Ukrainian State Expert Center

Ministry of Health of Ukraine

The regulatory landscape for biotech products in Ukraine

Yuriy Gamazin,Moscow, May, 2013

OBJECTIVE:

The Objective of the National Programme of Ukrainian legistation harmonization with the European Union approved by Law of Ukraine No.1629-IV of March 18, 2004 is to achieve compliance of the legal system of Ukraine with acquis communautaire taking into account the criteria set by the EU for the countries intended to join the EU.

Thus, the objective of the MOH is to harmonise Ukrainian regulations on quality, safety and efficacy of medicinal products with the Directives of the European Parliament and the European Council relating to registration and circulation of medicinal products.

Medicinal products are allowed for use in Ukraine after their state registration, except as provided by this Law

Law of Ukraine «On Medicines», 1996(Section ІІ, Article 9)

Medicinal product can not be placed on the market of a Member State unless a marketing authorization has been issued by the competent authorities of that Member State in accordance with this Directive or an authorization has been granted in accordance with Regulation (EEC) No 2309/93.

Directive 2001/83 of the European Parliament and the EU Council of November 06, 2001(Title ІІІ, Chapter 1, Article 6)

Prerequisites for the use of medicinal productsPrerequisites for the use of medicinal products

Essential regulations for medicinal product circulation

Law of Ukraine “On Medicines”;

Resolution of the Cabinet of Ministers of Ukraine No 376 “On Approval of the Procedure for State Registration (Re-registration) of Medicinal Products and Fee for Their State Registration (Re-Registration)” of May 26, 2005 (as amended by Resolution of the CMU No 717 of June 27, 2012);

Resolution of the Cabinet of Ministers of Ukraine No. 73 “On Approval of the Regulation on the Control of Conformity of immunobiological Products Used in Medical Practice with the Requirements of National and International Standards” of January 15, 1996;

Resolution of the CMU No 902 “On Approval of the Procedure for State Quality Control of Medicinal Products Imported to Ukraine” of September 14, 2005

Essential regulations for medicinal product circulation

Order of the MOH of Ukraine No 426 “On Approval of the Procedure for Conducting Expert Evaluation of Materials Pertinent to Medicinal Products which are Submitted for State Registration (Re-Registration) and Expert Evaluation of Materials about Introduction of Changes to the Registration Documents during the Validity Period of Registration Certificate" of August 26, 2005, (as amended by Order of the MOH of Ukraine No 3 of January 04, 2013;

Procedure for State Quality Control of Medicinal Immunobiological Rroducts that are Used, Manufactured or Proposed for Use in Medical Practice in Ukraine approved by Order of the MOH No 486 of December 06, 2001

REGISTRATION

OF MEDICINAL PRODUCTS

Resolution of the CMU No. 717 of June 27, 2012

State registration of medicinal products and medicinal immunobiological products under unified procedure with taking into account particularities (Ministry of the Health of Ukraine shall conduct state registration and re-registration of medicinal products under procedure set forth for medicinal products).

The state registration of a medicinal immunobiological product is certified by a registration certificate of the medicinal product (medicinal immunobiological product), not by a certificate of the state registration of the medicinal immunobiological product;

The MOH can decide to completely or temporarily prohibit the use of a medicinal product by terminating the registration certificate if the medicinal product was not released into circulation in the territory of Ukraine within two years from the date of the state registration (re-registration) unless it is due to particularities of manufacture and/or use of such medicinal product.

Order of the MOH No. 3 of January 04, 2013

Objective: Conformity with the acts of higher legal force (Law of Ukraine “On Medicines”, Resolution of the CMU No 376 of May 26, 2005); improvement of the registration procedure in general.

Revision of definitions;

The proposed Order of the MOH is the single document for medicines and medical immunobiological products;

Strengthening the role of the MOH as the regulatory authority that conducts the state registration of medicinal products and designates the registration procedure in accordance with the recoomendations of the expert body (The State Expert Center);

Order of the MOH No 3 of January 04, 2013

Revision of the Section relating to amending registration materials, classification of the types of changes;

Submission, in the course of expert evaluation of the medicinal product registration materials, a copy of a document confirming the compliance of manufacture with the requirements of Good Manufacturing Practice (GMP) that are in force in Ukraine, issued by the State Administration of Ukraine on Medicinal Products (for domestic manufacturers, a copy of the valid drug manufacturing license shall be provided);

Bringing the requirements for medicinal product labeling in line with Article 12 of the Law of Ukraine “On Medicines”;

Regulation of terms of the registration procedure

Order of the MOH No. 3 of January 04, 2013

Requirements as to orphan drugs and specifics of their registration materials;

Definition of criteria and procedure for conducting additional studies of medicinal products relating to:

pharmaceutical development,

confirmation of medicinal product quality,

preclinical studies,

medicinal product efficacy and/or safety studies,

studies of bioequivalence and equivalence of generic medicinal products

Order of the MOH No 3 of January 04, 2013

Requirements as to equivalence (interchangeability) studies of generics, in particular:

when in vivo equivalence study is not required;

when equivalence study is required;

conditions for biowaiver procedure;

general aspects of test for dissolution;

requirements for bioequivalence studies for different pharmaceutical forms;

requirements for confirmation of bioequivalence of additional doses of the medicinal product;

report on bioequivalence studies

Order of the MOH No 3 of January 04, 2013

Special requirements are provided for registration of original medicinal products and medicinal products that underwent the WHO pre-qualification procedure and are included in the WHO list of pre-qualified medicinal products used in treatment of socially dangerous diseases (tuberculosis, HIV / AIDS, viral hepatitis, and rare diseases):

Modules 1 and 2 (and their translation into Ukrainian of Russian) in hard copy. Modules 3, 4, and 5 may be submitted by the applicant in soft copy;

Expert evaluation of registration materials takes precedence and is conducted free of charge;

Pre-registration quality control of such medicinal products may be performed under «Lot Release» procedure;

Expert evaluation of the registration materials shall take not more than 90 working days from the date of receipt of the registration dossier by the Center

Order of the MOH No 3 of January 04, 2013

Control under «Lot Release» procedure is performed in the following cases:

the medicinal product is of high cost (equivalent to 500 EUR or more) and is imported to Ukraine in limited amounts;

Sterility, Microbiological purity, or other parameters are evaluated under this procedure if their testing requires large number of specimens and the cost of one specimen is equivalent to 100 EUR or more;

if none of the authorized laboratories has at disposal the equipment required for performing control tests for certain quality parameters;

the medicinal product is of limited use (orphan drug).

Biosimilars in Ukrainian legislation

Medicinal immunobiological products include allergens, antigens, vaccines (anatoxins), cytokines, immunomodulators of bacterial origin, as well as those that are based on organ and tissue preparations, products obtained from human blood and plasma, immune sera, immunoglobulins (including monoclonal antibodies) , probiotics, interferons, other medical products intended for use in medical practice for treatment, specific prevention and diagnosing the immune status (in vivo). They are produced by cultivation of microorganism strains and eukaryotic cells, extraction of substances from biological tissues, including tissues of human, animals and plants (allergens), and methods of genetic engineering, hybrid technologies, reproductions of alive agents in embryos or animals.

(Resolution of the CMU No 73; Order of the MOH No. 426 (as amended by Order No. 3)

Biosimilars in Ukrainian legislation

Similar biological medicinal product (biosimilar) is a biological medicinal product which efficacy, safety and quality are similar to those of registered reference biological product which patent protection has expired. Similarity of therapeutic efficacy, safety and quality of such medicinal product to those of the reference medicine should be confirmed with respective pre- and clinical studies.

(Order of the MOH No 426 (as amended by Order No 3)

Biosimilars in Ukrainian legislation

Special requirements to biosimilars are introduced :

In case of registration of similar biological products (biosimilars) that cannot be considered generics due to the specificity of the manufacturing process, raw materials used, characteristics of the molecular structure and therapeutic effects, in addition to Modules 1, 2, and 3 additional data are to be provided to support the appropriate level of safety (toxicological or other preclinical studies) and efficacy (clinical trials) (Chapter 3, Section Х of this Procedure)

(paragraph.6.6 of Section VI, Chapter 3 of Section Х, Order of the MOH No 426 (as amended by Order No 3))

Biosimilars in Ukrainian legislation

New chapter “Special requirements for the registration dossier materials of similar biological medicinal products (biosimilars)” has been added

When applying for registration of a similar biological medicinal product after the expiration of the patent protection of data relating to the original biological product registered before, the following materials are to be provided:

information submitted should not be limited to Modules 1, 2 and 3 (pharmaceutical, chemical and biological data), supplemented with bioequivalence and bioavailability data. The type and amount of additional data (i.e., toxicological and other preclinical and relevant clinical data) shall be determined in each individulal case in accordance with the relevant requirements and guidelines;

Biosimilars in Ukrainian legislation

New chapter “Special requirements for the registration dossier materials of similar biological medicinal products (biosimilars)” has been added

due to the diversity of biological medicinal products it may be necessary to provide information on the identification studies provided for in Modules 4 and 5 of the registration dossier, with due regard being had to the special characteristics of each medicinal product.

If the original medicinal product registered has more than one therapeutic indication, the efficacy and safety of a similar biological medicinal product shall be confirmed or, if necessary, demonstrated individually for each of the claimed indications.

STATE CONTROL OF MEDICINAL PRODUCTS

Main Regulations

Resolution of the Cabinet of Ministers of Ukraine No. 73 “On Approval of the Regulation on the Control of Conformity of Immunobiological Products Used in Medical Practice with the Requirements of National and International Standards” of January 15, 1996;

Resolution of the CMU No 902 “On Approval of the Procedure for State Quality Control of Medicinal Products Imported to Ukraine” of September 14, 2005;

Procedure for State Quality Control of Medicinal Immunobiological Rroducts that are Used, Manufactured or Proposed for Use in Medical Practice in Ukraine approved by Order of the MOH No 486 of December 06, 2001

State Control Procedure

State control is mandatory for all products both domestic and foreign manufacture that are used, manufactured or proposed for use in medical practice in the territory of Ukraine.

Control is carried out by expert evaluation of the materials of the (manufacturer's) quality control of the product batches (protocols of batch quality control, analytical reports) and laboratory testing of the product specimens in accordance with the specifications in the prescribed form and with the established regularity of the state control.

Conclusion on MIP quality conformance is a basis for further circulation of the biolobical product, including its marketing.

Order of the MOH No 486

Form and Frequency of State Quality Control of MIPs

ConductedConducted based on: based on:

whether the product is registered in Ukraine;whether the product is registered in Ukraine;

use of the product in the state programs, including use of the product in the state programs, including the program of the program of vaccination in Ukraine;vaccination in Ukraine;

availability of a copy of an official document of compliance of the availability of a copy of an official document of compliance of the manufacture with GMP requirements issued by a competent authority of manufacture with GMP requirements issued by a competent authority of Ukraine or Japan or a member country of Pharmaceutical Inspection Ukraine or Japan or a member country of Pharmaceutical Inspection Cooperation Scheme (PIC / S);Cooperation Scheme (PIC / S);

Data of side and non-specific effects monitoringData of side and non-specific effects monitoring;;

Data on stability of the qualityData on stability of the quality parameters parameters for the period of the product for the period of the product use in medical practice in Ukraine.use in medical practice in Ukraine.

Forms of State ControlForms of State Control

Detailed quality control: control of all the batch quality Detailed quality control: control of all the batch quality parameters in accordance with the specifications and methods parameters in accordance with the specifications and methods of quality control;of quality control;

SelectiveSelective quality control: control of selected quality parameters quality control: control of selected quality parameters of the product batches.of the product batches.

Conclusion of MIConclusion of MIBBP quality conformance issued by P quality conformance issued by the Ministry of Health is a result of the state the Ministry of Health is a result of the state control of the MIcontrol of the MIBBP batchP batch

Order of the MOH No 486 of December o6, 2001Order of the MOH No 486 of December o6, 2001Resolution of the CMU No 73 of January 15, 1996Resolution of the CMU No 73 of January 15, 1996

Certificate of approval of a biological product issued by a National authority on quality assurance for biological products

WHO Technical Report Series, No.822, 1992 GuidelinesWHO Technical Report Series, No.822, 1992 Guidelinesforfor national authorities on quality assurance for biological national authorities on quality assurance for biological

productsproducts

Procedure for state control of biological products

Thank you for attention!