmaceutical Legislation: Notice to Applicants: Procedures for marketing authorisation
Volume 2B: Pharmaceutical Legislation: Notice to Applicants: Presentation and content of the dossier (CTD)
Volume 2C: Pharmaceutical Legislation: Notice to Applicants: Regulatory guidelines
Volume 3: Scientific guidelines for medicinal products for human use
Volume 4: Medicinal products for human and veterinary use Good Manufacturing Practices
Volume 9A: Pharmacovigilance for Medicinal Products for Human use