Order No. 1413n (н) On Approval of Guidelines for Filing Procedures and Content of Documents Necessary to Assemble Master Dossiers of Medically Applied Drugs for the Purposes of the State Registration issued by the Ministry of Healthcare and Social Development of the Russian Federation on November 23, 2011.

 With a view to improving the procedure for assembling master dossiers of medically applied drugs for the purposes of state registration, I hereby order:

 TO approve the enclosed Guidelines for Filing Procedures and Content of Documents Necessary to Assemble Master Dossiers of Medically Applied Drugs for the Purposes of the State Registration, in accordance with the Appendix.

 

T.A. Golikova,

Minister

 

 Appendix

to the Order No. 1413n (н) issued by

the Ministry of Healthcare and Social Development

of the Russian Federation on November 23, 2011

 

Guidelines

For Filing Procedures and Content of Documents

Necessary to Assemble Master Dossiers of Medically Applied Drugs for the Purposes of the State Registration

 

1. These Guidelines for Filing Procedures and Content of Documents Necessary to Assemble Master Files of Medically Applied Drugs for the Purposes of the State Registration (hereinafter referred to as the “Guidelines”) have been prepared with a view to improving the procedure for assembling master dossiers of medically applied drugs for the purposes of the state registration.

2. The content of documents forming the master dossiers of medically applied drugs for the purposes of state registration is prescribed by the Order No. 750n (н) On Approval of Rules for Carrying out an Expert Evaluation of Medically Applied Goods and of the Format of an Expert Commission’s Report issued by the Ministry of Healthcare and Social Development of the Russian Federation on August 26, 2010 (registered by the Ministry of Justice of Russia on August 31, 2010 under registration No. 18315).

3. It is hereby recommended for organizations developing medically applied drugs or the legal entities representing such organizations (hereinafter referred to as the “Applicant”) to include in the master dossier the documents described below:

1) Designs of the primary and secondary (consumer) package for the drug.

 It is advisable to submit the designs of primary and secondary (consumer) package for the drug on a portrait-oriented А4 page (210 mm × 297 mm). In the upper right corner, a free space should be left for the drug registration details. Text on the package design should be printed using a readable font. The package design should contain labeling as prescribed by the Article 46 of the Federal Law No. 61-FZ (ФЗ) On Drug Circulation dated April 12, 2010. Primary and secondary (consumer) package designs for the drug shall be submitted in two copies.

2) A duly certified document confirming the manufacturer’s compliance with the good manufacturing practice standards issued by the competent authority of the manufacturer’s country of domicile; the above document should be translated into Russian.

In case the drug is manufactured within the Russian Federation, a copy of the drug production license issued under the Russian Federation Government Decree No. 684 On Approval of Regulations for Licensing Drug Production dated September 3, 2010 (ref. Legislative Bulletin of the Russian Federation, 2010, No. 37, art. 4698) shall be submitted to certify compliance with good manufacturing practice.

3) A draft of the drug regulatory documents or quotation of the relevant pharmacopoeia article.

It is recommended to include the following information in the draft drug regulatory documents: general information on the medically applied drug; drug description; drug ingredients; quality control methods applied to the drug and adjuvants used for the drug’s production; standard samples; description of the primary and the secondary package of the drug, validity term of the drug. *

It is advisable to submit the following details as validation of the draft regulatory documents for the drug:

а) Analytical findings (based on at least three series) confirming the quality indices of the drug; the above findings should be submitted as analytical methods validation reports.

b) Evidence of compatibility between the active ingredients and the adjuvants (validation of the drug ingredients).

c) Information evidencing the declared shelf life of the drug (results of the drug’s stability tests with the use of physical and chemical analysis, as well as other types of analysis whenever necessary); the above information shall also include microbiological features and properties of the drug and/or its ingredients as well as a summary of the work done and conclusions on the drug’s stability if packed in the package submitted for the state registration.

d) Description of the package, the basis for choosing the type of primary package and evidence that the primary package is appropriate for the drug storage and transport as well as that it ensures ease of use.

e) Proof of the viral safety of the drug’s ingredients that are derived from human or animal blood, blood plasma, organs and tissues; description of the tests performed should also be enclosed.

It is advisable to submit regulatory documents along with the validation materials for the analytical methods used to ensure the drug’s quality; copies of sample protocols (certificates or datasheets) pertaining to the drug should also be enclosed. The results of quality tests performed on the drug and pharmaceutical substance(s) that are enclosed with the draft regulatory documents (if any) may be in the form of copies or digital photographs, chromatograms, spectra, microphotographs, pictures and microscopy images for herbal raw materials.

To validate the quality indices declared by the regulatory documents, the applicant may quote pharmacopoeia articles, including foreign pharmacopoeia articles for comparison with similar quality control methods and rates prescribed by the draft regulatory documents.

It is recommended that one submit the draft regulatory documents in two copies on a portrait-oriented А4 page (210 mm × 297 mm). The upper right corner should be left free for the drug registration details.

4) A drug production flow chart with detailed description and/or pharmaceutical substance production flow chart with detailed description.

It is advisable to include the details of the control performed on the starting material, critical stages of production and intermediate products used to produce the drug in the drug production flow chart. *

The description of the drug production flow chart shall ensure evaluation of pharmaceutical aspects of the drug’s development (choice validation for the pharmaceutical substance, adjuvants, dosage form, drug production technology, and drug primary and secondary package).*

It is recommended to draw the drug production flow chart as a block diagram representing the sequence of all the stages and phases (operations) of the production process and including the main material flow (raw and other materials, intermediate products, ready drug output). It is advisable to indicate the manufacturing stage and internal control details for each of the stages (phases) of the production process listed on the block diagram.

Each production stage (operation) shall bear a name and/or a serial number. The stages (operations) should be numbered in sequence of the production process of the drug’s manufacture.

It is recommended to include in the production process description of all the essential (critical) parameters and indices relevant for the drug’s quality.

For biotechnologically produced drugs, it is advisable to begin the production process description with preparation of the pharmaceutical substance including its purification, dilution, concentration, lyophilization (if any), filling, packaging and labeling; details of production flow validation and choice of control parameters and tests in the course of production are also advisable.

For sterile drugs, it is recommended to add to the description of the production process the details of validation of aseptic processes, as well as of sterilization stages.

It is recommended to arrange the details of the drug production technology included in the master dossier in a way which permits validation of the choice of pharmaceutical substance(s), adjuvants, dosage form, production method and primary packaging.

The pharmaceutical substance production flow chart and a description thereof.

It is recommended to include the whole sequence of production stages in the description of pharmaceutical substance production including the control performed on the starting material, critical production stages and intermediate products.*

It is recommended to then describe all the production stages of the pharmaceutical substance, including control over the starting material, critical production stages and intermediate products; the file should also include details of organic and/or inorganic matter used to produce the pharmaceutical substance (to identify the impurities profile and the concentration thereof as proposed by the draft regulatory documents for the drug) and final production stages of the pharmaceutical substance including details of the primary and transport package.

For biotechnologically produced pharmaceutical substances, it is recommended to begin the production process description with the source for such substances (cell culture, microbial strain, cell line) including the details of production stages (cell cultivation and collection, purification, modification reaction, filling, prepacking and labeling); it is also recommended to include details of validation of the production process and the choice of control parameters and tests in the course of production.

5) A document evidencing quality parameters of the pharmaceutical substance used to produce the drug.

It is also recommended to include information or the relevant document issued by the manufacturer of the pharmaceutical substance and/or the competent authority of the country of domicile of such manufacturer.

6) Regulatory documents of the pharmaceutical substance or quotation of the relevant pharmacopoeia article.

For pharmaceutical substances filed with the State Register of Medically Applied Drugs, it is recommended to submit the copy of regulatory documents.

For pharmaceutical substances that are not filed with the State Register of Medically Applied Drugs, it is recommended to submit a document containing the following details:

а) General information on the pharmaceutical substance:*

- Name of the pharmaceutical substance (international nonproprietary name or chemical name, trade name).

- Name and address of the pharmaceutical substance’s manufacturer.

- Pharmaceutical substance’s structure.

- Main physical and chemical properties of the pharmaceutical substance. *

b) Methods suggested to explain the chemical and pharmaceutical properties of the pharmaceutical substance. *

c) Methods to identify impurities. *

d) Methods to identify immunological properties of the pharmaceutical substance. *

e) Methods to identify immunochemical properties of the pharmaceutical substances. *

f) Quality control methods applied to the pharmaceutical substance and standard samples. *

To validate the draft regulatory documents, it is advisable to enclose details on validation of the analytical methods applied to control the quality of the pharmaceutical substance, as well as the details on the pharmaceutical substance’s stability if packed in all the primary package types submitted for consideration; information on the shelf life of the pharmaceutical substance if packed in all the primary package types submitted for consideration as identified by the applicant as well as the reasoning for setting the storage conditions of the pharmaceutical substance should also be included. *

When submitting the master dossiers for biotechnologically produced drugs or lyophilization-produced pharmaceutical substances (in the drug’s primary package), or if the control methods applied to the pharmaceutical substance and the drug are the same, it is recommended to submit a single document on quality control of both the pharmaceutical substance and the drug.

It is recommended to submit the draft regulatory documents in two copies on a portrait-oriented А4 page (210 mm × 297 mm). The upper right corner space should be left free for the drug registration details.

7) Details of storage and transportation conditions of the drug and other information.

To validate the prescribed storage conditions, it is advisable to include in the information on the drug’s storage conditions details of the drug’s stability if packed in all the primary package types submitted for consideration and the details of setting the drug’s shelf life if packed in all the primary package types submitted for consideration. *

It is recommended to include the following details in the information submitted on the drug’s shelf life: details of storage temperature rate, lighting, humidity, mechanical influence and other features affecting the drug quality; the above details should be validated by the results of the drug’s stability tests in different storage conditions.

8) Report on preclinical research of the medically applied drug, including a description of this research, its results and a statistical analysis.

In cases of an original medically applied drug (hereinafter – the “drug”), the report on preclinical research should include the following:

а) Scientific rationale of the preclinical research program for the drug. *

b) Validation of choice for the research test model and/or test systems. *

c) Results of preclinical research of the drug’s pharmacodynamic effects, mechanism of action and potential side effects. *

d) Results of preclinical research of the drug’s pharmacological properties (main pharmacodynamic (immunologic) effects and effects not related with the declared therapeutic indications, effect on the cardiovascular system, central nervous system, respiratory system, gastrointestinal tract, as well as the drug’s pharmacodynamic interaction). *

e) Results of preclinical research of the drug’s pharmacokinetic properties (absorption, distribution, metabolism, excretion, pharmacokinetic interaction). *

f) Results of preclinical research of the drug’s toxicological properties (toxicity at single administration (acute toxicity), toxicity at repeated administration (subacute and chronic toxicity), mutagenicity, carcinogenicity, reproductive and ontogenetic toxicity, irritant action, other toxicological research (antigenicity, immunotoxicity etc.) (if any). *

g) Interpretation of the results of preclinical research (pharmacological, pharmacokinetic and toxicology) by the drug developer. *

h) Methods for statistical processing of the preclinical research results. *

In case of generic drugs, it is admissible to submit a preclinical research report containing details published by the industry-specific printed media.

9) The draft clinical research protocol (bioequivalence and/or therapeutic equivalence research) should reflect the objectives, organizational forms and methods applied to process the results of such research as well as measures taken to ensure security of subjects participating in the drug clinical research.

It is recommended to include the following details in the draft protocol:

a) Validation and objectives of the drug clinical research (bioequivalence and/or therapeutic equivalence research).

b) Parameters ensuring the expected results involving in the drug’s clinical research the minimum possible number of subjects.

c) Description of the cure type, drug dosage and dosage schedule used for research purposes.

d) The possible risk compared to the expected positive effect of the drug on the research subjects (whenever necessary).

e) Validation of the control subjects option (if any) for the purposes of the drug clinical research.

f) Validation of choice of population taking part the drug clinical research.

g) Selection criteria for the subjects participating in the drug clinical research (including entry and exclusion criteria).

h) Conditions and criteria to suspend and/or stop the drug clinical research, including cases when subjects voluntarily choose to stop their participation in this research.

i) Monitoring and audit conditions of the clinical research.

j) Ethical aspects of the research.

k) Methods for statistical processing the results of the drug clinical research.

l) Measures to ensure security of subjects participating in the drug clinical research.

It is recommended to execute the drug clinical research protocol (bioequivalence and/or therapeutic equivalence research) in compliance with the National Standard of the Russian Federation GOST R (ГОСТ Р) 52379-2005 Good Clinical Practice.

10) Investigator's brochure i.e. summarized results of the drug’s preclinical and clinical research.

It is advisable to include in the investigator's brochure the information on physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic and clinical properties of the drug under study as of the current stage of its clinical development.

11) Patient’s factsheet setting forth details of the clinical research conducted on the drug; the above factsheet should also include a written voluntary consent of the patient to take part in the drug’s clinical research upon receiving information about all the features of such research relevant to express such consent;

12) Report on the clinical research conducted on the drug.

To ensure comprehensive expert assessment, it is recommended to include the following details in the report on the clinical research conducted on the drug:

a) Confirmation of the compliance of the drug clinical research conducted with the duly approved clinical practice rules. *

b) Results of pharmacokinetic research that may affect the efficiency and safety of the dosage form. *

c) Results of clinical research of the pharmacodynamic and immunologic effects of the drug, its mechanism of action, efficiency, side effects, and interaction with other drugs including the following:*

Choice of population taking part in the drug’s clinical research (demographic parameters, disease state, including or excluding children and elderly subjects from the drug clinical research population).

Duration of the drug’s clinical research.

Interpretation of the results of the drug’s clinical research by the developer.

Clinical significance of the drug’s effects.

Choice of drug dosage and dosage schedule (vaccination schedule).

Administration safety for specific groups of patients subject to age, sex, ethnic background, organ functions, disease severity, genetic polymorphism.

Frequency of serious adverse reactions and connection thereof with the drug dosage, dosage degree and duration of treatment.

Description of drug overdosage symptoms, probability of addiction and dependence, withdrawal syndrome (if any).

Methods for statistical processing of the clinical research results.

d) Assessment of the positive effect compared to risk exposure based on the drug’s research results, including the following:*

Declared indication efficiency of the drug.

Choice for dosage schedule, including details of connection between dosage and effect and dosage and toxicity.

Possible hazard to the patient’s life and health due to serious adverse reactions and/or the drug’s interaction with other drugs prescribed for use at the same time or with food.

Details of admissibility and special features of the drug’s administration during pregnancy and lactation as well as by children and adults suffering from chronic diseases.

The drug’s effect on ability to drive and use machines.

It is recommended to execute the report on the clinical research conducted on the drug in compliance with the National Standard of the Russian Federation GOST R (ГОСТ Р) 52379-2005 Good Clinical Practice.

13) It is recommended to execute reports on the drug’s international multi-center clinical research partly conducted within the Russian Federation in compliance with the National Standard of the Russian Federation GOST R (ГОСТ Р) 52379-2005 Good Clinical Practice.

14) It is advisable to present the draft application instruction for the drug on a portrait-oriented А4 page (210 mm × 297 mm). The upper right corner should be left free for the drug registration details. The draft application instruction shall be submitted in two copies.

15) The details of healthcare organizations intended for hosting the drug’s clinical research should include the complete name, legal structure, location and place of activity, telephone and fax number, and e-mail address).

 

______________________________

 * Note: the contents of the documents submitted is prescribed by the Order No. 750n (н) On Approval of Rules for Expert Evaluations of Medically Applied Goods and of the Form of Expert Commission Reports issued by the Ministry of Healthcare and Social Development of the Russian Federation on August 26, 2010 (registered by the Ministry of Justice of Russia on August 31, 2010 under registration No. 18315).