Order 409n dated July 12, 2017
"On approval of the procedure for forming the registration dossier of a medicinal product..."

In accordance with subparagraphs 5.2.148, 5.2.148¹, 5.2.148² of the Provisions on the Ministry of Healthcare of the Russian Federation approved by the Resolution of the Government of the Russian Federation dated June 19, 2012 № 608 (Legislation Bulletin of the Russian Federation, 2012 № 26, Art. 3526; 2013, № 16, Art. 1970; №20, Art. 2477; № 22, Art. 2812; № 45, Art. 5822; 2014, № 12, Art. 1296; № 26, Art.3577; № 30, Art. 4307; № 37, Art. 4969; 2015, № 2, Art. 491; № 12, Art. 1763; №23, Art. 3333; 2016, № 2, Art. 325; № 9, Art. 1268; № 27, Art. 4497; № 28, Art.4741; № 34, Art. 5255, № 49, Art. 6922; 2017, № 7, Art. 1066),
I o r d e r:

1. To approve:

- the procedure for forming the registration dossier of a medicinal product for human use and the requirements for documents composing it according to Annex № 1;

- the requirements for the scope of information presented as part of the registration dossier for certain types of medicinal products for human use according to Annex №2;

- the procedure for submitting documents that form the registration dossier of a medicinal product for human use for the purpose of its state registration according to Annex № 3.

2. This order shall apply to registration dossiers of medicinal products for human use submitted to the Ministry of Healthcare of the Russian Federation together with applications for state registration of medicinal products for human use after this order enters into legal force.

3. The order of the Ministry of Health and Social Development of the Russian Federation dated August 26, 2010 № 759н On Approval of the Procedure for submitting required documents that form the registration dossier of a medicinal product or human use for the purpose of its state registration (registered by the Ministry of Justice of the Russian Federation on September 2, 2010, registration № 18331) shall be deemed to have lost force.

Minister /SIGNATURE/ V.I. Skvortsova

1. This Procedure establishes the rules for forming the registration dossier of a medicinal product for human use submitted to the Ministry of Healthcare of the Russian Federation by a legal entity acting on its own behalf or authorized to represent interests of another legal entity and applying a medicinal product for state registration [1] , and the requirements for documents composing such a dossier.

2. The registration dossier of a medicinal product for human use in form of a Common Technical Document is a set of documents and materials consisting of several sections – administrative documentation, chemical, pharmaceutical and biological documentation, pharmacological, toxicological documentation, clinical documentation.

3. The section of administrative documentation is formed of:

1) application for state registration of the medicinal product for human use, which specifies:

a) name and address of the applicant and the manufacturer of the medicinal product for human use and address of its manufacturing site (in case of several manufacturing process participants, it is necessary to specify each participant in accordance with the manufacturing stage performed);

b) name of the medicinal product for human use (international nonproprietary, or group, or chemical and trade names);

c) list of active ingredients and excipients included in the formulation of the medicinal product for human use, indicating the quantity of each;

d) pharmaceutical form, dosage, routes of administration and application, shelf life of the medicinal product for human use;

e) pharmacotherapeutic group, code of the Anatomical Therapeutic Chemical classification recommended by the World Health Organization, declared indications of the medicinal product for human use;

f) absence of necessity to provide the report on the results of clinical trial, bioequivalence study of the medicinal product approved for human use in the Russian Federation for over twenty years, indicating the regulatory legal acts confirming this term of application;

g) necessity to draw up the permission to import in the Russian Federation a particular batch of registered and (or) non-registered medicines intended for conducting expert examination of medicinal products for the purpose of state registration;

h) necessity to conduct expert examination of documents submitted to determine the possibility to consider the medicinal product for human use as an orphan medicinal product during the state registration;

i) necessity to apply the accelerated procedure of expert examination of medicinal products for the purpose of state registration of the medicinal product;

j) copies of documents confirming payment of the appropriate state fee:

- for conducting expert examination of documents submitted to determine the possibility to consider the medicinal product for human use as an orphan medicinal product during the state registration of the medicinal product;

- for conducting expert examination of the medicinal product quality and expertise of the ratio of expected benefit to possible risk in application of the medicinal product approved for human use in the Russian Federation for over twenty years during the state registration of the medicinal product;

- for conducting expert examination of the medicinal product quality and expertise of the ratio of expected benefit to possible risk in application of the medicinal product for human use during its state registration;

- for conducting expert examination of the medicinal product quality and expertise of the ratio of expected benefit to possible risk in application of the medicinal product for human use, in relation to which multi-center clinical trials were performed, part of which were performed in the Russian Federation, during the state registration of the medicinal product;

k) availability of the consent of the manufacturer of the medicinal product manufactured outside of the Russian Federation to conduct an inspection of the manufacturer for the compliance with the requirements of Good Manufacturing Practice;

l) availability of the consent of the reference medicinal product developer or the person authorized by him to use for commercial purposes the information on the results of preclinical studies and clinical trials of the reference medicinal product for human use while submitting the application for state registration of a generic medicinal product before the expiry of six years from the date of state registration of the reference medicinal product in the Russian Federation;

m) indicating the type of the medicinal product submitted for registration (reference medicinal product, generic medicinal product, biological medicinal product, biosimilar medicinal product (biosimilar), homeopathic medicinal product, herbal medicinal product);

2) a copy of document in Russian certified within the established procedure and confirming the eligibility of the applicant to submit the application for state registration of the medicinal product for human use (power of attorney);

3) a copy of the license for manufacture of medicinal products or a copy of the conclusion on the compliance of the medicinal products manufacturer with the requirements of Good Manufacturing Practice issued by the competent federal executive authority in case if the medicinal product is manufactured in the Russian Federation;

4) a copy of the license for manufacture of the medicinal product issued by the competent authority of the manufacturer's country and its translation into Russian certified within the established procedure, and a copy of the conclusion on the compliance of the medicinal products manufacturer with the requirements of Good Manufacturing Practice issued by the competent federal executive authority in case if the medicinal product is manufactured outside of the Russian Federation;

5) draft patient information leaflet of the medicinal product containing information specified in paragraph 5 of part 4 of Article 18 of the Federal Law № 61-ФЗ [2] ;

6) patient information leaflet or the summary of product characteristics of the medicinal product approved in the manufacturer's country;

7) draft mock-ups of primary packaging and secondary packaging of the medicinal product for human use;

8) draft normative documentation of the medicinal product for human use containing the list of quality indicators of the medicine for human use determinable by the results of appropriate expertise, methods of its quality control, and established by its manufacturer [3] , or directions of the appropriate pharmacopoeial monograph [4] ;

9) document containing information on the presence or absence of facts of registration of the medicinal product for human use outside of the Russian Federation;

10) copies of documents certified within the established procedure and confirming the fact of the medicinal product registration in foreign states as an orphan medicinal product;

11) risk management plan for biological medicinal products for human use containing detailed description of pharmacovigilance measures aimed to detect, assess and prevent or minimize risks associated with medicinal products, including evaluation of effectiveness of these measures [5] ;

12) document on pharmacovigilance system of the holder or owner of the registration certificate of the medicinal product [6] containing information on the system organized by the holder or owner of the medicinal product registration certificate intended for control of safety of the medicinal product, timely detection of all changes in the assessment of the ratio of expected benefit to possible risk in application of the medicinal product for human use, development and implementation of measures to ensure the medicinal product application in order to preserve a positive ratio of expected benefit to possible risk in application of the medicinal product for human use;

13) document confirming the quality of the medicinal product of three pilot-plant and (or) commercial scales (protocol of analysis or certificate of analysis), one batch of which should coincide with the sample batch of the medicinal product for human use submitted for state registration [7] .

4. The section of chemical, pharmaceutical and biological documentation is formed of documents containing information on the pharmaceutical ingredient and the medicinal product for human use, its production process and quality control methods, including of:

1) a copy of document containing the following information on the pharmaceutical ingredient or pharmaceutical ingredients included in the medicinal product's formulation:

a) name of the pharmaceutical ingredient, its structure, general properties;

b) name and address of the manufacturer;

c) production technology with description of manufacturing stages and control methods at all manufacturing stages;

d) description of the production process development in form of its brief summary;

e) description of control of critical manufacturing stages and intermediate products, including the data that can be presented in form of a flow chart, with the list of information on manufacturing stages, types and (or) methods of quality control of intermediate products;

f) documented confirmation (validation) of processes, including information confirming applicability of the chosen production scheme of the medicinal product, and (or) their evaluation;

g) properties and structure of active ingredients, including information on their physicochemical properties;

h) characteristics of impurities, including information on their origin and properties;

i) specification of the pharmaceutical ingredient and its justification;

j) analytical methods used to control quality of the pharmaceutical ingredient;

k) documented confirmation (validation) of analytical methods used to control quality of the pharmaceutical ingredient, including information demonstrating applicability and sufficiency of methods for quality control of the pharmaceutical ingredient;

l) results of batch analysis of the pharmaceutical ingredient, including analytical data confirming numerical quality indicators of the pharmaceutical ingredient in form of protocols (certificates or passports) of analysis;

m) list of reference standards or substances used for quality control, including indication of their manufacturers and purpose;

n) description of characteristics and properties of packaging materials and closure means;

o) data on stability of the pharmaceutical ingredient;

p) shelf life;

2) document containing the following information on the medicinal product for human use:

a) description and formulation of the medicinal product for human use;

b) description of the pharmaceutical development (justification of the choice of formulation, primary packaging and others);

c) production technology with description of manufacturing stages and control methods at all manufacturing stages, including indication of technological process scheme for production of pharmaceutical ingredient and its description, which can also include information on control of raw materials, critical manufacturing stages and intermediate products, methods of control of excipients used to manufacture the medicinal product;

d) description of control of critical manufacturing stages and intermediate products, which may include successive narration of all stages of manufacturing technological process;

e) name and address of the manufacturing site of the medicinal product for human use (in case of several manufacturing process participants, it is necessary to specify each of them);

f) pharmaceutical compatibility [8] , including data that demonstrate compatibility of active ingredients and excipients included in the medicinal product's formulation;

g) microbiological characteristics;

h) inventory balance for manufacture of batch of the finished product [9] , which can be presented in form of a flow chart reflecting the sequence of performing all phases and stages (operations) of technological process, indicating the main material flows (raw materials, starting materials, obtaining intermediate products, release of the finished medicinal product);

i) description of characteristics and properties of packaging materials and closure means;

j) documented confirmation (validation) of production process, including information on the manufacturing process validation and selection of control parameters and tests in the manufacturing process and (or) their evaluation;

k) requirements for quality of excipients (certificate, specification of excipients and their justification), in particular, information that confirms possibility to use excipients for manufacture of the medicinal product in order to ensure the dosage form stability may be presented as justification;

l) analytical methods used for quality control of excipients in form of the list with a brief description;

m) documented confirmation (validation) of analytical methods used to control quality of excipients, which can be presented in form of information demonstrating applicability and sufficiency of methods for quality control of excipients;

n) information on the use of excipients of human and animal origin;

o) information on the use of novel excipients;

p) requirements for quality of the medicinal product for human use (certificate, specification of the medicinal product and their justification);

q) analytical methods used to control quality of the medicinal product for human use, which inter alia can be specified in form of references to pharmacopoeial monographs or a detailed list of methods used for quality control;

r) documented confirmation (validation) of analytical methods used to control quality of the medicinal product for human use, including information demonstrating applicability and sufficiency of methods for quality control of the medicinal product;

s) results of batch analysis of the medicinal product for human use;

t) characteristics of impurities;

u) list of reference standards used for quality control of the medicinal product for human use;

v) data on stability of the medicinal product for human use.

5. The section of pharmacological, toxicological documentation is formed of the reports on the results of preclinical studies of the medicinal product for human use, including of:

1) report on pharmacodynamic studies, in particular, a brief summary of conducted pharmacodynamic studies can be presented in case if several such studies were performed;

2) report on pharmacokinetic studies, in particular, a brief summary of conducted pharmacokinetic studies can be presented in case if several such studies were performed;

3) report on toxicity studies, in particular, a brief summary of conducted toxicity studies can be presented in case if several such studies were performed.

6. The section of clinical documentation is formed of the reports on the results of clinical trials of the medicinal product for human use, including of:

1) reports on bioavailability and bioequivalence studies, the studies establishing the correlation of results obtained in vitro and in vivo;

2) reports on pharmacokinetic studies;

3) reports on pharmacodynamic studies;

4) reports on clinical studies of efficacy and safety, including reports on the results of clinical trials of a medicinal product not assigned to orphan medicinal products conducted in the Russian Federation, or international multi-center clinical trials of a medicinal product not assigned to orphan medicinal products part of which was conducted in the Russian Federation;

5) report on post-registration experience of application (if any).

7. Requirements for the scope of information presented as part of the registration dossier for certain types of medicinal products for human use are determined by Annex № 2 to the order of the Ministry of Healthcare of the Russian Federation dated July 12, № 409н.

[1] Part 1 of Article 18 of the Federal Law dated April 12, 2010, № 61-ФЗ On Circulation of Medicines (Legislation Bulletin of the Russian Federation, 2010, № 16, Art. 1815; № 42, Art. 5293; № 49, Art. 6409; 2014 № 52, Art. 7540; 2015, № 10, Art. 1404; 2016, № 27, Art. 4283) (hereinafter – the Federal Law № 61-ФЗ).

[2] Legislation Bulletin of the Russian Federation, 2010, № 16, Art. 1815; № 42, Art. 5293; № 49, Art. 6409; 2014 № 52, Art. 7540; 2015, № 10, Art. 1404; 2016, № 27, Art. 4283.

[3] Paragraph 20 of Article 4 of the Federal Law № 61-ФЗ.

[4] Paragraph 19 of Article 4 of the Federal Law № 61-ФЗ.

[5] Paragraph 52.2 of Article 4 of the Federal Law № 61-ФЗ.

[6] Paragraph 12 of part 4 of Article 18 of the Federal Law № 61-ФЗ.

[7] Paragraph 13 of part 4 of Article 18, part 2 of Article 23 of the Federal Law № 61-ФЗ.

[8] Subparagraph "f" of paragraph 2 of part 5 of Article 18 of the Federal Law № 61-ФЗ.

[9] Subparagraph "h" of paragraph 2 of part 5 of Article 18 of the Federal Law № 61-ФЗ.

1. In relation to medicinal products approved for human use in the Russian Federation for over twenty years (except for biological medicinal products) it is acceptable to include in the section of pharmacological, toxicological documentation and the clinical documentation section instead of the developer's report on the results of own preclinical studies of medicinal products and clinical trials of medicinal products for human use the review of scientific works on the results of preclinical studies of medicinal products and clinical trials of such medicinal products, including the experience of their post-registration application.

2. In case of the state registration of generic medicinal products for human use it is acceptable to include in the section of pharmacological, toxicological documentation and the clinical documentation section instead of the developer's report on the results of own preclinical studies of medicines the review of scientific works on the results of preclinical studies of the reference medicinal product and provide instead of clinical trials in full scope established by the clinical documentation section the report on the results of bioequivalence studies of the generic medicinal product for human use or the report on the results of therapeutic equivalence studies [1] . It is not required to provide the report on the results of bioequivalence studies of the generic medicinal product for human use or the report on the results of therapeutic equivalence studies of the medicinal product for human use, if generic medicinal products for human use being registered are:

1) intended for parenteral (subcutaneous, intramuscular, intravenous, intraocular, intracavitary, intraarticular, intracoronary) administration and are aqueous solutions;

2) solutions for oral administration;

3) manufactured in form of powders and lyophilizates for preparing solutions;

4) gases;

5) ear or eye medicinal products manufactured in the form of aqueous solutions;

6) intended for topical application and prepared in the form of aqueous solutions;

7) aqueous solutions for use in the form of nebulizer inhalations or as nasal sprays used with similar devices.

3. For cases specified in subparagraphs 1-3, 5-7 of paragraph 2 of these Requirements, the generic medicinal product for human use should contain the same excipients in the same quantity as the reference medicinal product. If compositions of excipients differ, the applicant shall provide the evidence that excipients used in such concentrations do not affect safety and (or) efficacy of the medicinal product for human use. In case the applicant is unable to provide such evidence and (or) has no access to appropriate data, he shall perform appropriate studies to prove the absence of impact of different excipients or auxiliary devices on safety and (or) efficacy of the medicinal product for human use within the procedure established by the competent federal executive authority.

4. In case of state registration of combinations of earlier registered medicinal products for human use it is acceptable to include in the section of pharmacological, toxicological documentation and the clinical documentation section instead of the developer's report on the results of own preclinical studies of medicines the review of scientific works on the results of preclinical studies of reference medicinal products included in the combination of medicinal products, and on the absence of their interaction within one dosage form.

5. For the purpose of expert examination of documents submitted to determine the possibility to consider the medicinal product for human use as an orphan medicinal product during its state registration, the applicant shall submit electronically and in a hard copy the documents specified in subparagraphs 1, 2, 5, 6, 10 of paragraph 3 and in paragraph 6 of the procedure for forming the registration dossier of a medicinal product for human use and the requirements for documents composing it approved by the order of the Ministry of Healthcare of the Russian Federation dated July 12, 2017 № 409н.

6. In case of state registration of the orphan medicinal product the applicant shall submit information necessary to form the clinical documentation section, in the scope established by the Ministry of Healthcare of the Russian Federation [2] .

7. When registering a biological medicinal product derived from human blood, blood plasma, the registration dossier of the medicinal product for human use should contain additionally:

1) in the section of administrative documentation, a document containing information on the subjects of circulation of the donor blood and (or) its components, on where the donation (blood and (or) blood plasma) was performed, as well as data on infectious diseases transmitted parenterally, information on the subjects of circulation of donor blood and (or) its components in respect of which the control of donor blood and (or) its components is performed;

2) in the section of chemical, pharmaceutical and biological documentation:

a) criteria and methods for taking, transporting and storing donor blood and (or) its components;

b) the results of testing taken donor blood and (or) blood plasma and pools for the presence of infectious agents, including information on the research methods used and in case of pooled blood plasma the results of documented confirmation (validation) of the methods used;

c) technical characteristics of packaging for taking donor blood and (or) blood plasma, including information on anticoagulant solutions used.

8. For medicinal products for human use in relation to which as a result of expert examination of documents submitted to determine the possibility to consider the medicinal product for human use as an orphan medicinal product such possibility is recognized and in relation to which clinical trials were conducted outside of the Russian Federation in accordance with the Rules of Good Laboratory Practice and the Rules of Good Clinical Practice, it is acceptable to include in the clinical documentation section instead of the report on the results of clinical trials of the medicinal product for human use conducted in the Russian Federation, the report on the results of clinical trials conducted outside of the Russian Federation.

[1] Paragraph 12 Article 4, part 10 of Article 18 of the Federal Law dated April 12, 2010, № 61-ФЗ On Circulation of Medicines (Legislation Bulletin of the Russian Federation, 2010, № 16, Art. 1815; № 42, Art. 5293; № 49, Art. 6409; 2011, № 50, Art. 7351; 2013, № 48, Art. 6165; 2014 № 52, Art. 7540; 2015, № 10, Art. 1404; 2016, № 27, Art. 4283).

[2] Subparagraph 5.2.148³ of the Provisions on the Ministry of Healthcare of the Russian Federation approved by the Resolution of the Government of the Russian Federation dated June 19, 2012 № 608 (Legislation Bulletin of the Russian Federation, 2012, № 26, Art. 3526; 2013, № 16, Art. 1970; № 20, Art. 2477; № 22, Art. 2812; № 45, Art. 5822; 2014, №12, Art. 1296; № 26, Art. 3577; № 30, Art. 4307; № 37, Art. 4969; 2015, № 12, Art. 1763; № 23, Art. 3333; 2016, №9, Art. 1268; № 27, Art. 4497; № 34, Art. 5255, № 49, Art. 6922; 2017, № 7, Art. 1066).

1. This Procedure establishes the rules for submitting by a legal entity acting on its own behalf or authorized to represent interests of another legal entity and applying a medicinal product for state registration (hereinafter – the applicant) to the Ministry of Healthcare of the Russian Federation the application for state registration of a medicinal product for human use (hereinafter – the application) and required documents that form the registration dossier of a medicinal product for human use (hereinafter – the registration dossier documents).

2. The application and the registration dossier documents shall be submitted electronically and in a hard copy in Russian or with translation into Russian certified within the established procure [*] .

3. In case if the registration dossier document has several sheets, they are bound, numbered and certified with signature of the authorized person on the reverse side of the document's last sheet in the place of binding with indication of the total number of the document's sheets. In case if the applicant submits the registration dossier documents having several sheets and certified within the established procedure, this requirement is not set.

4. For state registration of different pharmaceutical forms of the same medicinal product for human use the applicant shall submit separate applications and registration dossier documents for each pharmaceutical form. In case of simultaneous submission for state registration of one pharmaceutical form with different dosage, concentration, volume, the applicant shall submit one application for state registration of a medicinal product for human use and documents.

5. The application for state registration of a medicinal product for human use, the registration dossier documents and other documents related to the procedure of state registration of a medicinal product for human use shall be drawn up by the Department for State Regulation of Circulation of Medicines of the Ministry of Healthcare of the Russian Federation as a separate case, which is stored in the Scientific Center for Medical Products Expertise Federal State Budgetary Institution at the Ministry of Healthcare of the Russian Federation.

[*] Fundamental Principles of Legislation of the Russian Federation on the Notarial Services dated February 11, 1993 №4462-1 (Gazette of the Congress of People's Deputies of the Russian Federation and the Supreme Soviet of the Russian Federation, 1993, № 10, Art. 357; Legislation Bulletin of the Russian Federation, 2003, № 50, Art. 4855; 2004, № 45, Art. 4377; 2005, № 27, Art. 2717; 2007, № 1, Art. 21; № 27, Art. 3213; 2008, № 52, Art. 6236; 2009, № 1, Art. 14, 20; № 29, Art. 3642; 2010, № 28, Art. 3554; 2011, № 49, Art. 7064; № 50, Art. 7347; 2013, № 14, Art. 1651; № 51, Art.6699; 2014, № 26, Art. 3371; № 30, Art. 4268; 2015, № 1, Art. 10; № 13, Art. 1811; № 29, Art. 4385; 2016, № 1, Art. 11, №27, Art. 4293);

Convention Abolishing the Requirement of Legalization for Foreign Public Documents signed in Hague on October 5, 1961 (ratified by the Russian Federation on September 4, 1991, Bulletin of International Treaties, 1993, № 6).