Registration of medicines, pharmacovigilance and GMP
The medicinal product implies finished medicinal products for human use and active pharmaceutical ingredients (API).
The medicinal product is a substance or combination of substances (one or several API and excipients), which has the relevant properties and is intended to treat or prevent diseases in humans, any substance or combination of substances, which may be intended to prevent pregnancy, restore, correct or modify human physiological functions by means of pharmacological, immunological or metabolic actions or to determine a medical diagnosis.
Since 2005, the legislation of Ukraine concerning registration and circulation of medicinal products has been in the process of gradual harmonization with the EU legislation. Current requirements for establishing and maintaining registration, safety (pharmacovigilance), and quality are close to the European requirements.
The Ministry of Health of Ukraine performs the registration of medicinal products based on the expert assessment of the Application and registration materials (registration dossier). The competent authority for expert assessment is the State Enterprise State Expert Center of the Ministry of Health of Ukraine.
There are several routes of registration:
- “Standard” registration, approved by MoH Order No. 426.
- Fast-track registration through “recognition”, approved by MoH Order No. 1245.
- Fast-track registration through “authenticity verification”, approved by MoH Order No. 1391.
- Emergency use authorization of vaccines for COVID-19 prevention, approved by Resolution of the Cabinet of Ministers of Ukraine No. 95.
Fast-track registration routes have certain restrictions and particularities. For example, medicines approved in countries with high regulatory requirements can quickly access the market under the “recognition” procedure; however, maintaining such registration is much more expensive than the “standard” procedure.
Marketing Authorization Holder (MAH) is also responsible for pharmacovigilance in Ukraine and conforming the manufacturing conditions with the GMP requirements. Thus, MAH should:
- Establish and maintain the registration of the medicinal product;
- Establish and maintain the pharmacovigilance system in Ukraine;
- Confirm and maintain conformity with the GMP requirements.
Since 2006 our company has supported the pharmaceutical business in regulatory affairs, pharmacovigilance, and quality. We are a leading regulatory consultant in Ukraine and 11 countries of the CIS region.
We have deep expertise in various types of Applications and procedures. Our team includes more than 120 best experts that are fluent in English and have extensive experience. More than 200 manufacturers trust us for our professional, ethical and supportive approach.
Applicant (marketing authorization holder)
Marketing Authorization Holder (MAH) can be a resident or non-resident of Ukraine. MAH is responsible for the quality, safety, and efficacy of the medicinal product during its circulation in Ukraine.
If MAH differs from the manufacturer, the registration materials must include documentation explaining their relations.
The non-resident MAH is not required to establish a representative office or another entity in Ukraine. However, the MAH is required to:
- establish and maintain the pharmacovigilance system in Ukraine, designate the local contact person responsible for the pharmacovigilance (LQPPV);
- designate the person responsible for the quality and maintain the product’s quality requirements, including conformity to GMP.
MAH can outsource these obligations to a third party, for example, to Cratia.
Ministry of Health of Ukraine (MoH) is the central executive authority of the healthcare system, accepts Applications for registration of medicinal products, and approves decisions on registration by its Orders.
State Expert Center of the Ministry of Health of Ukraine (SEC) performs an expert evaluation of registration materials (dossier) for medicinal products during the registration procedure, performs supervision over the safety of medicinal products (pharmacovigilance).
State Service of Ukraine on Medicines and Drugs Control (SMDC) is responsible for implementing the state policy in controlling the quality of medicinal products and medical devices, performs works on confirmation (certification) of the medicinal product manufacturers’ consistency with the GMP requirements.
Choosing the route of registration
The law allows to choose between several routes of registration, each having its characteristics:
“Standard” registration procedure approved by Order of MoH No. 426 – a universal way for all types of medicinal products and Applications. The procedure describes various types of medicinal products, Applications, and corresponding registration dossier requirements, steps and timelines of the state expert assessment, procedures of variations, and renewals.
The assessment period varies from 45 to 210 working days depending on the type of the Application, not including clock stops for replies on the deficiencies and not including the time required for administrative and financial issues.
Fast-track registration through “recognition” approved by Order of MoH No. 1245 – is a route of registration based on the recognition of approval in the reference state: USA, Switzerland, Japan, Australia, Canada or by EMA under the centralized procedure.
The procedure does not include specialized expert assessment of the registration dossier. The fact of registration in the reference country and identity with the information in the Application is verified.
The assessment (verification) period is 10 business days plus the one clock stop for replies on the deficiencies.
Fast-track registration through “authenticity verification” approved by Order of MoH No. 1391 – is the route for registration for medicinal products procured by (1) international specialized procurement organizations and (2) the national authorized procurement organization (State Enterprise “Medical Procurements of Ukraine”). Registration obtained in this manner allows supplying the medicinal products only to specialized procurement organizations.
Registration under this route is possible only for the medicinal products approved by the competent authorities of the USA, Switzerland, Japan, Australia, Canada, approved by EMA under the centralized procedure or pre-qualified by WHO.
The procedure does not include specialized expert assessment of the registration dossier. The fact of registration in the reference country and identity (authenticity) of the translation of the instructions for use (SmPC) is verified.
The registration period is 9 business days; no deficiencies may be provided (either negative or positive decision).
Emergency use authorization of vaccines for COVID-19 prevention in approved by Resolution of Cabinet of Ministers No.95 allows obtaining authorization for emergency use of vaccines based on registration or authorization for emergency use, issued by the competent authorities of the EU member countries, USA, Great Britain, Switzerland, Japan, Australia, Canada, the People’s Republic of China or India.
The registration period is 9 business days; registration is granted for 1 year.
Types of Applications and requirements to the registration dossier
This chapter contains a description of the requirements for the registration dossier under the “standard” registration procedure. Registration dossier requirements for fast-track or emergency use Applications can be significantly different.
During the registration, the MAH prepares the Application (the registration form) and justifies its type:
- medicinal product with a full (autonomous) dossier;
- generic drug, hybrid medicinal product or biosimilar;
- medicinal product with a well-studied medical use;
- medicinal product with a fixed combination;
- informed consent;
- traditional medicinal product;
- medicinal product from in-bulk products.
The registration dossier requirements depend on the Application type chosen.
The registration dossier is submitted in the CTD format, considering the national requirements, e.g. language, specific national documents, presentation etc.
Dossier for the new registration includes:
- registration form (Application) and it’s annexes;
- the registration dossier in the CTD format, consisting of 5 Modules (Modules 2-5 are consistent with the ICH CTD requirements);
- Ukrainian translation of parts of the registration dossier;
- specific national documents, namely:
- QCM – quality control methods of the medicinal product, which include the composition of the product, specification for release and storage, detailed description of the methods, information about the manufacturers, description of the packaging system, shelf life and storage conditions;
- instruction for use – information about the use of the medicinal product, usually provided in the form of an insert;
- package labeling information – description of the information that will be placed on the primary and secondary packaging.
There are many specific requirements for the presentation of the dossier. The following criteria are the most important:
- the documentation should be submitted in hard copy (registration form; registration dossier, specific national documents); some exemptions can apply;
- the registration dossier has strict assembling requirements: number of pages in a file, information on the cover, cross-numbering and table of contents;
- the registration dossier should be submitted in several non-identical copies;
- the registration dossier should not be submitted along with the Application (the registration form); it is submitted only after obtaining the positive result of the Application’s assessment and payment of the state fees.
Timelines of expert assessment (depending on the route of and Application type):
“Standard” registration procedure (MoH Order No. 426):
- 210 business days: medicinal products submitted for registration with a full (autonomous) dossier, immunobiological medicinal products, biosimilars;
- 90 business days: for other types of medicinal products (generic drugs, well-studied use);
- 45 business days: for orphan drugs and medicinal products for the treatment of socially dangerous diseases (HIV, viral hepatitis, tuberculosis, oncological diseases);
- 30 business days: for vaccines, toxoids and medicinal products procured by specialized entities or organizations.
Fast-track registration through “recognition” (MoH Order No. 1245);
- 10 business days;
Fast-track registration through “authenticity verification” (MoH Order No. 1391);
- 5 business days;
Emergency registration of COVID-19 vaccines (CMU Resolution No. 95).
- 5 business days.
These timelines do not include:
- documentation analysis and translation, development of national forms and documents, filing and assembling of the registration dossier;
- period of initial expertise of the registration form;
- payment of state fees and receipt of payment confirmation;
- clock stops for the deficiencies;
- time required to import samples and standards, as well as to perform laboratory analysis (if necessary);
- finalizing actions after the expert evaluation (verification/proofreading of the draft marketing authorization and it’s annexes);
- signing the Order on registration of the medicinal product and issuance of the original certificate.
Marketing authorization is issued for 5 years after first approval (unless another period is defined by the registration route). After renewal, the authorization is issued without expiry, except for the cases if an additional 5 year period is approved by the Ministry of Health for pharmacovigilance reasons.
The marketing authorization consists of:
- the marketing authorization itself, printed on the special form with a hologram;
- annex: approved quality control methods (QCM) of the medicinal product;
- annex: approved instruction for medical use of the medicinal product;
- annex: packaging labeling;
All approved variations (of any type) are an integral part of the marketing authorization.
Labeling and instruction for use
Labeling information is an object of expert assessment during state registration. Labeling information is approved as an integral part of the registration certificate.
The language of the labeling and instructions for use is Ukrainian; additional languages are allowed.
After granting the marketing authorization, but before importing the medicinal product to Ukraine, the MAH must develop graphic mock-ups of the package and submit them for registration in the Unified Automated Electronic System (UAES) of the State Service of Ukraine on Medicines and Drugs Control (SMDC).
There are a lot of requirements to the registered package mock-ups, including font size, location of graphic elements, package size, description of technical elements, color codes, etc.
Each imported batch of medicinal products is subject to mandatory visual quality control, including control of the package’s consistency with the registered mock-ups. Even insignificant differences may lead to comments and suspension of the opinion on the quality and the requirement to laboratory quality control.
Conformity of the manufacturing conditions with GMP requirements
State control of the conformity of the manufacturing conditions of the medicinal products with the GMP requirements has been introduced in Ukraine since 2002. Conformity with GMP is assessed during the registration (renewal, variations) and during the import quality control.
MAH must amend the Application for new registration or renewal by the Decision on conformity with GMP requirements issued by the competent authority of Ukraine (SMDC) or by a guarantee letter stating that it will be submitted within the registration or renewal procedure.
The SMDC of Ukraine issues the Decision on GMP compliance based on:
- either recognition of the GMP certificate issued by the competent authority of the reference country;
- or positive results of the inspection.
Until the middle of 2020, Ukraine has recognized GMP certificates issued by the PIC/S members. Since July 2021, the list of the “recognition” states has been reduced to EU member states, the United Kingdom, and countries that have Mutual Recognition Agreements (MRA) with EU or Ukraine. Currently, Ukraine recognizes GMP certificates issued by the competent authorities of the following 35 countries:
- 27 EU member-states: Austria, Belgium, Bulgaria, Greece, Denmark, Estonia, Ireland, Spain, Italy, Cyprus, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Hungary, Finland, France, Croatia, Czech Republic, Sweden;
- United Kingdom;
- countries that have MRA with the EU: USA, Canada, Switzerland, New Zealand, Australia, Japan;
- countries that have ACAA with the EU: Israel.
Recognition of the GMP certificate is not unconditional: it is required to fill in the set of documents, submit to the competent authority, follow the assessment process, and reply on deficiencies if any.
If the manufacturer does not possess a GMP certificate issued by a competent authority of any of the 35 countries mentioned above, it will be necessary to apply for a Ukrainian GMP inspection. That requires filling set of documents and Application, submission to the competent authority, following the assessment, organization of inspection.
Quality control during import
Each imported batch of medicinal products is subject to mandatory state quality control (except for API and in-bulk products). SMDC of Ukraine is the competent authority responsible for state quality control.
The importer submits to SMDC the Application for state quality control within 5 days after customs clearance. During the period of control, the imported medicinal products are quarantined and separated from other products.
The SMDC assesses submitted documents and visually controls each imported batch. The documentation of the imported batch is verified for consistency with the approved marketing authorization and its annexes. Visual control includes verification of the package’s conformity with the approved and registered mock-ups and verification of the text of the instruction for use.
Laboratory quality control is performed in the following cases:
- first import of the medicinal product into Ukraine, except for products manufactured in EU countries, Great Britain, USA, Canada, Switzerland, New Zealand, Australia, Japan, and Israel;
- inconsistencies of the imported medicinal product’s package with the mock-ups registered in the UAES of the SMDC;
- packaging damage which may influence the quality;
- violation of storage conditions of the medicinal product during transportation or storage;
- inconsistencies of the CoA or product’s appearance with the approved control methods (Specification);
- prohibition of circulation of other batches of medicinal products in Ukraine;
- obtaining official information from competent authorities of other countries.
The pharmacovigilance system has been introduced in Ukraine since 2002. Current requirements are harmonized with the international practice, including EU Directive 2001/83 and EU Council Regulation 2309/93. The competent state authority is the State Expert Center of the MoH of Ukraine.
The medicinal product must comply with the pharmacovigilance requirements from the moment of its state registration. The MAH is responsible for the establishment and maintaining the pharmacovigilance system in Ukraine.
The MAH must designate the qualified person responsible for pharmacovigilance (QPPV). Non-resident MAH must designate the local contact person responsible for pharmacovigilance (LQPPV or LCP) in Ukraine.
QPPV and LQPPV must meet the educational and experience requirements. Application for new registration or renewal must include contact information and CV’s. Change of the QPPV or LQPPV is performed by submission of the Application for variations.
The establishment and maintenance of the pharmacovigilance system in the territory of Ukraine can be delegated to a third party, e.g. to Cratia.
Variations and maintaining registration
Established registration does not require any monthly or annual payments. MAH must maintain the pharmacovigilance system and the quality management system in the territory of Ukraine.
For that purpose, the MAH must ensure the presence and functionality of the person responsible for the pharmacovigilance and the person responsible for quality in Ukraine. The MAH’s can outsource these functions to a third party (e.g. Cratia).
Any changes to the registration materials must be applied by submission of the Application and set of documents, payment of the state fees, expert assessment, approval of the changes by order of the Ministry of Health, and the issue of the confirmation document.
The MAH must submit the Application to update the safety information within 60 calendar days after receipt of the information on the necessity of such variations.
Types of variations are similar to EU:
- correction of the technical mistake: correction of the mistake that took place during registration, renewal or variations;
- change of the marketing authorization holder (MAH transfer);
- type IA: variations having no significant influence on the quality, safety, and efficacy;
- type ІАIN: type IA variations with immediate notification;
- type IB: insignificant variations under type IA or II;
- type II: variations influencing the quality, safety, and efficacy;
- variations causing the new registration.
The concept of “notification” in Ukraine is different from European practice, and there is no “silent consent”. MAH submits an Application for preliminary assessment, pays state fees, submits the registration materials that follow specialized assessment, and finally should be approved by order of the Ministry of Health. In Ukraine, the notification-type variation procedure means that there will be no deficiency letters during the expert assessment: either positive or negative decision.
Renewal of registration
The MAH must submit an Application for renewal not later than 180 days before the expiration of the marketing authorization certificate. The recommended submission term is 12 months.
Re-registration requires a smaller set of documents compared to the new registration. Applications for variations can be submitted during the renewal. Assessment of variations is performed in parallel and independently.
The MAH initiates the renewal by submitting the Application form to the Ministry of Health of Ukraine. The Application form follows the preliminary assessment, then invoices for state fees are issued. MAH pays the state fees and submits the dossier. State Expert Center of the Ministry of Health performs the preliminary and specialized assessments of the renewal dossier. State Expert Center issues deficiency letters; MAH has 60 working days for a reply.
During the renewal, expert evaluation of the benefit-risk ratio is performed to confirm the positive ratio of expected benefit to possible risk related to the use of the medicinal product.
Ministry of Health approves renewal of registration of the medicinal product by an Order. A new registration certificate is issued with the same number.
The period for expert evaluation of the re-registration dossier is 90 business days. This period does not include:
- documentation analysis and translation, development and updating of national forms and documents, formation and preparation of the dossier;
- expert evaluation of the Application (renewal) form;
- payment of state fees and receipt of payment confirmation;
- time required to respond to deficiencies (up to 60 business days);
- finalizing actions after the expert evaluation (verification/proofreading of the draft marketing authorization and it’s annexes);
- signing the Order on renewal of registration of the medicinal product and issuance of the original certificate.
After renewal, the registration certificate is issued without expiry, except for the cases if the Ministry approves an additional five-year period for pharmacovigilance reasons.
The following VAT rates apply to the medicinal products:
- general case: preferential VAT rate of 7% for all registered medicinal products and API;
- exception 1: VAT rate of 20% for non-registered medicinal products or medicinal products with expired marketing authorizations;
- exception 2: VAT rate of 0% for the supply of medicinal products as humanitarian aid and/or in other special cases (e.g., medicinal products for treatment and prevention of coronavirus infection).
Manufacture, import, wholesale and retail sale of medicinal products are subject to licensing in Ukraine. The competent state authority is the State Service of Ukraine on Medicines and Drugs Control (SMDC).
The importer should comply with the requirements approved by the Resolution of the Cabinet of Ministers of Ukraine No. 929 of 30.11.2019, including implementing and maintaining a pharmaceutical quality system, including applicable GMP and GDP elements. The quality system should be documented.
To comply with the requirements, the importer should have:
- trained personnel with the necessary qualification;
- appropriate premises and areas;
- properly maintained equipment;
- approved written methodology (SOP) and instructions;
- appropriate means for storage and transportation;
The importer should have a Qualified Person (QP). Such an employee should comply with the education and qualification requirements and work on a full-time basis. QP makes sure that every imported batch of medicinal products undergoes quality control in Ukraine and issues authorization for release (sale).
Advertising and promotion
Only OTC medicinal products are allowed for advertising. Advertising of prescription medicinal products in non-specialized media is prohibited.
Advertising of OTC medicinal products is subject to severe restrictions, most of which are approved by Article 21 of the Law of Ukraine “On Advertising”. There are also other legal restrictions.
The promotion of prescription medicinal products is allowed in specialized media for medical institutions and physicians and in the media to be distributed at medical seminars, conferences, and symposia.
Ukrainian legislation regulating registration and circulation of medicines include the Law of Ukraine “On Medicinal Products”, Resolutions of the Cabinet of Ministers of Ukraine, and Orders of the Ministry of Health.
The list of main legislative acts that we use in our work daily is available on our website.
We also pay great attention to the EU legislation. In case if a dispute may not be resolved based on the national legislation, a reference to the relevant European document will be a strong argument.
Since 2006 we support the pharmaceutical business in regulatory affairs, pharmacovigilance, and quality. We are a leading regulatory consultant in Ukraine and 11 countries of the CIS region. Our extensive team has the necessary knowledge, experience, and skills and is proficient in English.
We have provided regulatory services for more than 200 manufacturers of medicines, many of which recommend us as a regulatory partner.
- consultation, development of registration strategy;
- establishment of new registration, renewals, and variations;
- establishment and maintaining a pharmacovigilance system, outsourcing the functions of the local contact person;
- confirmation of manufacturing conditions with GMP requirements through recognition or inspection.
In addition to the main services, we also offer:
- translation of the scientific, medical, technical, and legal documentation;
- back-office operations: preparation of the registration dossier or any of its parts without submission;
- development and pre-printing verification of labeling artworks and instructions for use;
- medical writing of parts of the registration dossier;
- development of documentation and import licensing;
- writing of documentation for inclusion of the medicinal product in the National List (HTA).