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State registration of medicines and active pharmaceutical ingredients

 

In order to import and market medicinal products in Ukraine, it is required to conduct state registration of the medicinal products, as well as to meet all the necessary quality requirements.

The Ukrainian legislation on registration and marketing of the medicinal products has been harmonized with the EU legislation since 2005. The general requirements for documentation and expert evaluation process are fairly close to the European directives, although there are many national features which significantly affect all regulatory processes.

Registration of a medicinal product in the EU indicates the compliance with the general requirements for the registration dossier but does not guarantee a quick and simple registration procedure in Ukraine.

 

Medicinal products include the following types:

-      finished medicinal products;

-      immunobiological products;

-      in-bulk products;

-      active pharmaceutical ingredients (APIs).

The legislation on registration of the medicinal products is very closely intertwined with the requirements for safety management (pharmacovigilance) and quality management of the medicinal products. Therefore, in order to obtain and maintain the Registration Certificate for the finished medicinal product, the Applicant has to:

-      conduct state registration by submitting the application to the Ministry of Health of Ukraine and by expert evaluation of the documents of the registration dossier in the SEC;

-      establish and maintain the pharmacovigilance system in Ukraine;

-      confirm or certify the manufacturing compliance with the GMP requirements;

-      register the layouts (artworks) of the primary and secondary packaging in the Unified Automated Information System (UAIS) of the State Service of Ukraine on Medicines and Drugs Control (SMDC).

As for the active substances (APIs), neither the recognition/certification of GMP compliance nor the layouts registration is required.

 

The Applicant (Marketing Authorization Holder) of the Registration Certificate:

Both a resident and a non-resident of Ukraine (for example, the manufacturer himself) may act as an Marketing Authorization Holder (MAH) for registration. In accordance with the law it is the MAH who has responsibility for the quality, safety and efficacy of the medicinal product during marketing within the territory of Ukraine.

If the MAH and the manufacturer are different entities, it is necessary to include the documentation clarifying association between them in the registration materials.

A non-resident MAH doesn't have to establish a local representative office or another corporate entity within the territory of Ukraine, however, the MAH is obliged to:

-      establish and maintain the pharmacovigilance system in Ukraine, including the necessity to appoint the local contact person (LCP) responsible for pharmacovigilance in Ukraine;

-      appoint the person in Ukraine, who will be responsible for the medicinal product quality.

Fulfillment of MAH's commitments with regard to establishment and maintenance of the quality and safety management system may be partially delegated to a third party under a delegation agreement (for example, to company Cratia).

In order to represent his interests, the MAH may issue a Power of Attorney, which describes authorized representative's authority with regard to registration, quality and safety management. The Power of Attorney must be drawn up according to the set of national requirements and legalized appropriately.

 

Competent authorities:

The Ministry of Health of Ukraine (www.moz.gov.ua, hereinafter referred to as the MOH) is the central executive body of the healthcare system. The Ministry of Health accepts the Applications for the medicinal product registration and approves decisions on registration by issuing Orders.

The State Expert Center of the Ministry of Health of Ukraine (www.dec.gov.ua, hereinafter referred to as the SEC) examines the registration materials (dossiers) for the medicinal product during registration procedure and supervises the medicinal products safety (pharmacovigilance).

The State Service of Ukraine on Medicines and Drugs Control (www.diklz.gov.ua, hereinafter referred to as the SMDC) implements the state policy on quality control of the medicinal products and medical devices, carries out activities on recognition (certification) of manufacturing compliance with the GMP requirements.

 

General requirements for the registration materials:

The documentation for the standard new registration procedure consists of the following parts:

-      Application for registration, completed according to the national application form;

-      Registration form (legal and administrative documentation that accompanies the Application);

-      Registration dossier in CTD format, consisting of 5 Modules (Modules 2-5 meet the ICH CTD requirements);

-      Translation of registration dossier parts into Ukrainian or Russian;

-      Specific national documents, namely:

o        QCMs are the quality control methods for the medicinal product that include the medicinal product composition, release and storage specifications, detailed method descriptions, data on the manufacturers, packaging description, shelf-life and storage conditions.

o        Instruction for medical use is the information on use of the medicinal product, which is most often supplied as a leaflet.

o        Layout and description of the packaging is the description of the information on the primary and secondary packaging of the medicinal product.

There is a large number of specific requirements for the registration documents, the most important of which are:

-      all the documents should be submitted in a paper form (Application, registration form, registration dossier, specific national documents);

-      the registration dossier has strict requirements for execution, namely: the number of pages in the folder, information on the cover, page numbering and table of contents;

-      the registration dossier is submitted in several non-identical copies;

-      the communication happens both by making a personal appointment, and via correspondence;

-      correspondence during expert evaluation of registration materials is carried out only in paper form, as well as any additional materials (responses to observations);

-      some documents (for example, the instruction for medical use) may be corrected during the process of expert evaluation for several dozen times.

 

New registration:

Depending on the type of the medicinal product, its indications, market status and other characteristics, different types of Applications and different time terms of expert evaluation are applied. It should be reminded that Ukraine undergoes the harmonization procedure with the EU, but the country has its own independent legislation and expert evaluation procedure.

The registration process begins from the moment when the Application is submitted to the so-called "single point of contact" of the MOH and ends when the appropriate Order is signed by the MOH and the paper original of the Registration Certificate is issued.

Since the moment when the Application is submitted, there is a strict timeframe, which must be adhered to by both the competent authorities and the Applicant. If the Applicant does not perform a specific action or does not submit all the necessary documents, or the documents are filled in incorrectly, then the registration procedure may be canceled and all paid amounts are not refunded.

During registration process it is necessary to make several payments to the accounts of the public authorities, including:

-      payment of the government levy for registration of the medicinal product to the account of the State Treasury of Ukraine;

-      payment of the costs of expert evaluation to the account of the SEC;

-      (if necessary) payment of the costs of the laboratory quality control of the medicinal product samples to the account of the authorized laboratory.

 

Time terms of expert evaluation of the registration dossier of the medicinal product, depending on the type of Applications:

-      210 working days: the medicinal product submitted for registration in accordance with the full (autonomous) dossier; medicinal immunobiological products; biosimilars;

-      90 working days: for other types of medicinal products (Applications for generics, well-known medical use and a number of other types);

-      45 working days: for orphan products and medicinal products for treatment of socially dangerous diseases (HIV, viral hepatitis, tuberculosis, oncological diseases);

-      10 working days: for medicinal products registered by competent authorities of the United States of America, Switzerland, Japan, Australia, Canada and medicinal products registered via the centralized procedure by the European Union competent authority;

-      5 working days: for medicinal products, which are supposed to be purchased by specialized international organizations.

NB! The specified terms are defined only taking into account the duration of the documents expert evaluation, and do not include:

-      The period of the initial consideration of the Application and the registration form;

-      Payment of the state payments and receiving the payment confirmation;

-      The time required to respond to observations;

-      The time required to import samples and standards and conduct laboratory analysis (if necessary);

-      Final actions after expert evaluation (verification/proofreading of drafts of the Registration Certificate and its Addenda);

-      Period of signing the Order on the registration of the medicinal product.

The actual duration of registration procedure consists of the expert evaluation period plus 2-4 months required for the actions listed above.

 

Registration Certificate:

After the first registration, the Registration Certificate is issued for a period of 5 years. After the re-registration, the Certificate of unlimited duration is issued (unless the MOH decides to conduct an additional re-registration after 5 years for justified reasons related to pharmacovigilance).

The Registration Certificate consists of:

-      the Certificate itself issued on the special form with a hologram;

-      the Addendum to the Certificate: QCM (quality control methods for the medicinal product);

-      the Addendum to the Certificate: the Instruction on medical use of the medicinal product;

-      the Addendum to the Certificate: packaging materials labeling.

All the changes (of any type) are also the integral parts of the Registration Certificate.

 

Maintenance of the Certificate and its amendments:

There are no monthly or annual payments associated with maintaining registration in Ukraine. At the same time, the Applicant must maintain the pharmacovigilance system and quality management system in Ukraine. Therefore, the Applicant must ensure:

-      the constant presence of the person responsible for pharmacovigilance;

-      the constant presence of the person responsible for the quality, safety, and efficacy.

The fulfillment of Applicant’s obligations with regard to maintaining quality and safety may be transferred under a Contract to a third party (for example, Cratia).

All changes to the Registration Certificate are made by submitting the Application and the set of documents, payment of the expert evaluation costs, approval by the Order of the Ministry of Health of Ukraine.

The Applicant must submit the Application for safety changes to the Instruction on medical use of the medicinal product no later than 60 calendar days from the date of receiving the information on the need to make such changes.

The types of changes are similar to the types of changes in the EU:

-      correction of a technical error: correction of inconsistencies appeared during registration, re-registration or amendment procedure;

-      new Applicant (Owner) of the Registration Certificate;

-      type IA: minor changes that do not have a significant impact on the quality, safety, and efficacy;

-      type ІАIN: type IA changes with immediate notification;

-      type IB: minor changes which are neither of type IA nor of type II;

-      type II: changes that affect the quality, safety, and efficacy;

-      changes which lead to new registration.

The term "notification" in Ukraine differs from the one in the European practice: in fact, "notification" changes do not imply any mistakes or questions from the competent authorities, as long as issuing an observation means a refusal to conduct an expert evaluation.

 

Re-registration:

Not later than 90 days before the end of registration, the Application for re-registration may be submitted (the recommended deadline is 10-11 months). After the re-registration, the Registration Certificate of unlimited duration is issued (unless the MOH decides to conduct an additional re-registration after 5 years for valid reasons related to pharmacovigilance).

Re-registration begins from the moment of submitting the Application to the Ministry of Health of Ukraine, ends with the approval of re-registration by the Order of the Ministry of Health of Ukraine and the issue of the new Registration Certificate. At the same time, the Registration Certificate number remains the same.

For re-registration significantly fewer documents are required, compared to new registration. During re-registration the main focus is on the management of the medicinal product safety, that is, on the documents of the pharmacovigilance system and the Instruction for medical use of the medicinal product.

Before submitting the Application for re-registration, it is necessary to submit separate Applications for all of the changes. These submitted Applications (changes and re-registration) are examined in parallel, and independently of each other.

 

Taxation:

The following VAT rates apply for medicinal products:

-      general case: a preferential VAT rate of 7% for all registered medicinal products and APIs;

-      exception 1: VAT rate of 20% for unregistered medicinal products, or for medicinal products with the expired validity of the Registration Certificate;

-      exception 2: VAT rate of 0% for the supply of medicinal products for humanitarian assistance.

All medicinal products are imported with a custom duty of 0%.

 

Advertising and promotion:

It is allowed to advertise non-prescription (OTC) medicinal products only. Advertising the prescription medicinal products in non-specialized media is prohibited.

There are rigorous restrictions regarding the OTC medicinal products advertising, most of which are described in Article 21 of the Law of Ukraine "On Advertising", and there are also other legislative restrictions.

The promotion of prescription medicinal products is allowed in specialized publications intended for medical institutions and doctors, as well as for distribution at seminars, conferences, symposiums on medical topics.

 

Business Associations

In the Ukrainian market there are a number of specialized associations that professionally protect and promote the interests of foreign and national pharmaceutical manufacturers. Membership in one or several Associations is a common practice in Ukraine. The largest associations are:

 

The main legislative acts:

1. The Law of Ukraine "On medicinal products";

2. Decree of the Cabinet of Ministers of Ukraine of 26.05.2005, No. 376 "On approval of the procedure for state registration (re-registration) of medicines and fees for their state registration (re-registration)";

3. Order of the Ministry of Health of Ukraine of 26.08.2005, No. 426 "On approval of the procedure for the examination of the materials for medicinal products which are submitted for the state registration (re-registration), as well as for the examination of materials on changes to registration materials during the validity of the Registration Certificate" (the version of the Order of the Ministry of Health of Ukraine of 23.07.2015, No. 460);

4. Order of the Ministry of Health of Ukraine of 27.12.2006, No. 898 "On approving the procedure for the supervision of adverse reactions of medicinal products permitted for medical use" (the version of the Order of the Ministry of Health of Ukraine of 26.09.2016, No. 996 "On approval of the procedure for the pharmacovigilance implementation");

5. Resolution of the Cabinet of Ministers of Ukraine of 14.09.2005, No. 902 "On approval of the procedure for conducting state control of the quality of medicinal products imported into Ukraine".

 

Services and activities of Cratia:

For more than 12 years our company professionally performs the activities related to registration, safety and quality management of medicinal products in Ukraine. Depending on your needs, we are ready to offer both a full range of activities to fulfill all the regulatory requirements, or any of the listed services:

-      Regulatory planning and preliminary consulting;

-      Patent search;

-      Checking whether the registration dossier complies with the legislative requirements;

-      Preliminary consultations with the competent authorities;

-      Confirmation of the status and/or type of the Application;

-      Translation of scientific, medical, technical and legal documents;

-      Juridical analysis and preparation of administrative documents;

-      Preparation of specific national documents: QCM, instructions, labeling of the packaging materials and layouts;

-      Preparation of the Application and registration form, collection and compilation of the registration dossier according to all requirements and recommendations;

-      Creation and maintenance of the pharmacovigilance system in Ukraine;

-      Development of the documents in the pharmacovigilance system;

-      Outsourcing the contact person responsible for pharmacovigilance in Ukraine;

-      Outsourcing the contact person responsible for the quality, safety and efficacy of the medicinal product in Ukraine;

-      Preparation and submission of the Application, registration form and registration dossier to the SEC of the MOH of Ukraine;

-      Organization of all payments and receiving the payment confirmation;

-      Support of expert evaluation process, communication with competent authorities;

-      Analysis of observations, preparation of recommendations to respond the observations;

-      Obtaining permission to import samples and standards for the quality control within registration;

-      Import (customs clearance) of samples and standards;

-      Control of deadlines at all the stages of expert evaluation;

-      Verification of drafts of the Registration Certificate and its Addenda;

-      Preparation of the Application and documents for obtaining the Conclusion or Certificate of compliance of the medicinal products manufacturing conditions with the GMP requirements.

 

To start cooperation or get advice call +38 044 361-48-28, +38 044 221-71-29, write a letter to info@cratia.ua or come and meet us in our office.