ORDER OF THE MINISTER OF HEALTH OF THE REPUBLIC OF KAZAKHSTAN

of June 15, 2018 No. 374

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 articles 63 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 the Collection of acts of the central executive and other central state bodies of the Republic of Kazakhstan, No. 5, 2010) the following changes:

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.

2. To provide to committee of pharmacy of the Ministry of Health of the Republic of Kazakhstan in the procedure established by the legislation 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 "The republican center of legal information" for official publication and inclusion in Reference control bank of regulatory legal acts of the Republic of Kazakhstan;

3) within ten calendar days after state registration of this order the direction it the copy on official publication in periodic printing editions;

4) placement of this order on Internet resource of the Ministry of Health of the Republic of Kazakhstan after its official publication;

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

3. To impose control of execution of this order on the vice-Minister of Health of the Republic of Kazakhstan Tsoi A. V.

4. 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 June 15, 2018 No. 374

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 republican state company on the right of economic maintaining (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 receives in the state expert organization scientific and preregistration consultation on contractual basis 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) bioavailability - the speed and degree with which active agent is soaked up from dosage form and becomes available in the scene of action;

2) 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;

3) биосимиляр - biotechnological medicine, similar with (original) medicine made for the first time on quality, safety, efficiency and provided on registration after expiration of the patent of original medicine;

4) 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;

5) original medicine - the medicine representing or containing new active agents which efficiency and safety is confirmed with results of preclinical and clinical trials, and registered based on the complete file;

6) 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;

7) homeopathic medicines - the medicines containing substances of natural origin in small doses and made on special technology;

8) medicine - the means representing or containing pharmacological the active agents coming into contact with human body or getting into its bodies and fabrics intended for prevention, diagnostics and treatment of diseases, and also change of condition and functions of organism: medicinal substance, medicinal raw materials, balk-products of medicines, medicines;

9) the conclusion about safety, efficiency and quality of medicine - the document containing results of examination of the declared medicine;

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

11) the instruction on medical application of medicine - the document containing information for the consumer and accompanying medicine in packaging;

12) the regulating document on control of quality and safety of means (further - the regulating document on quality) - the document establishing complex of the quality requirements of medicine, and also to techniques of its determination providing their identical parameters of safety and qualities;

13) medicinal substance - substance or mix of substances, regardless of the origin nature, having certain pharmacological activity, intended for production and production of medicines;

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

15) the manufacturing organization of medicine - the individual entrepreneur or the legal entity performing production, or one or several production stages;

16) medicinal vegetable raw materials - the fresh or dried-up plants or their parts used for production or production of medicines;

17) well studied medical application - medical application of the active agent which is part of medicine which efficiency is well studied, acknowledged degree of safety it is acceptable and confirmed with detailed bibliographic references to the published data on postregistration, epidemiological researches, and there passed at least 15 years from the date of the first systematic and documentary use of medicine;

18) immunobiological medicines - medicines for specific prevention, diagnostics and treatment of infectious and immune diseases (including allergic) by means of immunological methods of other diseases and physiological conditions, means for indication of infectious agents and their antigens in objects of external environment, blood medicines (irrespective of obtaining method), and also the medicines rendering medical and preventive effects through immune system;

19) the reproduced medicine (generic) - the medicine identical to original medicine on composition of active substances, dosage form, indicators of quality, safety, efficiency issued by different producers;

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

21) the periodic report on safety - report form and content for representation of assessment of ratio advantage risk of medicine the holder of the registration certificate during certain periods of time during post-registration stage of medicine;

22) 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 (or) 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));

23) 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.

24) orphan medicines - medicines for diagnostics and pathogenetic treatment of orphan (rare) diseases;

25) the production site - territorially isolated complex intended for accomplishment of all production process of medicine, product of medical appointment and medical equipment or its certain stages;

26) the applicant - the developer, the manufacturing organization, 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;

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

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

29) 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;

30) 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;

31) the holder of the registration certificate - the manufacturing organization, the organization having the document from the producer for ownership of the registration certificate;

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

33) 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).

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

8. For conducting examination 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:

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 for examination by foreign producers 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;

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 for examination by foreign producers 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. Materials of the registration file of the medicine provided for examination by foreign producers correspond to the appendix of 1 Rules of registration and examination of medicines for medical application approved by the Decision of Council of the Eurasian economic commission of November 3, 2016 No. 78.

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 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 side effects, serious side effects and about lack of efficiency of medicine to state body in form, the provided Rules of carrying out pharmakonadzor of medicines and monitoring of side effects of medicines, products of medical appointment and medical equipment approved by the order of the Minister of health and social development of the Republic Kazakhstanot on May 29, 2015 No. 421 (it is registered in the Register of state registration of regulatory legal acts at No. 11485).

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 "Examination of Medicines, Products of Medical Appointment and Medical Equipment" 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 with indication of the revealed notes and need of their elimination in time, not exceeding sixty calendar days is sent the applicant.

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 4 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 5 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 studying of documents of the registration file regarding safety, efficiency and quality of medicine by assessment of materials of preclinical (not clinical), clinical trials, testing for bioequivalence, data analysis on quality of medicine, including assessment of pharmacokinetic and (or) pharmakodinamichesky interaction regarding compliance to the List of irrational combinations of medicines according to appendix 6 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.

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 7 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 8 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 9 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 10 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 11 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 12 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 regulating document on quality approved by the applicant and approved by the expert organization;

the instruction on medical application of medicine in the Kazakh and Russian languages developed according to the Rules of creation and execution of the instruction on medical application of medicines and products of medical appointment approved by the order of the Minister of health and social development of the Republic of Kazakhstan of May 29, 2015 No. 414 (it is registered in the Register of state registration of regulatory legal acts at No. 11495) 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) lower safety and efficiency in comparison with earlier registered analogs;

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) receipt of negative results of one of examination stages;

7) 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;

8) 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.

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 13 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 report on 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 approved instruction on medical application, the regulating document on quality of medicines with the assigned number, the approved 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 instructions on medical application, markings of prototypes of packaging, labels, stickers.

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

In the instruction on medical application of medicine information on excipients, their nominal content in medicines, and also restrictions of use of medicine according to appendix 14 to these rules is reflected.

49. The instruction on medical application of the reproduced medicine and biosimilyar corresponds to general characteristic of original medicine. In case of difference in the instruction on medical application of the reproduced medicine and biosimilyar 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 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 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 based on the notification (in any form) 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, products of medical appointment and medical equipment (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 performs periodic assessment of ratio of advantage or risk based on pharmakonadzor with expense recovery of the state expert organization based on the contract between the applicant and the state expert organization.

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 15 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 15 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 11 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 15 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 15 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 15 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 8 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 12 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. 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 twenty calendar days from the moment of the beginning of specialized examination;

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

Original medicine (in case of the known combination)

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

6)

Medicine with well studied medical application

Balk-produkt

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