ORDER OF THE MINISTER OF HEALTH OF THE REPUBLIC OF KAZAKHSTAN

of April 19, 2019 No. KR DSM-43

About introduction of amendments to the order of the Minister of Health of the Republic of Kazakhstan of November 18, 2009 No. 736 "About approval of Rules of conducting Examination of medicines, products of medical appointment and medical equipment"

According to Item 1 of Article 63 and Item 9 of article 71 of the Code of the Republic of Kazakhstan of September 18, 2009 "About health of the people and health care system", I ORDER:

1. Bring in the order of the Minister of Health of the Republic of Kazakhstan of November 18, 2009 No. 736 "About approval of Rules of conducting examination of medicines, products of medical appointment and medical equipment" (it is registered in the Register of state registration of regulatory legal acts at No. 5926, it is published in 2010 in the Collection of acts of the central executive and other central state bodies of the Republic of Kazakhstan, No. 5) the following changes:

state heading in the following edition:

"About approval of Rules of conducting examination of medicines and medical products";

state Items 1 and 2 in the following edition:

"1. Approve:

1) Rules of conducting examination of medicines according to appendix 1 to this order;

2) Rules of conducting examination of medical products according to appendix 2 to this order.

2. Determine the Republican state company on the right of economic maintaining "The national center of examination of medicines and medical products" of the Ministry of Health of the Republic of Kazakhstan by the state expert organization in the field of drug circulation and medical products for conducting examination in case of state registration, re-registration and modification of the registration file of medicines and medical products.";

The rules of conducting examination of medicines approved by the specified order to be reworded as follows, according to appendix 1 to this order;

The rules of conducting examination of products of medical appointment and medical equipment approved by the specified order to be reworded as follows, according to appendix 2 to this order.

3. To provide to committee of pharmacy of the Ministry of Health of the Republic of Kazakhstan:

1) state registration of this order in the Ministry of Justice of the Republic of Kazakhstan;

2) within ten calendar days from the date of state registration of this order the direction it the copy in paper and electronic type in the Kazakh and Russian languages in the Republican state company on the right of economic maintaining "Institute of the legislation and legal information of the Republic of Kazakhstan" the Ministries of Justice of the Republic of Kazakhstan for official publication and inclusion in Reference control bank of regulatory legal acts of the Republic of Kazakhstan;

3) placement of this order on Internet resource of the Ministry of health and social development of the Republic of Kazakhstan;

4) within ten working days after state registration of this order in the Ministry of Justice of the Republic of Kazakhstan submission to Department legal services of the Ministry of Health of the Republic of Kazakhstan of data on execution of the actions provided by the subitem 1), 2) and 3) of this Item.

4. To impose control of execution of this order on the supervising vice-Minister of Health of the Republic of Kazakhstan.

5. This order becomes effective after ten calendar days after day of its first official publication.

Appendix 1

to the Order of the Minister of Health of the Republic of Kazakhstan of April 19, 2019 No. KR DSM-43

Approved by the Order of the Minister of Health of the Republic of Kazakhstan of November 18, 2009 No. 736

Rules of conducting examination of medicines

Chapter 1. General provisions

1. These rules of conducting examination of medicines (further - Rules) are developed according to article 63 of the Code of the Republic of Kazakhstan of September 18, 2009 "About health of the people and health care system" (further - the Code) and determine procedure for conducting examination of medicine.

2. Expertize of medicines according to Item 2 of article 63 of the Code is carried out by the state expert organization in the field of drug circulation and medical products (further - the state expert organization), performing production economic activity in the field of health care on safety, efficiency and qualities of medicines.

3. The medicines made in the Republic of Kazakhstan, and also imported on its territory are subject to examination.

4. Expertize is not carried out on medicines under one name having different composition of active agents. Examination on the medicines made in the Republic of Kazakhstan for export is carried out according to the decision of producers of the Republic of Kazakhstan.

5. Before filing of application for examination the applicant on own initiative receives in the state expert organization scientific and preregistration consultations on the questions connected with conducting examination.

6. The state expert organization involves specialists from the profile organizations performing activities in the field of service of blood to conducting examination of medicines of blood and components of blood.

7. In these rules the following terms and determinations are used:

1) biosimilar medicine (bioanalogue, biosimilar medicine, биосимиляр) - biological medicine which contains the version of active ingredient of the registered biological original medicine or reference medicine and on which similarity (similarity) on the basis of comparative researches on indicators of quality, biological activity, safety and efficiency is shown;

2) bioavailability - the speed and degree with which active agent is soaked up from dosage form and becomes available in the scene of action;

3) biological medicine - medicine which active ingredient is made or emitted from biological source and the description of properties and which quality control requires combination of biological and physical and chemical methods of the analysis to assessment of production process and methods of its control;

4) biotechnological medicine - the medicine made by means of bioengineering procedures and application of methods with use of technology of recombinant deoxyribonucleic acid, controlled expression of the genes coding development of biologically active proteins, gibridomny technologies, monoclonal antibodies or other bioengineering procedures;

5) biopharmaceutical classification system (further - BSK) - scientific classification system of active agents on the basis of their solubility in circles with certain indicator of acidity/alkalinity (pH) and extent of penetration through intestines wall;

6) biological equivalence (bioequivalence) - lack of significant distinctions on the speed and degree with which active ingredient or active part of molecule of active ingredient of pharmaceutical equivalents or pharmaceutical alternatives become available in the place of the action in case of introduction in identical molar dose in similar conditions in research with proper design;

7) original medicine - medicine with new active ingredient which was registered and placed by the first in the world pharmaceutical market based on the file containing results of the complete preclinical (not clinical) and clinical trials confirming its safety, quality and efficiency;

8) the bioveyver procedure - the procedure according to which determination of equivalence of the reproduced medicine (generic) is carried out based on biopharmaceutical classification system and results of comparative researches out of organism (in-vitro) with testing use "Dissolution" and is applied to firm dosage forms of immediate release (1 and 3 class on biopharmaceutical classification system);

9) hybrid medicine - the medicine which is not falling under determination of the reproduced medicine in case of impossibility of confirmation of its bioequivalence by means of bioavailability researches and also if in this medicine there were changes of active ingredient (substances), indications to application, dosages, dosage form or way of introduction in comparison with original medicine;

10) homeopathic medicine - the medicine made on homeopathic technology with use of homeopathic raw materials according to requirements of pharmacopeias of the Republic of Kazakhstan and (or) the Eurasian Economic Union or in case of their absence according to requirements of homeopathic pharmacopeias;

11) medicine - the means representing or containing the substance or combination of substances coming into contact with human body, intended for treatment, prevention of diseases of the person or recovery, correction or change of its physiological functions by means of pharmacological, immunological or metabolic impact or for diagnosis of diseases and condition of the person;

12) the conclusion about safety, efficiency and quality of medicine - the document containing results of examination declared on state registration, re-registration or modification of the registration file of medicine;

13) irrational combination of composition of medicines - the composition of medicine which is not corresponding to expected pharmacological properties and action;

14) the instruction on medical application of medicine (leaf insert) - the document containing information for the consumer and accompanying medicine in packaging;

15) the regulating document on quality of medicine - the document establishing requirements to quality control of medicine during the post-registration period based on the carried-out expertize of medicine in case of its registration and containing the specification, the description of analytical techniques and testing of medicine or the reference to such testing, and also the corresponding eligibility criterions for quality indicators;

16) standard samples of medicinal substances and their impurity - the comparison substances used when conducting examination of examinees of medicines;

17) producer of medicines - the organization which is performing activities for production of medicines and having the license for production of medicines;

18) medicinal vegetable raw materials - the fresh or dried-up plants, seaweed, mushrooms or lichens or their parts, integral or crushed, used for production of medicines;

19) general characteristic of medicine - the document approved by authorized body in case of state registration of medicine, containing information for health workers on safe and effective use of medicine;

20) medicine with well studied medical application - medicine which active ingredient is well studied during medical application at the same time its efficiency and acceptable degree of safety confirmed with detailed bibliographic references to the published data on post-registration and (or) epidemiological researches are acknowledged and there passed at least 10 years from the date of the first systematic and documentary use of active ingredient (active ingredients) of this medicine;

21) high-tech medicine - medicine, being the gene therapeutical medicine, medicine on the basis of somatic cages or medicine of fabric engineering;

22) immunological medicine (immunobiological medicine) - the medicine intended for forming of active or passive immunity or diagnostics of availability of immunity, or diagnostics (development) of the specific acquired change of the immunological answer to allergiziruyushchy substances;

23) the risk management plan - the detailed description of risk management system;

24) the periodic updated report on safety - the report of the holder of the registration certificate of medicine for certain period of time during the post-registration period provided for ratio assessment "advantage - risk" medicine;

25) the reproduced medicine (generic) - medicine which has the same quantitative and high-quality composition of active ingredients and the same dosage form, as original medicine and which bioequivalence to original medicine is confirmed by the corresponding researches of bioavailability. Different salts, ethers, isomers, mixes of isomers, complexes or derivatives of active ingredient are recognized the same active ingredient if their safety and efficiency significantly do not differ. Different dosage forms for intake with immediate release of substances are recognized within the bioavailability researches the same dosage form;

26) the countries of the region of the International conference on harmonization of technical requirements to registration of medicines for medical application (ICH) (АйСиЭйч) - the states which regulatory bodies are part of founders and permanent members of ICH (the country of the European Union, the United States of America, Japan, Switzerland, Canada) (further - the countries of the region of ICH (АйСиЭйч));

27) Advisory council of the state expert organization (further - Advisory council) - the collegiate organ created in the state expert organization for consideration of matters of argument in results of examination, the bases (reasons) of issue of the negative conclusions on efficiency, safety and quality of medicines, products of medical appointment and medical equipment and acceptance of the final decision;

28) orphan (rare) medicine - the medicine intended for diagnostics, etiopatogenetichesky or pathogenetic treatment of orphan (rare) diseases which frequency does not exceed officially certain level in the Republic of Kazakhstan;

29) the production site - territorially isolated complex of the producer of medicines, medical products intended for accomplishment of all production process of medicines, medical products or its certain stages;

30) the applicant - the developer, the producer, the holder of the registration certificate or their authorized representative, authorized to submit the application, documents and materials and to perform the operations provided by the power of attorney of the principal on conducting examination in case of registration, re-registration and modification of the registration file of medicines;

31) radio pharmaceutical medicine - the medicine containing in condition, ready for application, one or several radionuclides (radioactive isotopes) as active ingredient or as a part of active ingredient;

32) reference medicine - medicine which is used as medicine of comparison and is standard by which are determined properties of medicine (are normalized);

33) proper production practice - the component of system of quality assurance guaranteeing production and quality control of medicines according to standards according to their purpose and requirements of the registration file;

34) the registration file - the set of documents and materials of the established content represented to the statement for examination;

35) the holder of the registration certificate - the legal entity addressed to whom the registration certificate on medicine is issued;

36) modification of the registration file - the changes made by the applicant to the registration file during action of the registration certificate, which are not influencing negatively safety, efficiency and quality of medicine and subject to examination according to these rules;

37) pharmaceutical substance (active pharmaceutical substance) - the medicine intended for production and production of medicines;

38) equivalence research - research which determines equivalence between generic and original (reference) medicine when using researches in-vivo (in organism) and (or) in-vitro (out of organism).

Chapter 2. Procedure for provision of the registration file for conducting examination of medicines

8. For conducting examination for the purpose of state registration, re-registration and modification of the registration file of medicine the applicant signs the contract for conducting examination with the state expert organization and provides in Service center of applicants of the state expert organization (further - TsOZ) the following documents and materials:

1) the statement on conducting examination of medicine (further - the statement) in form according to appendix 1 to these rules;

2) the registration file on the electronic medium:

the list of the documents provided for examination by producers of the Republic of Kazakhstan in form according to appendix 2 to these rules;

the list of the documents provided in format of the General technical document in form according to appendix 3 to these rules;

3) samples of medicines, standard samples of chemicals, standard samples of biological medicines, test strains of microorganisms, cultures of cages, in the quantities sufficient for triple laboratory researches with residual expiration date at least six months (except as specified, not requiring laboratory testing);

4) the specific reagents, consumable materials applied in case of laboratory testing of medicines;

5) the copy of the document confirming payment by the applicant of the amount for conducting examination on the settlement account of the state expert organization.

Forming of the statement on conducting examination of medicines with appendix of the list of the documents provided for examination by producers of the Republic of Kazakhstan according to appendix 2 to these rules or the list of the documents provided in format of the General technical document according to appendix 3 to these rules is performed by the applicant in information system of the state expert organization for the individual password.

9. The list of the provided materials of the registration file depending on type of medicine corresponds to appendix of 4 these rules.

10. The specialist of TsOZ within one working day after documents acceptance, stipulated in Item 8 these rules:

1) performs registration of a statement in the software;

2) posts information on the official site of the state expert organization on the medicines (the trade name, the international non-proprietary name, dosage form, dosage, concentration, the manufacturing organization, the country) given for examination;

3) is checked by residual expiration date of samples of medicines, standard samples of chemicals, standard samples of biological medicines, test strains of microorganisms, cultures of the cages, specific reagents, consumable materials necessary for reproducibility of techniques of laboratory researches of medicine and enters data in the software.

For observance of storage conditions (temperature condition, humidity) samples of medicines, including drugs, psychotropic substances and precursors are provided directly in test laboratory.

11. For examination of different dosage forms of the same medicine the applicant submits applications and registration files on each dosage form.

12. On condition of simultaneous giving for examination of medicine in one dosage form, with different dosage, concentration, filling amount the applicant submits one application and the registration file with appendix of prototypes of packagings and labels on each dosage, concentration, amount of filling and quantity of doses in packaging, and also the regulating document on quality in case of distinction in control techniques.

13. In case of provision of the reproduced, biosimilar medicine by domestic manufacturer for examination without these researches of equivalence, the applicant in the registration file provides the draft of the protocol and the guaranty letter in any form of provision of the report of clinical trials. At the same time the term of carrying out researches does not enter conducting examination in case of registration in time.

14. In case of examination of orphan medicines the applicant reports the research program which results will be the basis for revaluation of ratio "advantage risk", with observance of use of medicine under strict observation of the doctor and immediate provision of maps messages about undesirable reactions, serious undesirable reactions and about lack of efficiency of medicine according to procedure stipulated in Item 3 articles 85 of the Code.

15. In cases of representation by the applicant of incomplete document package, and also not observance of conditions, stipulated in Item 8 these rules the specialist of TsOZ refuses reception of an application.

Chapter 3. Procedure for conducting examination of medicines

Paragraph 1. Stages of conducting examination of medicines

16. Examination of medicine consists of the following stages:

1) initial examination (validation of the registration file);

2) specialized examination;

3) laboratory researches.

17. Expertize is carried out with use of the electronic program of the state expert organization integrated with the single database "Management System of Provision of Medicines" of the Unified information system of health care.

Paragraph 2. Procedure for conducting initial examination (validation of the registration file) of medicine

18. After reception of an application by the expert initial expertize (validation of the registration file) of medicine in the terms provided by Chapter 6 of these rules is carried out.

19. In case of initial examination (validation of the registration file) of medicine assessment of completeness, completeness and correctness of document creation, provided by the applicant in the registration file concerning proofs of safety, efficiency and quality of medicine is carried out.

20. In case of availability of notes to documents of the registration file the letter certified by the electronic and digital signature, with indication of the revealed notes and need of their elimination in time, not exceeding sixty calendar days is sent the applicant through information system.

21. In case of not elimination of notes the state expert organization sends to the applicant the notification (in any form) about the medicine examination termination.

22. By results of initial examination (validation of the registration file) of medicine taking into account the exposed notes the report of initial examination (validation of the registration file) of medicine according to appendix 5 to these rules or the report of initial examination (validation of the registration file) of the changes made to the registration file of medicine according to appendix 6 to these rules is constituted.

Paragraph 3. Procedure for conducting specialized examination of medicines

23. The positive result of initial examination (validation of the registration file) of medicine is the basis for conducting specialized examination of medicine in the terms provided by Chapter 6 of these rules.

24. Specialized examination of medicine includes quality evaluation, safety, efficiency and ratio advantage risk of medicine based on the analysis and examination of data in documents of the registration file, including results of laboratory researches of samples of medicine, and also assessment of rationality of combination of active ingredients as a part of medicine according to the List of irrational combinations of medicines according to appendix 7 to these rules.

25. Specialized examination of medicine is performed by the group of experts of the state expert organization with attraction (in need of) non-staff profile experts.

26. By results of studying of documents of the registration file at stage of specialized examination to the applicant the summary inquiry (in any form) is sent by safety, efficiency and quality of medicine.

The summary request certified by means of the electronic and digital signature goes through information system.

27. The applicant within sixty calendar days directs the response and required materials to request of the state expert organization.

In case of the additional questions concerning the data provided by the applicant in the response to prior request, the applicant within thirty calendar days from the moment of receipt of request directs the response and required materials to additional request of the state expert organization.

28. By not provision by the applicant of replies to the request of the state expert organization at the scheduled time according to Item 27 of these rules, and also provision of the incomplete answer and required materials the negative summary report of experts in assessment of medicine is constituted and materials go to Advisory council for decision making about refusal and the termination of examination of medicine.

The advisory council considers the arrived materials monthly and results of the decision go to the applicant within ten calendar days.

29. By results of specialized examination the Summary report of experts according to medicine in form according to appendix 8 to these rules is constituted and the Summary report of experts in medicine assessment in case of the changes made to the registration file according to appendix 9 to these rules. In the report of experts in assessment of medicine all aspects of safety, efficiency and quality of medicine are reflected.

Paragraph 4. Procedure for laboratory testing of medicines

30. In case of the positive report of specialized examination laboratory researches of medicine are carried out to the terms provided by Chapter 6 of these rules.

31. Laboratory researches of medicine are performed in test laboratories of the state expert organization for the purpose of confirmation of conformity of indicators of safety and quality of medicine and include:

1) testing of samples of medicine;

2) determination of reproducibility of analysis techniques.

Testing of samples of medicines with use of complex of physical and chemical, biological researches is directed to determination of quantitative and qualitative content acting and excipients, impurity, and also degree of biological safety (microbiological purity, toxicity, pyrogenicity).

Determination of reproducibility of analysis techniques on quality control of medicine is performed for the purpose of confirmation of their compliance, provided by the regulating document on quality.

32. Laboratory researches are not carried out in case of:

1) prolongation of effective period of the registration certificate of the medicine (in case of lack of claims for quality of medicine and by results of pharmakonadzor on safety of medicine) made in the conditions of proper production practice and the attendee at the pharmaceutical market of the Republic of Kazakhstan at least eight years;

2) to examination of the medicine made in the countries of the region of ICH (АйСиЭйч);

3) to examination of medicines, prekvalifitsirovanny World Health Organization;

4) prolongation of effective period of the registration certificate of the medicine made in the Republic of Kazakhstan.

33. In case of detection of notes by results of laboratory researches the letter with indication of the revealed notes and need of their elimination in time, not exceeding ninety calendar days is sent the applicant.

34. By not provision by the applicant of answers the notes exposed in the letter of the state expert organization at the scheduled time according to Item 33 of these rules and negative results of laboratory researches materials go to Advisory council for decision making about refusal and the termination of examination of medicine.

35. By results of laboratory researches of medicine by test laboratory the test report in form according to appendix 10 to these rules is constituted.

36. In cases of impossibility of laboratory testing of samples of medicines in test laboratory of the state expert organization, including in case of their reference to category of the orphan, narcotic, psychotropic or intended for treatment highspending nozologiya owing to their high cost, impossibility of observance of conditions of transportation of the specified samples on the territory of the Republic of Kazakhstan and (or) their storage, lack of the special equipment and consumable materials in the expert organization and in cases if regulating documents on product quality establish the testing connected with big costs of means of the producer, high cost of samples with the samples requiring special conditions of transportation, the specific equipment and supportive applications laboratory researches are carried out in the presence of representatives of the expert organization in laboratory of quality control of the producer or in contractual laboratory, used by the producer.

By results of laboratory researches the Report on results of conducting laboratory research in laboratory of quality control of the producer or in the contractual laboratory used by the producer according to appendix 11 to these rules is constituted.

Chapter 4. Procedure for forming of results of the carried-out expertize of medicines

37. Upon termination of examination (initial examination (validation of the registration file), specialized examination and laboratory researches) the applicant within thirty calendar days which are not entering in time conducting examination approves with the state expert organization the general (administrative) information about medicine, resulting documents (the regulating document on quality, the instruction on medical application and markings of prototypes of packaging, labels, stickers).

Approval is performed in electronic form according to the individual password through personal account or by provision of leaf of approval.

38. By results of the carried-out medicine expertize the state expert organization constitutes the conclusion about safety, efficiency and quality of the medicine declared for examination according to appendix 12 to these rules and the conclusion about safety of efficiency and quality of the medicine declared for examination of the changes made to the registration file according to appendix 13 to these rules.

39. The state expert organization sends the head, in electronic form with the electronic and digital signature (or the authorized person) and the responsible persons who were carrying out expertize to state body:

conclusion about safety, efficiency and quality of medicine;

the general characteristic of medicine, the registered instruction on medical application of medicine (leaf insert) in the Kazakh and Russian languages developed according to procedure stipulated in Item the 5th article 75 of the Code and approved by the expert organization;

prototypes of packagings, labels, medicine stickers, in the Kazakh and Russian languages, approved by the expert organization.

40. Conclusion about safety, efficiency and quality of medicine really hundred eighty calendar days. In case of expiration of the conclusion, the applicant repeatedly submits the application, documents and materials for conducting examination of medicine, provided in Item 8 of these rules.

41. For the medicines of national production made for export and the domestic market of the country under different trade names, expertize is carried out with issue of one conclusion about safety, efficiency and quality.

42. The bases of issue of the negative conclusion about safety, efficiency and quality of medicine are:

1) non-presentation of complete set of the registration file after issue of notes to the applicant in the course of conducting examination in the terms established by these rules;

2) submission of false information by the applicant;

3) the attitude of the expected advantage towards the possible risks connected using medicine is not favorable;

4) lower indicators of quality and safety regulated by the State pharmacopeia of the Republic of Kazakhstan or pharmacopeias, acknowledged acting in the territory of the Republic of Kazakhstan, or in comparison with earlier registered analogs;

5) availability as a part of medicine of the substances and materials prohibited to application in the Republic of Kazakhstan;

6) availability as a part of firm dosage forms of preservatives;

7) receipt of negative results of one of stages of examination and (or) negative expert opinions of the profile organizations;

8) discrepancy of the actual conditions of production and system of quality assurance to the conditions ensuring the declared safety, efficiency and quality by results of assessment of production and system of quality assurance;

9) refusal of the applicant of the organization of visit of the company (production site) for the purpose of assessment of conditions of production and system of quality assurance, according to requirements of the legislation of the Republic of Kazakhstan;

10) identification of irrational combinations of medicines;

11) the applicant does not prove clinical efficiency and safety of medicine;

12) quality of medicine is not confirmed;

13) the proved adverse ratio "advantage risk" or the revealed lack of therapeutic efficiency in case of observance of the conditions of use of medicine described in the approved general characteristic of medicine during the post-registration period;

14) the facts specifying adverse ratio "advantage risk", including considerable exceeding of frequency of reportirovaniye of undesirable reactions in comparison with the data specified in the approved general characteristic of medicine determined according to pharmakonadzor;

15) discrepancy of high-quality and quantitative composition of medicine declared or numerous discrepancy of quality of medicine during its market circulation declared at the time of its registration;

16) failure to carry out by the holder of the registration certificate of obligations on pharmakonadzor or obligations within the procedure of registration;

17) the made changes exert negative impact on ratio "advantage risk" of medicine.

43. In cases of the negative conclusion about safety, efficiency and quality of medicine or response the applicant of the statement for examination after the beginning of conducting examination, the cost of carrying out expert works to the applicant does not return.

44. By results of examination the state expert organization creates the summary report on safety, efficiency and quality of medicine according to appendix 14 to these rules which part places on Internet resource of the state expert organization.

45. After examination completion of the procedure the state expert organization creates the electronic archive copy of the registration file containing documents and materials of result of examination (the additional materials provided by the applicant at the request of the state expert organization, the conclusion of initial examination (validation of the registration file), the final summary report of experts in critical evaluation of medicine, protocols of test laboratory), the conclusion about safety, efficiency and quality, the registered instruction on medical application, the regulating document on quality of medicines, the registered prototypes of packagings, labels, stickers which are stored in electronic archive.

During action of the registration certificate the archive registration file, is supplemented with the registration file submitted on modification, containing documents and materials of results of examination.

The registration file is stored in electronic archive on the electronic medium within ten years.

Chapter 5. Features of conducting examination of medicine

46. The explanations or amendments arising during conducting examination between the state expert organization and the applicant are performed through TsOZ by forming of the electronic document according to the individual password of the applicant through information system with the electronic and digital signature of the applicant and the state expert organization or on papers.

For the period of provision by the applicant of required documents examination stops.

47. Within examination the state expert organization performs check of authenticity of transfer into Kazakh of general characteristic of medicine, the instruction on medical application (leaf insert), markings of prototypes of packaging, labels, stickers.

48. Information in the instruction on medical application (leaf insert) of original medicine offered for the Republic of Kazakhstan corresponds to information stated in general characteristic of medicine.

In general characteristic of medicine, the instruction on medical application of medicine (leaf insert) information on excipients, their nominal content in medicines, and also restrictions of use of medicine according to appendix 15 to these rules is reflected.

49. The general characteristic of medicine, the instruction on medical application (leaf insert) of the reproduced, biosimilar medicine corresponds to general characteristic of original medicine. In case of difference in the instruction on medical application (leaf insert) of the reproduced, biosimilar medicine from original medicine according to indications to application towards expansion, or the mode of dosing or way of introduction results of the corresponding clinical trials are reported.

50. The holder of the registration certificate of original medicine submits the application for modification of the instruction on medical application (leaf insert) within ninety calendar days after updating of general characteristic of medicine in the country of the producer or holder of the registration certificate.

51. The state expert organization after modification of the instruction of original medicine or in case of identification on the international sources and results of pharmakonadzor about changes in general characteristic of original medicine informs through information resources of all holders of registration certificates of generic medicines on need of entering of corresponding changes into the instruction on medical application (leaf insert) and general characteristic of medicine through the procedure of modification of the registration file within ninety calendar days after modification of the instruction of original medicine of information on safety and within twelve months in other cases. The holder of the registration certificate of original medicine makes changes to the instruction on medical application (leaf insert) and general characteristic of medicine based on the notification (in any form) from the state expert organization for the discrepancies revealed as a result of pharmakonadzor and on official international sources within ninety calendar days.

52. In case of failure of consideration, specified in Items 50 and 51 of these rules, the state expert organization notifies (in any form) state body in the field of drug circulation and medical products (further - state body) on need of suspension of action of the registration certificate.

53. On the medicines having the termless registration certificate the state expert organization "advantage risk" based on pharmakonadzor performs periodic assessment of ratio.

54. Examination of the changes made to the registration file is performed on medicine during action of the registration certificate and the advantage risk of medicine does not exert negative impact on ratio.

55. Changes are classified according to the List of the changes made to the registration file of medicine according to appendix 16 to these rules on:

1) changes like IA - not requiring new registration (minor changes which exert insignificant impact or do not exert impact on quality, safety and efficiency of medicine, and concern amending content of the materials of the registration file given to the period of action of the registration certificate of medicine);

2) changes like IB - not requiring new registration (minor changes which are not changes like IA and type II);

3) changes like II - any changes to materials of the registration file which are not requiring new registration of medicine and which can exert considerable impact on its quality, safety and efficiency;

4) the urgent changes concerning safety of medicine - the urgent temporary restrictions connected with safety of use of medicine which take root the applicant in case of identification of risk for public health in case of use of the registered (re-registered) medicine. The holder of the registration certificate within twenty four hours notifies state body on the restrictions introduced by it. If within twenty four watch after receipt of this information from state body objections did not arrive, the emergency restrictions connected with safety are considered as accepted. Terms of realization of restrictions make a reservation the holder of the registration certificate and state body.

The emergency restrictions connected with safety are initiated by state body with risk for life and health of the person.

The statement on modification, the emergency restrictions concerning introduction (initiated by the holder of the registration certificate or state body), moves the holder of the registration certificate for consideration no later than within sixty calendar days from the moment of the notification.

56. Each specific change, even on condition of their simultaneous introduction is subject to examination.

57. In case of modification which is not classified in these rules the applicant addresses to the state expert organization through the procedure of consultation with the purpose of receipt of the recommendation about change classification.

The state expert organization within thirty calendar days after receipt of request sends the answer to the applicant in electronic and (or) paper type.

58. In case of modification like IA:

1) changes like IA are subject to assessment by the state expert organization without conducting specialized examination. The applicant submits the application in form according to appendix 1 to the presents Rules and the documents confirming the made changes within twelve months from the date of introduction of corresponding changes according to appendix 16 to these rules;

2) the applicant informs the state expert organization in case of changes like IA, requiring the immediate notice for the purpose of continuous control of medicine;

The holder of the registration certificate within one statement specifies 3) about several minor changes like IA concerning one registration certificate;

4) the state expert organization during thirty calendar from the moment of payment receipt carries out assessment of changes like IA and notifies the holder of the registration certificate on the conclusion about safety of efficiency and quality of the medicine declared for examination for the purposes of modification of the registration file in form according to appendix 13 to these rules;

5) in case of modification, the data of the registration certificate requiring change, the state body issues the new registration certificate at former number on residual effective period of the registration certificate.

59. In case of modification like IB:

1) the applicant submits the application in form according to appendix 1 to these rules and documents according to appendix 16 to these rules;

Holders of the registration certificate within one statement can notify 2) on several changes like IB concerning one registration certificate or to group one or several changes like IB with other changes like IA connected with one registration certificate provided that such group corresponds to the conditions listed in appendix 16 to these rules;

3) in case of modification of the data of the registration certificate requiring change, the state body issues the new registration certificate at former number on residual effective period of the registration certificate.

60. In case of modification like IB involving other consecutive changes like IA and the IB type one application containing all consecutive changes like I is submitted.

61. In case of introduction of considerable changes like II:

1) the applicant submits the application in form according to appendix 1 to these rules and documents according to appendix 16 to these rules;

2) the statement contains one change like II. In case of introduction of several changes like II, the separate application is submitted concerning each change, each statement contains references to other statement;

If change like II leads 3) to other consecutive changes like II, one statement includes all consecutive changes together with the description of compliance between such consecutive changes like II.

The state expert organization in case of modification like II within ninety calendar days after adoption of the statement carries out expertize of documents.

62. The summary report according to the made changes of medicine in case of changes made to the registration file like I and II which are not requiring new registration is constituted in form according to appendix 9 to these rules.

63. By results of the carried-out expertize the state expert organization constitutes the conclusion about safety of efficiency and quality of the medicine declared for examination of the changes made to the registration file in form according to appendix 13 to these rules.

Chapter 6. Terms of conducting examination of medicine

64. Medicine examination, except for the medicines made in the Republic of Kazakhstan or the countries of the region of ICH (АйСиЭйч) is carried out in time, not exceeding two hundred ten calendar days, including:

1) initial examination (validation of the registration file) of medicine - thirty calendar days;

2) specialized examination - ninety calendar days (including, check of authenticity or transfer into Kazakh of the instruction on medical application, markings of prototypes of packaging, labels, stickers, within twenty calendar days);

3) laboratory researches - seventy calendar days;

4) forming of the conclusion about safety, efficiency and quality - twenty calendar days.

65. Expertize of medicine in case of prolongation of effective period of the registration certificate is carried out within hundred twenty calendar days, including:

1) initial examination (validation of the registration file) of medicine - twenty calendar days;

2) specialized examination - ninety calendar days, including laboratory researches (including, confirmation of authenticity or transfer into Kazakh of the instruction on medical application, prototypes of marking of packaging, labels, stickers, within fifteen calendar days);

3) forming of the conclusion about safety, efficiency and quality - ten calendar days.

66. Examination of the changes made to the registration file like ІА is carried out in time, not exceeding thirty calendar days from them:

1) initial examination (validation of the registration file) of medicine - ten calendar days;

2) confirmation of authenticity or transfer into Kazakh of the instruction on medical application, prototypes of marking of packaging, labels, stickers - ten calendar days;

3) forming of the conclusion about safety, efficiency and quality - ten calendar days.

67. Examination of the changes made to the registration file like ІБ and type II is carried out in time, not exceeding ninety calendar days with stage of laboratory testing, including:

1) initial examination (validation of the registration file) of medicine - fifteen calendar days;

2) specialized examination - sixty five calendar days, including laboratory researches (including, confirmation of authenticity or transfer into Kazakh of the instruction on medical application, prototypes of marking of packaging, labels, stickers - ten calendar days);

3) forming of the conclusion about safety, efficiency and quality - ten calendar days.

68. Examination of the changes made to the registration file like ІБ and type II is carried out not exceeding sixty calendar days without stage of laboratory testing in time, including:

1) initial examination (validation of the registration file) of medicine - ten calendar days;

2) specialized examination - forty calendar days (including, confirmation of authenticity or transfer into Kazakh of the instruction on medical application, prototypes of marking of packaging, labels, stickers, within ten calendar days);

3) forming of the conclusion about safety, efficiency and quality - ten calendar days.

69. Examination of the medicine made in the Republic of Kazakhstan is carried out within hundred eighty calendar days, including:

1) initial examination (validation of the registration file) of medicine - twenty calendar days;

2) specialized examination - ninety five calendar days (including, check of authenticity or transfer into Kazakh of the instruction on medical application, markings of prototypes of packaging, labels, stickers within twenty calendar days);

3) laboratory researches - fifty calendar days;

4) forming of the conclusion about safety, efficiency and quality - fifteen calendar days.

70. Examination of the medicine made in the Republic of Kazakhstan in case of prolongation of term action of the registration certificate is carried out within hundred calendar days, including:

1) initial examination (validation of the registration file) of medicine - fifteen calendar days;

2) specialized examination - seventy calendar days (including confirmation of authenticity or transfer into Kazakh of the instruction on medical application, prototypes of marking of packaging, labels, stickers within fifteen calendar days);

3) forming of the conclusion about safety, efficiency and quality - fifteen calendar days.

71. Examination of the changes made to the registration file like ІА for the medicine made in the Republic of Kazakhstan is carried out in time, not exceeding thirty calendar days from them:

1) initial examination (validation of the registration file) of medicine - ten calendar days;

2) forming of the conclusion about safety, efficiency and quality (including, confirmation of authenticity or transfer into Kazakh of the instruction on medical application, prototypes of marking of packaging, labels, stickers) - twenty calendar days.

72. Examination of the changes made to the registration file like ІБ and type II for the medicine made in the Republic of Kazakhstan is carried out within ninety calendar days with stage of laboratory testing, including:

1) initial examination (validation of the registration file) of medicine - fifteen calendar days;

2) specialized examination - sixty calendar days, including laboratory researches (including, confirmation of authenticity or transfer into Kazakh of the instruction on medical application, prototypes of marking of packaging, labels, stickers, within ten calendar days);

3) forming of the conclusion about safety, efficiency and quality - fifteen calendar days.

73. Examination of the changes made to the registration file like ІБ and type II for the medicine made in the Republic of Kazakhstan is carried out within sixty calendar days without stage of laboratory testing, including:

1) initial examination (validation of the registration file) of medicine - ten calendar days;

2) specialized examination - forty calendar days (including, confirmation of authenticity or transfer into Kazakh of the instruction on medical application, prototypes of marking of packaging, labels, stickers within ten calendar days);

3) forming of the conclusion about safety, efficiency and quality - ten calendar days.

74. Examination of the medicines made in the countries of the region of ICH (АйСиЭйч) is carried out within hundred eighty calendar days, including:

1) initial examination (validation of the registration file) of medicine - thirty calendar days;

2) specialized examination - hundred twenty calendar days (including, check of authenticity or transfer into Kazakh of the instruction on medical application, markings of prototypes of packaging, labels, stickers, within twenty calendar days);

3) forming of the conclusion about safety, efficiency and quality - thirty calendar days.

75. Examination of the medicines made in the countries of the region of ICH (АйСиЭйч) in case of prolongation of effective period of the registration certificate is carried out within hundred calendar days, including:

1) initial examination (validation of the registration file) of medicine - twenty calendar days;

2) specialized examination - seventy calendar days (including, confirmation of authenticity or transfer into Kazakh of the instruction on medical application, prototypes of marking of packaging, labels, stickers, within fifteen calendar days);

3) forming of the conclusion about safety, efficiency and quality - ten calendar days.

76. Examination of the changes made to the registration file like ІА for the medicines made in the countries of the region of ICH (АйСиЭйч) is carried out within thirty calendar days, from them:

1) initial examination (validation of the registration file) of medicine - ten calendar days;

2) issue of the conclusion about safety, efficiency and quality (including, confirmation of authenticity or transfer into Kazakh of the instruction on medical application, prototypes of marking of packaging, labels, stickers) - twenty calendar days.

77. Examination of the changes made to the registration file like ІБ and type II for the medicines made in the countries of the region of ICH (АйСиЭйч) is carried out within sixty calendar days without stage of laboratory testing, including:

1) initial examination (validation of the registration file) of medicine - ten calendar days;

2) specialized examination - forty calendar days (including, confirmation of authenticity or transfer into Kazakh of the instruction on medical application, prototypes of marking of packaging, labels, stickers, within ten calendar days);

3) forming of the conclusion about safety, efficiency and quality - ten calendar days.

78. The accelerated expertize of medicine is carried out in the terms which are not exceeding hundred twenty calendar days including:

1) initial examination - no more than twenty calendar days;

2) laboratory researches - no more than fifty calendar days;

3) specialized examination - no more than forty calendar days, including confirmation of authenticity of transfer of marking of prototypes of packaging, labels, stickers, general characteristic of medicine, the instruction on medical application (leaf insert) (no more than ten calendar days)

4) forming of the conclusion about safety, efficiency and quality of medicine, drafts of resulting documents of examination of medicines - no more than ten calendar days.

79. Does not enter terms of conducting examination of medicine:

1) time of completion of shortage of the registration file;

2) time of provision by the applicant of documents and materials on demand on any of examination stages;

3) time of the organization of evaluating conditions of production and system of quality assurance of the manufacturing organization, conditions of performing preclinical and (or) clinical trials, system of pharmakonadzor of the holder of the registration certificate;

4) terms of provision of the report of clinical trials in case of observance of the conditions determined by Item 13 of these rules. At the same time terms of provision of the report do not exceed hundred eighty calendar days from the date of the planned completion of clinical trial, specified in the approved protocol of clinical trial;

5) organization and carrying out Advisory council;

6) approvals by the applicant of resulting documents.

Appendix 1

to Rules of conducting examination of medicines

Form

The statement on conducting examination of medicine *

1.

Trade name

in Kazakh

in Russian

in English

2.

Trade name for export (for domestic manufacturers)

in Kazakh

in Russian

in English

country

3.

International unlicensed name

in Kazakh

in Russian

in English

4.

Dosage form

in Kazakh

in Russian

5.

Dosage / concentration (It is filled in the presence. The amount is filled in packaging)

Concentration is specified for liquid, soft and gaseous dosage forms

6.

Анатомо - therapeutic and chemical classification

Code

The name in Kazakh

The name in Russian

7.

Medicine type (it is filled for the corresponding medicine)

1)

Original medicine

One-component

Multicomponent

biological medicine

Balk-produkt

The active pharmaceutical substance made not in the conditions of GMP or medicinal vegetable raw materials

2)

The reproduced medicine

One-component

Multicomponent

Balk-produkt

Original medicine:

name of medicine, dosage, dosage form

the holder of the registration certificate (the company addressed to which the registration certificate is issued), registration date, number of the registration certificate, the state where original medicine is registered

Reference medicine for domestic manufacturer who was used in equivalence researches (if those were carried out):

name of medicine, dosage, dosage form

the holder of the registration certificate (the company addressed to which the registration certificate is issued), registration date, number of the registration certificate, the state where reference medicine is registered

give reasons for use of reference medicine in case of its difference from original medicine

Note. The Section needs to be filled in for each medicine which was used in equivalence researches.

3)

Biosimilar medicine (Биоаналог)

Balk-produkt

Original biological medicine:

name of medicine, dosage, dosage form

the holder of the registration certificate (the company addressed to which the registration certificate is issued), registration date, number of the registration certificate, the state where original medicine is registered

Reference biological medicine:

name of medicine, dosage, dosage form

the holder of the registration certificate, registration date, number of the registration certificate, the state where reference medicine is registered

distinctions in comparison with reference biological medicine (if those are available):

distinctions in initial material; distinctions in production process; other indications to application; distinctions in dosage form; other dosage; (quantitative changes of active pharmaceutical substance); other method of introduction; other differences ___________________________________ _____________________________________

4)

Hybrid medicine

One-component

Multicomponent

Balk-produkt

Original medicine:

name of medicine, dosage, dosage form

the holder of the registration certificate, registration date, number of the registration certificate, the state where original medicine is registered

Distinctions in comparison with original medicine:

changes of active pharmaceutical substance; other dosage form; other dosage (i) (quantitative changes of active pharmaceutical substance); other method(s) of introduction; other pharmacokinetics (including other bioavailability); other indication to application; other differences ____________________________________ _____________________________________

5)

The combined medicine

known combination

new combination

Balk-produkt

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