Registration of medicines
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.
Medicinal products are allowed for import, sale, and use in Ukraine only after the state registration, provided that they meet the quality and safety 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.
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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,
Competent authorities
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.
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.
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.
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Marketing authorization
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.
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.
Variations and maintaining Registration Certificate
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.
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.
Re-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.