Marketing, Manufacturing, Packaging & Labeling, Advertising
Marketing, manufacturing, packaging & labeling, advertising in Bulgaria – a comprehensive legal overview. Prepared in association with Kinstellar, a leading law firm in Bulgaria, this is an extract from The Pharma Legal Handbook: Bulgaria, available to purchase here for USD 99.
1. What is the authorisation process for the marketing of new drugs, biologics, medical devices, over-the-counter medications, and other medicinal products?
Homeopathic and traditional herbal medicinal products may be placed on the market in Bulgaria based on registration certificate. All other medicinal products may be placed on the market subject to the issuance of a marketing authorisation. Only marketing authorisation holders whose place of residence or seat is located in a Member State of the European Economic Area (EEA) can apply for the marketing authorisation. A medicinal product may be marketed in Bulgaria based on a marketing authorisation, issued under one of the following procedures: (i) National Procedure; (ii) Decentralized Procedure; (iii) Mutual Recognition Procedure or (iv) Centralized Procedure at the European Medicines Agency (EMA).
Under the National Procedure, the marketing authorisation is issued by the Executive Director of the BDA based on submission of application and proper documentation, in Bulgarian and/or English language – the dossier is filed in e-CTD format. The application is a standard-form template and may be submitted by an individual or a legal entity established in EEA, whereas, in case this is not Bulgaria, an authorized representative for representation before the Bulgarian regulatory authorities must be appointed. The marketing authorisation is granted subject to fulfilment of all applicable legal requirements aiming at providing scientific evidence for the quality, safety and therapeutic efficacy of the medicinal product.
Under the Decentralized Procedure (DCP), the application for the issuance of a marketing authorisation is filed simultaneously with the BDA and with the regulatory authorities of other member states, in which the product is intended to be marketed. The applicant must indicate the state, which shall be the reference member state (RMS) leading the assessment process. The applicant must also indicate, which are the other concerned member states (CMS). The BDA have limited capacity to act as RMS and Bulgaria is usually appointed as CMS. The product dossier is submitted in e-CTD format. The outcome of the procedure is that the BDA (along with RMS and the rest of the CMS) issues a marketing authorisation for Bulgaria, together with the approved summary of product characteristics (SPC), patient’s leaflet and packaging mock-up (all together referred to as the product information or PI).
The Mutual Recognition Procedure (MRP) is similar to DCP, however in this case the product has already been authorized in an EEA state, and the MAH further applies to authorize this same product for marketing in other countries – CMS. Again, usually BDA acts on the CMS side. The applicant must submit the identical product dossier, as such is provided to the reference state and the concerned member states. Again, the outcome of the procedure is that the BDA (along with the rest of the CMS) issues a marketing authorisation for Bulgaria, together with the approved PI.
The DCP and MRP result in multiple national marketing authorisations and this is the main difference from the centralized procedure where there is one marketing authorisation for all member states.
Under the centralised authorisation procedure, pharmaceutical companies submit a single marketing-authorisation application to EMA. This allows the marketing authorisation holder to market the medicinal products throughout the EEA on the basis of a single marketing authorisation granted by the European Commission. The centralised procedure is compulsory for certain type of medicinal products and optional for others; some medicinal products are not eligible to this procedure.
Regarding medical devices the general rule is that the manufacturer shall be liable for applying the CE Marking, which is a process that indicates that the medical device complies with European Union legislation on medical devices Bulgarian Law on Medical Devices (LMD) follows the EU classification rules pertaining to medical devices. Apart from CE marking, a registration or notification procedures at the BDA could be applicable (see question 3 in the Regulatory, Pricing, and Reimbursement Overview).
2. What is the authorisation process for the marketing of generic versions of these products?
For the generic versions of these products, the same authorisation procedure to obtain the marketing authorisation is followed, except that the applicant must evidence bioequivalence with the reference medicinal product and does not need to submit the results and documentation of the clinical and preclinical data. The generic application would result in marketing authorisation only after the data exclusivity period has expired (usually 10 years from the date of the first authorisation).
3. What are the typical fees for marketing approval?
The typical fees for marketing approval are described in the answer to question 4 in the Regulatory, Pricing, and Reimbursement Overview.
4. What is the period of authorisation and the renewal process?
Marketing authorisations are valid for 5 (five) years. Renewals must be applied for not later than 9 (nine) months prior to the expiration date, after an assessment of the benefit-risk ratio is made. After the first renewal, marketing authorisations are valid for an indefinite term. In the event of duly justified reasons related to pharmacovigilance, the BDA may require an additional 5 (five) year renewal.
5. What are the requirements, if any, for post-approval pharmacovigilance?
The reporting modalities and rules governing the post-approval pharmacovigilance are harmonised for the EU. The pharmacovigilance system at union level is managed by European Medicines Agency (EMA) and they maintain the online reporting system EudraVigilance. EudraVigilance is a single repository for reports of suspected adverse reactions seen in healthcare practice. It is used by EMA, BDA and industry. At national level the BDA also maintain pharmacovigilance system in full compliance with the requirements of the EU regulations and EMA guidelines. In addition, in order to abide by Bulgarian and EU pharmacovigilance requirements, marketing authorisation holders are under the obligation to maintain their own internal pharmacovigilance systems, which systems must regularly be audited internally and is subject to inspections by the competent authorities.
The Bulgarian LMPHM is harmonized with EU pharmacovigilance requirements: suspected serious adverse reactions occurring within and outside the EEA are subject to reporting by marketing authorisation holders to the EudraVigilance within 15 days. Suspected non-serious adverse reactions occurring within the EEA must be reported within 90 days.
6. Are foreign marketing authorisations recognized?
Marketing authorisations issued by the competent authorities within the EEA are recognised via MRP or DCP: both procedures resulting in a national marketing authorisation. Medicinal products authorised via the centralised procedure managed by EMA are recognised and valid without the need of further national marketing authorisation. Marketing authorisations issued outside the EEA are not recognised.
7. Are parallel imports of medicines or devices allowed?
Bulgarian law expressly regulates parallel import from EEA pertaining to medicinal products. Parallel importers of medicinal products may be individuals or legal entities having commercial registration in Bulgaria or other EU-member state, which have received a parallel import permit from the BDA. The BDA maintains a public register with all registered parallel importers. Parallel import is allowed in Bulgaria, provided that the medicinal product is authorized for marketing in an EU-member state and is identical or similar (same active substance, pharmaceutical form and primary packaging, and similar outer packaging design) to a product already authorised for use in Bulgaria.
There are no special rules for the parallel import of medical devices. The general principle of free movement of goods within the EEA applies, as well as the principle of exhaustion of the rights conferred by a trademark. If the medical device is placed on the EEA market bearing CE marking, it could be subject to parallel import, provided that it meets the requirements for labelling and instructions for use in the local language. Considering that Bulgaria is the only EU member state using the Cyrillic alphabet, this may bring the need for repackaging or applying a local label which, depending on the case, may have implications – see the case-law of the European Court of Justice in that respect (e.g. Junek Europ-Vertrieb, C-642/16; Servoprax C-277/15).
8. What are the restrictions on marketing practices such as gifts, sponsorships, consultancy agreements, travel and entertainment, or other incentives for healthcare organizations and individual medical practitioners?
In terms of interactions with HCPs – Bulgarian law prohibits provision of gifts and other pecuniary benefits (cash, as well as in-kind) to HCPs. In addition to the legal restrictions, there are also the ethical rules adopted by the local pharma trade associations of originators and of generic companies, which in general follow the corresponding rules adopted by the relevant trade associations at EU level (e.g. EFPIA). These rules are coded and are binding on member companies.
HCPs may not be compensated solely for their attendance of an event or a training. Consultancy agreements must be in writing and against payment of remuneration. Written consultancy agreements are not required for incidental marketing survey services (telephone interviews, questionnaires by post/ internet/email), provided that the agreed remuneration does not exceed 60 Bulgarian Leva, VAT inclusive.
Under the law, hospitality to HCPs is restricted to travel expenses, accommodation and registration fees, whereas under the ethical rules, meals are covered as well, but only up to a threshold of 100 Bulgarian Leva, VAT inclusive per meal. There are certain restrictions as to the acceptable accommodation and flight arrangements.
9. How is the manufacturing of medicines and devices regulated and by which agencies?
Manufacturing of medicinal products is subject to authorisation by the BDA. The rules and requirements are provided in the LMPHM and the Good Manufacturing Practices (GMP) rules. The supervision over the premises, equipment and manufacturing conditions pertaining to medicines, is vested with the BDA.
Although regarding medical devices there is no manufacturing authorisation similar to the one for drugs, the BDA is responsible for the registration of manufacturers of medical devices established in Bulgaria.
10. Are local manufacturing requirements compatible with Good Manufacturing Practices (GMPs) as defined by the US Food & Drug Administration (US FDA) and/or the European Medicines Agency (EMA)?
The BDA has announced that after auditing, the US FDA confirmed the BDA capacity and ability to perform GMP inspections equivalent to the US standards. Based on the sector agreement between the European Commission and the USA, there will be mutual recognition of GMP inspections of drug manufacturing sites. Currently the sector agreement covers the medicinal products for human use except vaccines, plasma-derived medicinal products and medicinal products intended for clinical trials.
Bulgarian GMPs is compliant with EU-GMP defined by the European Medicines Agency. EU directives, regulations and guidelines, pertaining to medicinal products and to medical devices are implemented in Bulgarian law, and it is in line with the European Medicines Agency expectations and requirements.
11. What is the inspection regime for manufacturing facilities?
The BDA is responsible for inspection of manufacturing sites in Bulgaria. Inspections may be requested by the industry in relation to a marketing or manufacturing authorisation procedure. Inspections could also be triggered at the initiative of the BDA as part of the on-going control activities.
The BDA may participate in inspections of manufacturing sites located in other EU-member states or third states at the request of the European Commission, the European Medicines Agency or a member state. The BDA cooperates with the European Medicines Agency in coordinating inspections in third states.
Compliance with GMPs is verified by means of a certificate, issued within 90 days as of the inspection.
12. Are manufacturing facilities open for inspection by foreign inspectors or third-party inspectors as authorized by the FDA/EMA?
No. Only officials from the BDA may conduct inspections.
13. What are the requirements for storage, packaging, and handling of medicines and devices and their constituent components?
Storage and handling of medicinal products in Bulgaria is done in accordance with the Good Distribution Practices (GDPs), outlined in the secondary legislation on implementation of the LMPHM, and namely Ordinance 39 dated 13 September 2007 on the Good Distribution Practices. Bulgarian GDPs are harmonized with EU GDPs. Storage premises and transportation means are subject to inspection by the BDA within the procedure for issuance of a wholesale distribution authorisation, and thereafter – for compliance with GDP.
Packaging/repackaging of medicinal products is considered to be a manufacturing activity and is subject to a manufacturing authorisation.
Storage and handling of medical devices is regulated under the LMD. Such activities must be performed in appropriate premises or transportation means and further to the requirements, set forth in the device documentation issued by the manufacturer of the specific device. Responsibility for compliance with such requirements is vested with the wholesale distributors with medical devices. If the manufacturer does not provide specific conditions for the handling and storage of medical devices, they must be handled in such a way, so as their safety is not compromised.
14. What information must be included in medicine and device labeling?
With respect to medicinal products, labelling and packaging requirements are set forth in the Bulgarian secondary legislation, and namely Ordinance 38 dated 13 September 2007 on the requirements for the information on packaging and leaflets of medicinal products. Such information (except, when a product for use in a clinical trial is concerned) must follow strictly the product SPC, as approved by the BDA, and the product marketing authorisation. The Ordinance sets forth an express list, detailing the information to be included on the product package, including product and active substance name (including in the Braille alphabet), pharmaceutical form, administration route, expiry date, registration and batch number, specific storage conditions, children warnings, indication whether the product is prescription product or OTC, etc. In the cases of small primary packages of medicinal products, manufacturers are allowed to refrain from putting on the package some of the required elements, provided that the available packaging space is insufficient.
With respect to medical devices, labelling is done by the manufacturer. It must be in abidance with medical device classification rules. The requirements are provided in the LMD and the regulations on the essential requirements for the concerned type of medical device. As a rule, the labelling and the instructions for use (where such instructions are applicable) have to be in the Bulgarian language. Certain exceptions are allowed for the labelling in case the medical device is intended for professional use only.
The labelling of drugs and medical devices is also affected by the requirements of other legislation, e.g. the waste management legislation in respect of the recycling symbols found on consumer packages.
15. What additional information may be included in labeling and packaging?
Product packages may contain an indication as to whether the product is reimbursed with public funds, as well as a barcode for verification of product identity and authenticity. Multi-lingual packs are allowed (where the information on the packaging and leaflet is presented in more than one language), provided that one of the languages is Bulgarian. There are exceptions when the information could be provided in foreign language upon ad hoc request to the BDA. On case by case basis, if needed, the BDA may request additional information to be included in the leaflet or labelling.
The labelling and packaging of medical devices additionally may contain symbols explaining the provided mandatory information.
16. What items may not be included in labeling and packaging?
Labelling and packaging of medicinal products may not contain items of promotional nature, as well as misleading information and indications.
17. What are the restrictions and requirements for the marketing and advertising of medicines and devices?
Only authorized medicinal products may be advertised and promoted in Bulgaria. Any advertising or promotion of a medicinal product must correctly indicate the products’ therapeutic effect, and must not over-exaggerate therapy, prophylaxis or diagnostics’ options. Advertising and promotional materials pertaining to medicinal products may not be misleading and may not imply gifts and/or other pecuniary and non-pecuniary benefits. Such materials must strictly follow the latest approved SPC. Off-label advertising and promotion is prohibited. In addition, prescription products may not be advertised directly to patients, but only to healthcare professionals (HCPs). Prescription products cannot be advertised over Internet.
There are no specific rules with respect to advertising and promotion of medical devices. However, the general rules of the safeguarding consumers and fair competition would apply.
18. Where can medicines and devices be sold or delivered? Can medicines and devices be sold or delivered via post?
With respect to patients (retail sales), medicines may be sold (dispensed) only in pharmacies (including also hospital pharmacies) and drugstores. In some cases, dentists and medical doctors are also able to dispense medicinal products to patients. For medical devices the scope of dispensing places/entities is wider.
Prescription medicinal products may not be traded over the internet, only OTCs. Internet trade of OTCs may be performed only by pharmacies and drug stores which have obtained a specific authorisation for retail trade over the internet, issued by the BDA.
No special provisions exist in Bulgaria concerning sales of medicinal products by post. However, both wholesalers and retailers trading over the Internet are responsible for ensuring appropriate means of transportation, especially if special conditions are necessary (e.g. temperature, humidity, etc.). Between wholesalers, medicines and devices may be sold and delivered to duly authorized warehouses and in accordance with the respective contractual arrangements.
Natural persons may import/export only medicinal products intended for their treatment and certain limitations apply.
Regarding medical devices the law requires from wholesalers to engage appropriate means of transportation. However, there are no specific rules for retail sales via post service.
19. What are the restrictions and requirements for electronic marketing and advertising via email, by internet, social media, and other channels?
Prescription medicinal products may not be advertised and promoted over the internet. In addition, certain requirements prohibit the sending of commercial notices via e-mail without customer consent.
20. May medicines and devices be advertised or sold directly to consumers?
Only OTCs may be advertised to the population directly. An exception is the advertising of vaccine campaigns, which are allowed to be conducted directly to the consumers. Prescription drugs may be promoted and advertised only to healthcare professionals, and following strict rules in the LPMHM, the secondary regulation and the applicable industry ethical codes.
Prescription medicinal products may be sold to consumers directly only in pharmacies. Bulgarian law allows trade over the internet, but only of OTCs. Wholesale traders may sell to other wholesale traders, pharmacies and drugstores, the Ministry of Healthcare, the Ministry of Interior and the Ministry of Defence, and hospitals.
21. How is compliance monitored?
Compliance is monitored by means of periodic and planned, as well as ad-hoc, on-site inspections of the competent regulatory authority the BDA.
22. What are the potential penalties for noncompliance?
Penalties for noncompliance vary depending on the infringement, and whether it is a one-time violation, or a repetitive one (in which case, the double amount of the penalty is usually levied). Penalties represent monetary sanctions, levied at the discretion of the penalizing bodies, within a certain range, whereas minimum and maximum amounts are set forth in the LMPHM. For different infringements, penalties may range between BGN 750 (appr. EUR 385) and BGN 150 000 (appr. EUR 76 923). In case the infringer is a legal entity, sanctions are the triple amount envisaged for the respective infringement. Additional ancillary sanctions in the form of pecuniary measures are also levied in cases of serious violations, whereas these include (possible) suspension of an authorisation, a license or a permit, deprivation in favour of the State of products and equipment used by the infringer, or such subject of the infringement, prohibition to exercise professional activities for up to 2 years, etc. For the purposes of the administrative penal procedures, the regulatory authorities partner with the customs, the revenue and internal affairs authorities.