Structure of State Regulatory Authorities REGISTRATION CERTIFICATE ISSUING AUTHORITY ROSZDRAVNADZOR

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1 PRESENTATION REGISTRATION OF PHARMACEUTICAL PRODUCTS IN RUSSIA Alyona Chorich, Regulatory Affairs Manager PharmaReg, Moscow 1. Registration in Russia conception. Pharmaceutical products / food supplements /cosmetics different registration ways. To enter into Russian market all pharmaceutical products must be registered. Registration is a procedure of expertise of the pharmaceutical product quality, efficacy and safety by State Regulatory Authority. After such expertise it is issued Registration Certificate and the product is introduced in the database of registered products in Russian Federation. From 2008 Registration Certificate is unlimited. But before this date Registration Certificates were issued only for 5 years. A big number of already registered products must pass re-registration. Registration Certificate is the same document as Marketing Authorization. In Russia there are 2 strictly divided categories: pharmaceutical products (one category) and food supplements and cosmetics (another category). The product must be associated with one from these categories. It is absent such category as curative cosmetics. The registration expertise of these 2 categories differs very much. Pharmaceutical products pass more detailed and strict examination; need more documentation and additional expertise. The most import legislative acts about registration of pharmaceutical products are: - Medicines Act "Administrative Regulations of the Roszdravnadzor on execution of the state function of pharmaceutical products registration" approved by order of Ministry of Health and Social Development of Russian Federation No. 736 dated At the present moment it is under approval revised version of Medicines Act. 2. State Russian Regulatory Authorities (Roszdravnadzor, Rospotrebnadzor, National Center of Pharmaceutical Products Expertise (FGU), National Center of Nutrition) structure; interaction with applicants; differences in requirements for Russian and Foreigner Manufacturers. State Regulatory Authority is called Federal Service on Supervision in Sphere of Public Health Services and Social Development (Roszdravnadzor). Roszdravnadzor takes the decision to register the product and issues Registration Certificate. The expertise of all pharmaceutical products quality, efficacy and safety is done by National Center of Pharmaceutical Products Expertise (FGU). Only this National Center is authorized to execute independent expertise especially for Roszdravnadzor. According to new Medicines Act which is under approval additional Centers will be authorized to make registration expertise of pharmaceutical products. Structure of State Regulatory Authorities REGISTRATION CERTIFICATE ISSUING AUTHORITY ROSZDRAVNADZOR Department of pharmaceutical products registration

2 PHARMACEUTICAL PRODUCTS EFFICACY AND SAFETY EXPERTISE AUTHORITY National Center of Pharmaceutical Products Expertise (FGU) of Roszdravnadzor Section of coordination and data-base handling Institute of Products Quality Control Institute of Preclinical and Clinical Expertise Section of trade name expertise Quality Control Laboratory Specialized Commissions (bioequivalence, clinical, preclinical) National Center of Pharmaceutical Products Expertise consists from different Sections and Institutes. The biggest and the most important part of the registration procedure pass in the mentioned Center. Applicants for products registration submit registration documents directly to National Center. The registration procedure is organized in the way that regulatory affairs specials must communicate with experts every week. It is fixed the schedule of visiting days. Terms of registration depend a lot from the correctly organized work of the regulatory affairs specialist. The registration procedure is the same for Russian and Foreigner manufacturers. Differences appear in cost and documents. Also the important fact is that foreigner manufacturer must have GMP-certificate. The product is not necessary to be registered in the country of origin or another country. It is admitted to apply for registration products which will be authorized only in Russian Federation. State Regulatory Authorities are situated only in Moscow. There are absent divisions in other regions on Russian Federation. 3. Registration file list of documents, comparison of European and Russian registration files. Who can be the Applicant for registration, Marketing Authorization holder, Manufacturer? Official docs issued by Foreigner State Authorities legalization for Russia. Registration file (or dossier) represents the documents submitted to State Regulatory Authority for registration. Russian registration file consists from 6 parts: Administrative documents Description of pharmaceutical properties Data about manufacturing of pharmaceutical product Data about quality control of the finished pharmaceutical product Data about PRE-CLINICAL pharmacological and toxicological studies of pharmaceutical product Data about CLINICAL studies of pharmaceutical product European registration file consists from 5 modules. The structure of Russian and European registration files is very similar. If manufacturer has European registration file it is not necessary to prepare separated docs for Russia. All data required for Russian dossier are available in European file. Russian registration file must be presented to State Regulatory Authorities in Russian language.

3 In the Registration Certificate there are mentioned the following participants in Manufacturing process: Marketing Authorization Holder Manufacturer of the finished product Primary packaging Secondary packaging Batch release site On each of the above mentioned manufacturing stage can be indicated 2 companies. And also all of these stages can be represented by different companies. The important is to submit the contract agreement between all participants. The applicant for registration can be: Marketing Authorization Holder or its Representation in Russia Physical person Russian juridical company (third party) The rights to represent the interests of marketing Authorization Holder must confirmed by legalized Power of attorney. Thus it is not necessary to open Representation of the company in Russia especially to register pharmaceutical products. It is possible to register the products and after that to begin the business activity. Official documents such as Certificate of Pharmaceutical Product, GMP-certificate, Manufacturing License, Power of Attorney must be legalized. If the state of official documents issue is a State- Member of Hague Convention such documents must be apostilled. If not the documents must be legalized by Russian Embassy. 4. Registration of original and generic pharmaceutical products stages, terms and cost. Registration process conditionally can be divided into 3 basic stages Scheme of registration process Compiling of Registration dossier in Russian and its submission to the National Center of Pharmaceutical Products Expertise (FGU). I stage Expertise of the pharmaceutical product Quality, Efficacy and Safety in the National Center of Pharmaceutical Products Expertise (FGU). II stage Institute of Products Quality Control Quality Control Expertise Institute of Preclinical and Clinical Expertise Efficacy and Safety Expertise Finishing of the expertise and submission of the dossier to Roszdravnadzor for issuing of Registration Certificate. III stage At I stage of registration process it is necessary to collect all necessary documents, to translate them into Russian and to compile registration dossier.

4 The most difficult and longest is the II stage. Registration dossier after submission and payment of necessaries fees is directed to appointed experts from Institute of Products Quality Control and Institute of Preclinical and Clinical Expertise. In the Institute of Products Quality Control it is done the verification of Finished Product Specification called in Russian Normative Document and also is performed the laboratory control. In the Institute of Preclinical and Clinical Expertise it is checked the Instruction for administration. In case if necessity of preclinical or clinical tests the product is directed to specialized Research Institute. Original and generic products pass the same stages of registration. Original products must pass through all registration procedures while the generic products are exempted from some of them. For example for original product must conducted clinical trials in Russia. For generic products can be conducted only bioequivalence studies and not only in Russia. Preclinical and clinical studies performed in foreigner countries are accepted. Terms of registration process: I stage + II stage + III stage 2 months 12 months 4 months = TOTAL 18 months The time of registration can be increased in the following cases: The necessity to carry out of additional preclinical and clinical trials The necessity to carry out of repeated laboratory quality control. Delay of granting of additional required data by State Regulatory Authority more than 30 days. COST OF REGISTRATION The cost of registration of one pharmaceutical product consists from 2 parts: Official payments to State Authorities + payment of regulatory affairs specialist or company services = approx $ $ = approx $ approx approx $ = approx $ OFFICIAL PAYMENTS paid to State Authority (National Center of Pharmaceutical Products Expertise (FGU)) for one pharmaceutical product registration for foreigner manufacturers are the following: Name of procedure Cost, $ Cost, Note Examination of documents (one registration dossier) $ The whole sum must be paid at the beginning of the registration process. The registration expertise will not begin until the customer will not pay the invoice.

5 Laboratory quality expertise $ TOTAL $ The cost of Laboratory quality expertise depends on the number of dosages and the analytical methods used. 5. Laboratory Control of pharmaceutical products during registration and post-registration Control at the stage of import for selling (essential moments, possible difficulties). During registration process all products must pass laboratory control according to approved Normative Document. Possible difficulties are: necessary of introduction in finished product specification of additional tests, importing of standards and samples. Normative Document in Russia is compiled according to manufacturer s finished product specification, European/British Pharmacopoeia, United States Pharmacopoeia and Russian Pharmacopoeia. To import the samples and standards for laboratory control it is necessary to receive special Import permission from Roszdravnadzor. It takes 1-2 months and prolonged the time of registration. The full analysis of the pharmaceutical product is done on the stage of registration and on the first 3 batched imported into Russian market for selling. The time of laboratory control is 4 months, plus 2 months to import necessary standards. It is necessary to take in consideration that within this time (6 months) the product will be holed at the custom. 6. Post-Registration Variations types, documents, terms. The result of registration process is obtaining of Registration Certificate. Along with it are given Normative Document, Instruction for administration and Colored design of packaging. All these documents are signed by representative of the License Authorization (Registration Certificate) Holder and approved by Roszdravnadzor. Any changes introduced in these documents must be approved by State Regulatory Authority as Variation. There are 2 types of Variations: Type Classification Examples Variation type I Don t need Quality, Efficacy or Safety expertise Variation type II Need Quality, Efficacy or Safety expertise Change of the Manufacturer s name; Change of Marketing Authorization holder; Change of package design Change of manufacturing site; change of quality or quantity composition; change of instruction for administration Terms of variation approval: Type Variation type I Variation type II Terms 2-3 months 6-12 months