ORDER OF THE MINISTER OF HEALTH AND SOCIAL DEVELOPMENT OF THE REPUBLIC OF KAZAKHSTAN

of January 14, 2015 No. 10

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

change in Kazakh is made to heading, the heading in Russian does not change;

Rules of conducting examination of medicines to be reworded as follows according to appendix 1 to this order;

Rules of conducting examination of products of medical appointment and medical equipment to be reworded as follows according to appendix 2 to this order.

2. To provide to committee of control of medical and pharmaceutical activities of the Ministry of health and social development of the Republic of Kazakhstan:

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

2) official publication of this order the procedure established by the legislation;

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

3. To impose control of this order on the Vice-Minister of health and social development 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 and social development of the Republic of Kazakhstan of January 14, 2015 No. 10

Appendix 1

to the Order of the Minister of Health of the Republic of Kazakhstan of November 19, 2009 No. 736

Rules of conducting examination of medicines

1. General provisions

1. These rules of conducting examination of medicines (further - Rules) determine procedure for examination of medicine in case of state registration, re-registration, modification of the registration file.

2. Examination of medicines belongs to the state monopoly, is performed by the republican state company on the right of economic maintaining which is the state expert organization in the field of drug circulation, products of medical appointment and medical equipment (further - the state expert organization) and conducted in the Examination of Medicines Program of the state expert organization with use of the single database of the Management system of provision of medicines of the Unified information system of health care (further - SULO).

3. The state expert organization after acceptance and registration of a statement for examination during the working day places on the www.dari.kz Internet resource (in the Section "Data on Expert Works") information on receipt of the statement and transfers this information from the program of the State expert organization to the SULO system.

4. Information on the medicine given for examination for carrying out state registration of re-registration and modification of the registration file, and also all stages of examination is confidential information.

Persons having access to the confidential information relating to examination of medicines keep its confidentiality.

5. Payment of cost of examination of medicine is made by the applicant into the account of the expert organization according to article 63 of the Code of the Republic of Kazakhstan "About health of the people and health care system of" the Code of the Republic of Kazakhstan "About health of the people and health care system"

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

1) the state expert organization in the field of drug circulation, products of medical appointment and medical equipment (further - the expert organization) - the organization determined by authorized body in the field of health care for conducting examination of medicines, products of medical appointment and medical equipment;

2) 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 for conducting examination of medicines for their state registration, re-registration, modification of the registration file;

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

4) the holder of the registration certificate - developer, the manufacturing organization, the organization having the document from the producer on right of possession the registration certificate bearing responsibility for safety, efficiency and quality of medicine;

5) the registration file - the set of documents and materials of the established content represented to the statement for examination based on which the valid conclusion about efficiency, safety and qualities of medicine is drawn;

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

7) the conclusion about safety, efficiency and quality of medicine - the document containing results of examination of the declared medicine and the recommendation of its state registration, re-registration, modification of the registration file or of refusal in them;

8) the regulating document on control of quality and safety of medicines, products of medical appointment - the document establishing complex of quality requirements of medicine, to products of medical appointment, and also the techniques of its determination ensuring their equal security and quality;

9) safety of medicines - lack of the unacceptable risk connected with possibility of harming of life, to health of the person and the environment;

10) efficiency of medicines - set of the characteristics providing achievement of preventive, diagnostic, medical and (or) rehabilitation effect;

11) the reproduced medicine (generic) - the medicine identical to original medicine on composition of active substances, dosage form, indicators of quality, safety, efficiency and arrived in the address after expiration of security documents on original medicine;

12) bioequivalence - the comparative characteristic of two medicines under identical conditions which confirms their pharmaceutical and biological equivalence concerning efficiency and safety after use in identical molar doses;

13) 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;

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

15) medicines of biological origin - the medicines containing biological proteins (the hormones, cytokines, fibrillation factors, including the low-molecular heparins, insulin, monoclonal antibodies, enzymes, colony stimulating factors, medicines created based on cells of fabrics, received by means of gene engineering and gibridomny technologies);

16) биосимиляр - medicine of biological origin or biotechnological medicine, similar with the made original medicine and provided on registration after expiration of the security document for original medicine;

17) homeopathic medicines - one - or the multicomponent medicines containing the midget doses of substances of plant, animal, mineral origin made or made on special technology, applied by homeopathic rules;

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

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

20) 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 (рН) and extents of penetration through intestines wall;

21) reference medicine - the original medicine intended for comparison with it of generic or biosimilyar;

22) the 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;

23) biotechnological medicines - the biological medicines made by bioengineering procedures using technology of recombinant DNA, method of controlled expression of the genes coding development of biologically active proteins, method of hybrid and monoclonal antibodies and also gene therapeutical and somatotherapeutical medicines of genetically engineered modification;

24) radio pharmaceutical medicines - the medicines containing one or several radionuclides (radioactive isotopes) and applied to diagnostics and treatment of disease. Generators radionuclide, radionuclide set, radionuclide precursor belong to radio pharmaceutical medicines;

25) the generator radionuclide - the system containing the fixed primary (parent) radionuclide of which the secondary (affiliated) radionuclides which are extracted by eluating or in a different way and applied to diagnostics or treatment of disease are formed;

26) radionuclide set (whale) - medicine which shall be integrated or mixed with radionuclide or radionuclides in ready radio pharmaceutical medicine, as a rule, before its application;

27) radionuclide precursor - the radionuclide intended for introduction of radioactive tag in other substance before its application;

28) 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 later registration, epidemiological researches, and there passed at least 15 years from the date of the first systematic and documentary use of medicine;

29) equivalence research - research which determines equivalence between generic and reference medicine when using researches in-vivo and (or) in-vitro;

30) equivalence research in-vitro based on BSK - the complex research which is based on classification of active agent according to BSK and medicine dissolution and also includes comparison of profiles of dissolution of generic and reference medicine in three circles;

31) the instruction on medical application of medicine - the approved information on medical application of medicine in the Republic of Kazakhstan;

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

33) the authorized generic (autogeneric) - the medicine identical to the registered medicine issued by the same producer, but differing in trade names and the price.

7. The medicines registered in the manufacturing country are subject to examination in case of state registration in the Republic of Kazakhstan.

8. Expertize is not carried out on the medicines under one name having different composition of active agents.

9. For the medicines of national production made for the domestic market of the country and intended for export under different trade names expertize with issue of one conclusion about safety, efficiency and quality on condition of confirmation of identity of structure by the producer, engineering procedure, methods and techniques of quality control of medicine is carried out.

10. Clinical trials of the medicines declared to examination are developed, carried out according to provisions of proper clinical practice.

11. Preclinical researches of the medicines declared to examination are developed, conducted according to provisions of proper laboratory practice.

12. Information in the instruction on medical application of medicine offered for the Republic of Kazakhstan shall correspond to the information stated in general characteristic of medicine, approved by authorized state bodies of the country of the producer or the country of the holder of the registration certificate (the instruction on medical application for countries of the Commonwealth of Independent States (further - the CIS)).

The instruction on medical application of generic shall correspond to general characteristic of medicine (the instruction on medical application for the CIS countries) original medicine. In case of difference of indications to application towards expansion, or the mode of dosing or way of introduction to instructions on medical application of generic from original medicine it is necessary to report results of the corresponding clinical trials.

2. Procedure for provision of the registration file

13. Examination of medicines in case of state registration, re-registration, modification of the registration file is also carried out based on the statement on conducting examination of medicine in the Republic of Kazakhstan according to appendix 1 to these rules, the agreement signed between the applicant and the state expert organization on conducting examination.

To the statement are provided:

1) the registration file containing the documents and materials specified in the List of the documents of the registration file provided in case of examination of the medicines in the Republic of Kazakhstan made not in the conditions of the Proper production practice) according to appendix 2 (further - the List) and in the List of the documents of the registration file provided in case of examination of medicines to the Republic of Kazakhstan in format of the General technical document (for the medicines made in the conditions of the Proper production practice) according to appendix 3 to these rules (further - the OTD format). The registration file is provided on the electronic medium in format of the cross-platform electronic document (pdf format);

2) samples of medicines, standard samples of medicinal substances and their impurity in the quantities sufficient for the triple analysis;

3) the specific reagents, consumable materials applied when carrying out testing of medicines (in exceptional cases and on terms of return).

14. Expertize is carried out after payment of all-in cost for examination in case of state registration, re-registration and modification of the registration file.

15. Documents of the Module 1 (except Items 1. 4, 1.5, 1.6) of the OTD format, OTD format Module 3: specifications (3.2.P.5.1.), analytical techniques (3.2.P.5.2.), reasons for specifications (3.2.P.5.6.), and also parts 1-2 Lists are provided with authentic transfer into Russian.

16. The registration file on the medicine made in the conditions of the Proper production practice is constituted on the OTD format.

The registration file in the OTD format is constituted:

1) manufacturing organizations of foreign countries;

2) the manufacturing organizations of the CIS countries - in two years after receipt of the certificate of the Proper production practice;

3) the manufacturing organizations of the Republic of Kazakhstan - in four years after receipt of the certificate of the Proper production practice.

17. The registration file on the medicine made by the manufacturing organizations in the conditions of the Proper production practice, but earlier registered in the manufacturing country not in the OTD format is provided according to the List of appendix 2 to these rules.

18. Each module on the electronic medium shall be provided by the separate file (folder) with reference bookmarks on Sections of the module; the applicant provides proper quality of the scanned documents in the electronic version of the registration file.

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

20. On condition of simultaneous giving for examination of 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.

21. For examination in case of re-registration of medicine Modules 1-3 of the OTD format or part 1-2 Lists, and also from part 4 List and the OTD format Module 5 documents and materials are provided:

reports of post-registration clinical trials of efficiency and safety, in the presence;

periodically updated report on safety over the last 5 years findings of medicine in the pharmaceutical market of the Republic of Kazakhstan with short authentic transfer into Russian of the main Sections.

22. Materials of Modules 4 and 5 of the OTD format and parts 3 and 4 of the List shall conform to requirements to materials of the registration file according to appendix 4 to these rules; the instruction on medical application of medicine is developed on each dosage form; in the instruction information which shall be reflected in the instruction on medical application according to appendix 5 to these rules is reflected.

3. Features of provision of documents and materials of the registration file on different types of medicines

23. For examination in case of state registration of original medicine and its new dosage forms, including immunobiological medicine two complete sets of the registration file are provided.

At the time of filing of application for examination of medicine in the registration file there shall be I-III phases this clinical trials, except for pandemic vaccines.

24. For the proof of equivalence of generic with referens-medicine in the Module 5 of the OTD format or part 4 Lists of the registration file of generic depending on pharmacological properties and dosage form are provided:

1) report of comparative pharmacokinetic researches (bioequivalence research);

2) report of comparative phracodynamic of clinical trials;

3) report of comparative researches of therapeutic equivalence;

4) report comparative in-vitro researches.

Reasons for the choice of research of equivalence are carried out taking into account the following:

for medicines for which it is possible to receive the measured concentration of active agent in biological liquid (plasma, urine) reports of comparative pharmacokinetic researches are submitted;

for medicines for which it is impossible to receive the measured concentration of active agent in the corresponding biological liquid reports of comparative phracodynamic of clinical trials are submitted;

for medicines for which it is impossible to determine pharmacokinetic profile, to find acceptable phracodynamic final points of active agent, reports of comparative clinical trials of therapeutic equivalence are submitted;

the procedure bioveyver for the medicines of system action for oral application with immediate release containing substances of class of 1 biopharmaceutical classification system (BCS).

25. From the applicant having the document confirming compliance of production of proper production practice of the countries regions the International conference on harmonization of technical requirements to registration of medicines for the person (ICH) the International system of cooperation of pharmaceutical inspections (PIC/S), the Republic of Kazakhstan provision of reports of researches of equivalence in organism (in vivo) is not required provided that:

1) medicines for parenteral application (intravenously, hypodermically or intramuscularly) in the form of the water solutions containing identical high-quality and quantitative composition of active agent, as reference medicine with identical or similar excipients in the concentration compared to reference medicine; some excipients (in particular buffer solutions, preservatives, antioxidants) can differ on condition of the proof in any manner that in these concentration they do not influence safety and (or) efficiency of medicine (exception - medicines of iron, amino acids, derivatives of starch, gelatin, complexing medicines);

2) medicines for intake in the form of the water solutions containing identical high-quality and quantitative composition of active agent, as reference medicine with identical or similar excipients in compared to reference medicine;

3) medicines in the form of powders for preparation of water solutions if solution meets the requirements of subitems 1 or 2 of this Item;

4) medicines which are gases;

5) the ear or eye medicines made in the form of the water solutions containing identical high-quality and quantitative composition of active agents, as reference medicine with identical or similar excipients in the concentration compared to reference medicine; some excipients (in particular the buffer solutions, preservatives, substances adjusting density, or thickeners) can differ on condition of the proof in any manner that in these concentration they do not influence safety and (or) efficiency of medicine;

6) medicines of local action in the form of the water solutions containing identical high-quality and quantitative composition of active agents, as reference medicine with identical or similar excipients in the concentration compared to reference medicine;

7) medicines which are water solutions and are intended for inhalations by the nebulizer or in the form of nasal sprays, the deliveries of medicine applied by means of almost identical devices and the containing identical high-quality and quantitative compositions of active agents, the same excipients in comparable concentration, as reference medicine; some excipients can differ on condition of the proof in any manner that in these concentration they do not influence safety and (or) efficiency of medicine (exception - the medicines containing hormones, medicines with antiobstructive action);

8) medicines of system action in the form of the water solutions for rectal or vaginal application containing identical high-quality and quantitative composition of active agents, as reference medicine with identical or similar excipients in the concentration compared to reference medicine, some excipients can differ on condition of the proof in any manner that in these concentration they do not influence safety and (or) efficiency of medicine;

9) medicines are made in the conditions of complete transfer (transfer) of production and engineering procedures to the Republic of Kazakhstan.

Requirements of this Item extend to the medicines which are at stage of expert works.

26. The applicant provides proofs of equivalence in-vivo in case there is risk that possible distinctions in bioavailability can result in therapeutic nonequivalence of generic to referens-medicine:

1) medicines of system action for oral application with immediate release if one or several following criteria are applied to them:

narrow range of therapeutic action (limit efficiency/safety), abrupt inclination of curve dose - the answer;

documentary confirmed problems on bioavailability or biononequivalence connected with active agent or its forms (not having relations to dissolution);

data that can influence bioequivalence polymorphism of active agent, excipients which are known that they influence passing in digestive tract (further - GIT), permeability in GIT and, thus, on absorption and (or) stability of active agent in GIT;

2) the medicines of system action which are not intended for oral or parenteral application (such as transdermalny plasters, suppositories, nicotinic chewing gums, gels of testosterone and transdermalny contraceptives);

3) medicines of system action with modified (prolonged, slowed down) release;

4) medicines of system action with the fixed combination in which at least one active agent requires carrying out research in-vivo;

5) medicines of not system action, in particular for oral, nasal, ophthalmologic, dermatological, rectal or vaginal application, without system absorption which is not water solutions; in that case equivalence is proved by carrying out, comparative clinical trials of therapeutic equivalence or phracodynamic of researches, dermatofarmakokinetichesky researches and (or) researches in-vitro;

6) for generic which active agent is provided by other salt, ether or to derivatives of active agent of the registered medicine the reports of the corresponding preclinical and (or) clinical researches / researches of bioequivalence proving lack of changes in pharmacokinetics, pharmakodinamika and (or) toxicity of generic in case of non-presentation of such proofs are provided, this substance is considered as new active agent.

27. For generics in firm dosage forms of immediate release for intake and concentration of active agent which it can be measured in biological liquids of organism (blood plasma, urine) the bioequivalence this researches are provided.

For generics in firm dosage forms of immediate release for intake which concentration of active agent cannot be measured in biological liquids of organism data of comparative phracodynamic of clinical trials or researches of comparative therapeutic equivalence are provided.

28. Registration materials on the generics registered according to the procedure bioveyver in case of additional dosage shall meet the following conditions:

1) identical production process for different dosages of medicine;

2) identical high-quality structure (active and excipients) different dosages of medicine;

3) quantitatively pro rata structure, that is ratio between quantity of each filler to amount of active agent it shall be identical to all dosages (except for components of covering of covers of capsules, dyes and flavoring additives).

29. In the presence of difference in proportionality of quantitative structure of different dosages of medicine, condition 3) of Item 28 it is considered executed if conditions 1) and 2) or 1) and 3), this Item are carried out concerning dosage of the medicine used in research of bioequivalence and dosages for which the bioveyver is considered:

1) the amount of active agent (substances) makes less than 5% of tablet kernel weight, or capsule content weight;

2) identical quantitative composition of the different excipients entering tablet kernel, or capsule content for different dosages;

3) the quantity of filler changes according to change of amount of active agent; the amount of other excipients in kernel of tablet or content of the capsule shall be identical to the considered different dosages.

30. Adequacy of refusal of additional researches of bioequivalence is confirmed by the relevant data of dissolution in-vitro:

1) similarity of dissolution in-vitro need to be shown for all conditions рН and with batches of medicine, used in research, i.e. between additional dose and dose medicinal means for bioequivalence research;

2) in case of values рН when it is not possible to reach proper dissolution for all dosages of medicine, dissolution in-vitro can be different for different dosages; at the same time it is necessary to confirm that such difference arises at the expense of medicinal substance, but not at the expense of composition of medicine, having carried out comparison with the corresponding dosage of reference medicine.

31. Registration materials on the generics registered according to the procedure bioveyver in case of substances of class 1 BSK shall meet the following conditions:

1) it is proved that substance of medicine is well soluble and it is completely absorbed (class I BSK);

2) very bystry (> 85% within 15 min.) or identical solubility (85% within 30 min.) in-vitro the tested and reference medicines is shown in required conditions;

3) excipients which can influence bioavailability are identical quantitatively and qualitatively with reference medicine.

32. In Section 5.3.1 of the module 5 complete documentation of research of dissolution in-vitro is provided:

1) reasons for the procedure bioveyver as alternatives of comparative pharmacokinetic researches with participation of the person: the risks assessment, proofs of pharmaceutical equivalence, the description of the active ingredient researched and reference medicine, engineering procedure, excipients which can influence bioavailability shall be qualitatively and quantitatively identical in generic and in reference medicine;

2) the protocol of research, this to absorption (penetrability) of active ingredient;

3) information on series tested (series, date of production, expiration date, series amount, quantitative determination of active ingredient) and reference (source of reference medicine, series, expiration date, quantitative determination of active ingredient) medicines;

4) description and reasons for the choice of experimental conditions in-vitro researches (conditions of preparation of circles for dissolution, sampling method, description analytical method and sample preparation);

5) validation of techniques of determination in each circle with primary data;

6) hromatogramma in all temporary points of sampling for every environment;

7) final statistics: the calculated data of the areas of peaks, concentration, schedules, calculation of factor of similarity.

33. Assessment of factor of similarity to be made taking into account the following conditions:

1) at least three temporary points (except for zero);

2) temporary points shall be identical to both medicines;

3) twelve individual values for each temporary point for each medicine;

4) no more than one average value> 85% of dissolution for any medicine;

5) the relative standard deviation or coefficient of variation of any medicine shall be less than 20% for the first point and less than 10% since the second to the last temporary point.

34. F2 value in the range from 50 to 100 confirms that two profiles of dissolution are similar.

35. The procedure bioveyver is applied in case of identity of active ingredient in the researched and reference medicine, also, when medicines contain different salts of active ingredient which belong to the I class BSK (high solubility and complete absorption).

36. The procedure bioveyver is not applied in cases when medicine:

1) it is intended for knocking over of medical emergencies;

The narrow therapeutic range has 2);

Other ether, isomer, mix of isomers, complex or derivative active ingredient unlike reference medicine as such distinctions can result in different bioavailability which cannot be found by means of the researches conducted in the concept of bioveyver contains 3);

4) contains excipients in composition of medicine, influencing absorption of active ingredient;

5) in sublingual, bukalny and dosage forms with the modified release;

6) in the dosage form dispersed in mouth when absorption of active ingredient in mouth is not excluded.

37. In case of examination of the medicines made by domestic manufacturers on the basis of complete transfer (transfer) of production and engineering procedures in the registration file confirmations of the fact that conditions of production on the production site in the Republic of Kazakhstan completely correspond to platform conditions of production out of Kazakhstan are provided:

1) the contract on transfer of production and engineering procedures with right to use by all documents and the registration file, including data of researches of bioequivalence, clinical trials between domestic manufacturer and the foreign producer;

2) the report on results of the carried-out transfer including the project description of transfer, the transfer scale, critical parameters received by the main and additional platforms, final conclusions of transfer;

3) validation of production processes on the domestic production site;

4) confirmation of the fact that quality of the initial raw materials (active substance, excipients, etc.) used on the domestic platform does not influence process or ready-made product;

5) quality control of the medicines made on the domestic production site and medicines of the foreign producer is performed according to one specification (identical profile of impurity, pharmacokinetic profile of dissolution (for firm dosage forms), and others in-vitro researches);

6) reports of researches of bioequivalence or clinical trials of the medicines made on production sites out of Kazakhstan (in case of absence - reasons).

Requirements of this Item extend to the medicines which are at stage of expert works.

38. For examination in case of state registration of biosimilyar data of comparative researches it with original biological medicine in Modules 2, of 3, of the 4 and 5 OTD format are provided. The amount of the provided comparative researches of Modules 4 and 5 depends on characteristics of the appropriate biological medicine. During all program of development, since complex physical and chemical and biological characterization, it is necessary to apply the step-by-step approach. Scales and nature preclinical in-vivo researches and clinical trials depend on the level of reliability of the evidence obtained at previous stage(s). Quality, safety, efficiency and immunogenicity of biosimilyar on production, preclinical and clinical phase of its development are compared to the same reference reference biological medicine.

39. Modules 2, of 3, of the 4 and 5 OTD format of the registration file of biosimlyar shall contain the following information:

1) confirmation of similarity of molecular and biological characteristics of active agents of biosimilyar and reference biological medicine (detail on primary structure and structures of higher procedure, post-transmitting modifications (including, in particular glycoforms), biological activity, purity, impurity);

2) confirmation of similarity of characteristics of ready medicine (dosage form, quantitative and high-quality structure, dosage, method of application, storage conditions, storage duration, stability, profile of impurity) of biosimilyar and reference biological medicine; distinction in profile of impurity and excipients of biosimilyar and reference medicine is allowed, the applicant should take availability of the latest technologies into account, it is necessary to show compliance of the chosen structure by such criteria as profile of impurity, stability, compatibility (with excipients, solvents and materials of packaging), integrity (as at the biological, and physical and chemical level), activity and force of effect of active agent;

3) criteria of the choice of reference biological medicine;

4) in case of distinctions in case of development of biosimilyar which can have potential impact on its safety or efficiency additional data on researches on animals and to clinical trials can be required to characterize distinctions;

5) complete description and packet of data on production process, since development of vectors of expression and banks of cages, culture/fermentation of cages, collection, cleaning, reactions of modification, filling of containers for balk-product and ready dosage form, storage;

6) the researches conducted during pharmaceutical development for determination and validation of dosage form, structure and system of packaging/packing (including their integrity for prevention of microbic pollution);

7) the specification of biosimlyar which shall reflect and control the important qualitative indexes of medicine known for reference biological medicine (such as identification; purity; activity; molecular heterogeneity in respect of the sizes, charge and water repellency where their determination is possible; extent of sialylation; quantity of separate polypeptide chains; glycosylation of functional area; aggregation levels; impurity, such as protein and DNA of cage owner);

8) stability researches;

9) results preclinical (not clinical) researches (preclinical researches the approach based on risks assessment, and, there shall be the cornerstone where it is possible, it is necessary to avoid carrying out researches on animals): in-vitro researches of linkng with receptor or cellular analyses (for example, the analysis of proliferation of cages or the analysis of cytotoxicity) are necessary preclinical researches; in-vivo researches on suitable type of animals (on which pharmakodinamichesky and (or) toxicological activity of reference biological medicine was studied); curve of dependence of effect of dose ("dose effect"), determination of initial safe dose and schemes of increase in dose in the subsequent clinical trials, researches of pharmacological safety; results of at least one research of toxicity in case of repeated introduction, including toksikokinetika assessment, determination and characteristics of immune answers, including credits of antibodies, cross reactivity with homologous endogenous proteins and neutralized capability; assessment of local portability; the data of toxicological researches including assessment of reproductive toxicity, genotoxicity, mutagenicity and carcinogenicity (if necessary) are required to be provided when results of research of toxicity in case of repeated introduction, researches of local portability reveal potential risks and (or) when toxicological properties of reference biological medicine are known (for example, the known side effects of reference biological product on reproductive function);

10) results of clinical trials (nature and complexity reference medicine, the similarity degree observed in physical and chemical, biological researches will influence planning of clinical trials):

pharmacokinetic researches (pharmacokinetic researches in case of single introduction; pharmacokinetic researches in case of repeated introduction with dependence of pharmacokinetics on dose and time; pharmacokinetic comparison of biosimilyar and reference medicine includes absorption, bioavailability, characteristics of removal (clearance and (or) elimination half-life));

phracodynamic of research (phracodynamic effects are estimated on suitable population and using doses from abrupt part of curve dependence dose effect in preclinical researches; phracodynamic markers get out depending on their clinical importance);

comparative clinical trials, including assessment of type, frequency and weight of the undesirable phenomena / collateral reactions;

immunogenicity researches on target group (comparison of frequency and type of the formed antibodies and potential clinical effects of the immune answer for biosimilyar and reference medicine; the immunogenicity is researched on population of patients with the highest risk of the immune answer and immune collateral reactions; reasons for strategy of determination of antibodies, including the choice, assessment and the characteristic of methods, establishment of time of sampling, including at the initial level, amounts, processing and storage of tests, and also statistical techniques of data analysis are provided; analytical methods of determination of antibodies shall be validirovana for the planned purpose, the screening analysis of sufficient sensitivity of method shall be carried out, determination of neutralized antibodies shall be carried out; the observation period in case of researches on immunogenicity shall correspond to the planned duration of treatment and expected time of formation of antibodies, and there shall not be less than 12 months, with other duration of research reasons are represented; in case of significant cases of formation of credits of antibodies, their firmness during certain time, potential changes of nature of the immune answer and clinical effects it is required to research in to - and after the registration period);

the main clinical data shall be obtained with use of the medicine made by final production process, i.e. medicine on which the application is submitted for state registration;

for any variations from these requirements the applicant represents reasons, and if necessary, data of the additional pharmacokinetic researches comparing pharmacokinetic profiles of medicine to final and earlier structure.

11) the specification of safety (with the description of the important revealed and potential problems of safety of reference biological product, class of medicinal substance and (or) biosimilyar) and the plan of pharmakonadzorabiosimilyar during the post-registration period (with the description of the planned post-registration actions and methods which are based on specifications of safety, the management plan and risk minimization, including educational materials for patients and (or) attending physicians);

12) extrapolation of data on efficiency and safety from one therapeutic indication on another: if reference medicine has more than one indication to application, the applicant provides reasons for lack of clinical trials of efficiency and safety of biosimilyar according to other indications to application according to which clinical trials of biosimilyar are not conducted; in reasons experience of clinical application, availability of data of literature, mechanisms of effect of active agent of reference medicine for each indication (including degree of their reliability) and the involved receptors is reflected; in the presence of proofs that in case of different indications to application the different active centers of active ingredient of reference medicine either different receptors of cage of target are involved or that the profile of safety of medicine differs for different indications to application, data of clinical trials are provided; for extrapolation of data on safety it is necessary to take into account the factors connected with the patient (the accompanying treatment, associated diseases and the immune status), the factors connected with disease (the reaction similar to those of cages of targets); the amount of such data shall be considered in the light of body of evidence, the received in case of establishment of comparability of biosimilyar and potential remaining uncertainty.

40. For examination in case of the state re-registration of biological medicine, including biosimilyar, OTD format Modules 1-3, from the OTD format Module 5 are provided:

1) periodically updated report on safety or periodically the report;

2) results of monitoring of the Risk management plan and risk minimization, immunogenicity, in case of use of biological medicine, including in the Republic of Kazakhstan, received as a result:

post-registration observation researches of safety and efficiency of medicines (method of active monitoring, method case - control or cohort retrospective and (or) prospective researches);

the analysis of Registers of the patients receiving treatment by certain biological medicine;

post-marketing clinical trials;

holding the training actions for increase in knowledge of doctors, druggists and patients for the purpose of decrease in the risks connected using biological medicine in the Republic of Kazakhstan.

41. For examination in case of the state re-registration of biosimilyar, but registered in the Republic of Kazakhstan before entry into force of requirements for state registration of biosimilyar the registration file, as for registration according to Item 37 of these rules is provided.

For examination in case of the state re-registration of biological medicines in dosage forms for outside application, suppositories (rectal, vaginal), but the these rules registered in the Republic of Kazakhstan before entry into force, the registration file according to Item 38 of these rules is provided.

In case of absence at the time of carrying out expert works in case of the state re-registration of biological medicines in dosage forms for outside application, the suppositories (rectal, vaginal) this according to the subitem 2 Items 38, the applicant presents them within 12 months after state registration.

42. For examination of medicines with the fixed combination of the known active agents which were not applied in this combination to the therapeutic purpose earlier the complete file according to appendices 2, 3 to these rules is provided. Modules 4, of the 5th OTD format, or part 3, 4 Lists, shall contain results of pharmacological, toxicological and clinical trials which belong to this combination of active agents.

43. For examination of medicines of natural origin results of the corresponding pharmacological, toxicological and clinical trials are reported. Materials and documents on preclinical (not clinical) and (or) clinical trials shall include:

1) materials of preclinical (not clinical) researches of specific activity;

2) materials of research of acute and chronic toxicity;

3) data on local irritant action;

4) data on allergiziruyushchy properties.

At the same time materials of rather high-quality aspects of medicine are provided in full.

For charges of medicinal vegetable raw materials, phyto-teas the overview of scientific literature on herbs, being their part is provided.

44. In case of examination of orphan medicines the positive conclusion about safety is issued under the obligation of the applicant on the following terms:

1) accomplishment in certain terms of certain research program which results will be the basis for revaluation of ratio "advantage risk";

2) use of medicine under strict observation of the doctor;

3) the immediate notification of state body on any side effects which arose in case of use of orphan medicine and the taken measures.

During accomplishment of the set conditions the expert organization provides in state body information obtained from the applicant about carrying out certain research program for annual reassessment of ratio "advantage risk" for the orphan medicine registered thus. The instruction on medical application and other medical information about the orphan medicine registered thus shall contain instructions about insufficiency of data.

45. For examination of the medicines containing vitamins and (or) representing complex of vitamins and (or) vitamins and minerals, the applicant represents one of the following documents and materials:

1) the bibliographic overview of the medicines this on safety, together with the report of the expert, including information on the expert;

2) scientific publications on the declared medicine;

3) data of researches of acute and (or) chronic toxicity.

46. For examination of homeopathic medicines the applicant submits the documents and materials including the following information on Modules 4 and 5 or parts 3 and 4 of the List:

1) for the medicines having long experience of application: the overview of data of scientific literature on efficiency and safety of homeopathic medicine in the declared scope;

2) for the new homeopathic medicines which are not mentioned in pharmacopeias and monographs: the data of toxicological researches, reasons for matching of different potentialities this clinical experience of application;

3) the instruction on medical application with indication of that medicine is homeopathic medicine.

47. For examination of radio-pharmaceutical medicines and their precursors the documents and materials including the following specific information on Modules 3, of the 4 and 5 OTD format or to parts 2, 3 and 4 Lists are submitted.

For radio-pharmaceutical medicines:

for the Module 3:

1) in radionuclide set which shall be with radioactive tag after delivery by the producer active agent will be part of structure which is intended for transfer or binding of radionuclide; the description of production method of radio pharmaceutical set shall include detailed these productions of set and detailed data of recommended final processing for production of radioactive medicine; required specifications of radionuclide shall be described according to the general monograph or special monographs of the European Pharmacopoeia; in amendment, it is necessary to describe any connections which are essential to introduction of radioactive isotopes; also it is necessary to describe structure of connection with radioactive tag; for radionuclides it is necessary to consider possible nuclear reactions;

in the generator maternal and affiliated radionuclides will be considered as active agents.

2) need to be provided detailed data on the nature of radionuclide, identity of isotope, possible impurity, the carrier, use and specific activity;

3) initial materials include target materials of irradiation;

4) it is necessary to consider chemical/radio pharmaceutical purity and its communication with biodistribution;

5) it is necessary to describe radionuclide purity, radiochemical purity and specific activity;

6) for generators detailed data of testing of maternal and affiliated radionuclides are required; for generators eluates it is necessary to provide testing of maternal radionuclides and other components of system of the generator;

7) the requirement to express content of active agents based on the mass of active components shall be applied only to radionuclide sets; for radionuclides radioactivity needs to be expressed in becquerels, with indication of date and if it is necessary, time and the time zone; it is necessary to specify radiation type;

8) for sets of the specification of ready medicine shall include testing by determination of effect of medicines after introduction of radioactive isotopes; it is necessary to include the connections with radioactive tag corresponding control on radiochemical and radionuclide purity; it is necessary to determine and analyze any material which matters for introduction of radioactive isotopes;

9) need to be provided information on stability for isotope generators, isotope sets and medicines with radioactive tag; it is necessary to specify stability when using radio pharmaceutical medicines in bottles for reusable use;

for the Module 4:

toxicity of radio pharmaceutical medicines is connected with radiation dose; in the diagnostic purposes this consequence of use of radio pharmaceutical medicines; in therapy: it is desirable property; in case of assessment of safety and efficiency of radio pharmaceutical medicines it is necessary to specify requirements to medicines and aspects of radiation dosimetry; it is necessary to document action of radiation on body/fabric; the indicator of the absorbed dose of radiation needs to be calculated according to the international system in case of certain way of introduction;

for the Module 5:

results of clinical testing should be reported if it is acceptable, or, to prove in clinical reviews.

For precursors of radioactive and pharmaceutical medicines for the purposes of radioactive branding:

in case of the radio pharmaceutical precursor intended only for introduction of radioactive isotopes it is necessary to provide information which will concern possible effects of insufficient efficiency of introduction of radioactive isotopes or dissociation in-vivo conjugate with radioactive tag, i.e. the questions connected with effect which free radionuclide has on patients; it is also necessary to provide the relevant information concerning risk factors, i.e. radioactive impact on personnel of hospital and the environment;

in particular, it is necessary to provide the following information:

for the Module 3:

provisions of the module 3 shall be applied in case of registration of radio pharmaceutical precursors as it is stated above;

for the Module 4:

concerning toxicity in case of single and repeated introduction it is necessary to report results of the researches conducted according to regulations on proper laboratory practice if it is not proved differently;

researches on mutagenicity of radionuclides are not considered applicable in this specific case;

it is necessary to provide information of rather chemical toxicity and disposition corresponding "cold" (not containing radioactive materials) nuclide;

for the Module 5

the clinical information obtained during clinical trials with use of precursor in itself is not considered significant in case of radio pharmaceutical precursor which is intended only for introduction of radioactive isotope;

however it is necessary to provide information showing clinical efficiency of radio pharmaceutical precursor in case of accession to molecules of the corresponding carrier.

48. The following special requirements to materials of the registration file are applied to medicines which active agent is well studied in medical application with the confirmed efficiency and acceptable level of safety.

For materials of the registration file of parts 3 and 4 of the List in the detailed scientific bibliography it is necessary to specify preclinical and clinical characteristics of medicine.

For confirmation of well studied medical application the following data shall be provided:

1) factors which need to be considered in case of determination of well studied medical application of components of medicines:

time during which active agent in medical practice is used;

quantitative aspects of use of active agent;

degree of scientific interest and relevance in use of active agent in the last 5 years before filing of application (with reference to the published scientific sources);

sequence of scientific estimates.

For determination of well studied use of different active agents assessment for different periods of time is provided. The period of time necessary for determination of well studied medical application of active agent, shall be at least 15 years from the date of the first systematic and documentary use of this active agent as medicine;

2) the materials of the registration file provided by the applicant will include all aspects of assessment of safety and efficiency, to contain or give the reference to the overview of the corresponding literature taking into account before - and post-registration researches and the published scientific literature concerning results of epidemiological researches and especially comparative epidemiological researches, all documentation, both positive, and negative. "The bibliographic reference" to other sources of proofs (post-registration researches, epidemiological researches), except the data concerning monitoring and test methods can be the proof of safety and efficiency of medicine provided that in materials of the registration file use of these sources of information is accurately explained and proved;

3) need to be proved why the acceptable level of safety and (or) efficiency, despite the lack of some researches can be taken for granted;

4) in preclinical and (or) clinical reviews need to be explained the importance of any provided data concerning already registered medicine, other than that which is offered to registration. It is necessary to provide reasons concerning whether it is possible to consider the declared medicine similar to already registered medicine, despite the existing disagreements;

5) post-registration experience of use may contain information on use of other medicines containing the same components;

6) the periodic updated report on safety of medicine over the last 5 years before filing of application by foreign producers.

4. Procedure for carrying out and stages of examination of medicines

49. The applicant along with the statement represents to the expert organization the registration file and materials necessary for conducting examination by the principle of "one window".

50. Examination of medicine in case of state registration, re-registration consists of the following stages:

1) primary examination;

2) analytical examination;

3) specialized pharmaceutical examination;

4) specialized pharmacological examination;

5) forming of the conclusion about safety, efficiency and quality.

51. Specialized pharmaceutical and pharmacological expertizes are carried out in parallel (except for examinations in case of implementation of transfer of engineering procedure and examination of water solutions of generic medicines).

52. The state expert organization if necessary requests from the applicant of explanation or refining by specific provisions in the provided documents and materials of the registration file.

53. The state expert organization in case of non-presentation by the applicant within thirty calendar days of the requested materials or written reasons for other terms for their preparation, but no more than for sixty calendar days, stops examination and issues the negative conclusion about safety, efficiency and quality. Total quantity of the calendar days necessary for provision of requested; materials, constitutes no more than ninety days at each stage.

After conducting specialized examination no more than thirty calendar days which are not entering in time conducting examination for final approval of resulting documents (the regulating document on quality and safety, the instruction on medical application and packaging prototypes) by electronic approval according to the individual password and provisions of leaf of approval are provided to the applicant.

54. During conducting examination in case of state registration according to the decision of state body based on representation to the expert organization assessment of conditions of production and system of quality assurance, conditions of performing preclinical and (or) clinical trials, systems of pharmakonadzor of the holder of the registration certificate by specialists of state body and expert organization is performed.

55. The applicant organizes visit of production within thirty calendar days after receipt of information on need of its carrying out or provides the specific term of visit, but no more than in ninety calendar days after receipt of information.

Terms of preparation, carrying out, registration and decision making by its results, are not included into terms of conducting examination.

56. In case of provision of generic 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 warranty obligation about 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.

57. After examination completion of the procedure the state expert organization creates the electronic archive copy of the registration file which is stored in archive.

During action of the registration certificate the archive registration file, is supplemented with electronic copies of registration certificates about modification with all enclosed documents of the applicant, reports on safety and efficiency.

The registration file is stored in archive with observance of requirements of confidentiality.

The registration files on paper which are stored in archive and submitted for examination are subject to return to the applicant after transfer by their expert organization in electronic format.

The registration file on the electronic medium is stored before the termination of term of presence of medicine in the market.

58. The state expert organization taking into account indicators "advantage risk", stability determines the term for which the registration certificate is issued: on medicine for the period up to five years, on medicinal substance, medicinal vegetable raw materials for the period up to ten years. After re-registration the termless registration certificate on medicines is issued.

59. After effective period of the registration certificate, medicine is subject to re-registration.

60. The applicant submits the application for re-registration before the termination and no later than six months after the end of action of the registration certificate.

5. Procedure for conducting primary examination of medicine

61. Primary examination of the registration file of medicine includes:

1) assessment of completeness, reliability and correctness of execution of the submitted documents of the registration file;

2) verification of presence of samples:

medicine, sufficiency of their quantity and expiration date for conducting analytical examination;

medicinal substances, standard samples of medicinal substances and their impurity, consumable materials (in exceptional cases and on terms of return), techniques of analytical examination of medicine, necessary for reproduction;

3) assessment of composition of medicine on availability of the prohibited dyes and other excipients, substances received from tissues of the person and animal products and, in case of their availability, the document confirming safety of the active agents of proteinaceous origin used in production of medicines (prion safety);

4) assessment of composition of medicine on content of drugs, psychotropic substances and precursors;

5) examination of the name regarding absence in it:

graphical similarities to earlier registered medicines and words with dissonant expressions;

capabilities to mislead rather true composition and effect of medicine;

advertisement concerning use of medicine and its representation as side effects, unique, effective, safe and exclusive on absence;

similarities the International unlicensed name (further - MNN) and (or) names, similar to them, for medicine of other chemical composition or action;

6) examination on availability in the state register of the identical name of medicine (further - HP) with other composition of active agents;

7) examination of the regulating document on quality control and safety of medicine to the established requirements;

8) verification of presence of specifying of procedure for leave from the pharmaceutical organizations (according to the recipe or without recipe);

9) assessment of marking of samples of prototypes of packaging, labels, stickers on compliance to requirements of the legislation;

10) check of compliance of the declared changes in the registration file (changes like I or type II) and check of correctness of specifying of Sections, pages of the registration file to which changes shall be made.

62. By results of primary examination of medicine the expert opinion in form according to appendices 6, 7 to these rules is constituted. To the applicant information on the revealed notes goes.

6. Procedure for conducting analytical examination of medicine

63. Analytical examination of medicine includes:

1) physical, chemical, physical and chemical and biological testing of samples for compliance to requirements of the regulating document for quality control and safety of medicines;

2) assessment of the regulating document on quality control and safety of medicines regarding reproducibility of analysis techniques and compliance of registration samples to the regulating document on quality control and safety.

64. By results of analytical examination of medicine by test laboratory the test report in form according to appendix 8 to these rules is constituted.

65. Analytical expertize in case of the subsequent re-registration is not carried out in case of lack of claims for safety, efficiency and quality of the 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.

7. Procedure for conducting specialized pharmaceutical examination of medicine

66. Specialized pharmaceutical examination of medicine includes assessment:

1) chemical safety and quality of medicine, influence of the made changes in the registration file on safety and quality of medicine;

2) composition of medicine and conclusion about its rationality (pharmaceutical development), qualities of medicinal substances and excipients;

3) medicine productions (production formula, the production technology, control in production process, validation of production processes);

4) ready-made product (compliance of the parameters specified in the quality certificate finished goods to the described quality control methods in the regulating document of quality control and safety of medicines, the analysis of the protocol of test laboratory, assessment of possibility of reproduction and objectivity of techniques of quality control, adequacy of composition of medicine and techniques of quality control);

5) compliance of the indicators of quality specified in the regulating document on quality control and safety of medicines of the manufacturing organization, the State pharmacopeia of the Republic of Kazakhstan and the pharmacopeias recognized acting in the territory of the Republic of Kazakhstan;

6) stability of medicine, justification of the declared conditions and storage duration, the application period after the first opening of packaging or dissolution;

7) data on chemical, pharmaceutical equivalence of medicine;

8) markings and packagings regarding their sufficiency for ensuring preserving quality of medicine in storage time and transportations;

9) names regarding absence in it:

graphical similarities to earlier registered medicines and words with dissonant expressions;

capabilities to mislead rather true composition and effect of medicine;

advertisement concerning use of medicine and its representation as side effects, unique, effective, safe and exclusive on absence;

similarities of MNN and (or) names, similar to them, for medicine of other chemical composition or action;

10) the text of the instruction on medical application of medicine, prototypes of packagings, labels regarding compliance of data on storage conditions, transportation, storage duration, the application period after the first opening of packaging or dissolution and availability of necessary warning labels;

11) composition of medicine on belonging to drugs, psychotropic substances and precursors, opportunity or impossibility of extraction by easily accessible method of under control substance in the quantities sufficient for abuse for the purpose of possibility of exception of some control measures.

67. By results of specialized pharmaceutical examination of medicine the expert opinion on quality and safety of the medicine given for examination in form according to appendix 9 to these rules is constituted.

The expert opinion is considered at meeting of the pharmacopoeian commission which is held at least two times a month. Commission session is drawn up by the protocol with the taken-out recommendations.

8. Procedure for conducting specialized pharmacological examination of medicine

68. Specialized pharmacological examination includes:

1) the analysis of reliability of high-quality and quantitative structure active and the excipients specified in the instruction on medical application in comparison with the declared structure in the statement, the analytical regulating document and prototype of packaging;

2) assessment of pharmacological compatibility of components, including excipients; in case of registration of generic or biosimilyar comparison with composition of original medicine is carried out;

3) scientifically based determination of risk degree of abuse: the high risk of abuse, or risk of abuse is absent, or is insignificant; determination of the most admissible content of drugs, psychotropic substances and precursors in medicines;

4) the analysis of documentation on preclinical testing - assessment of results of research of toxicity, influence on reproductive function, embriotoxities, teratogenecity, mutagenicity, carcinogenicity, pharmakodinamika, pharmacokinetics, correctness of the choice of objects and methods of research, methods of introduction and dosages of the researched substance, compliance of researches to provisions of proper laboratory practice;

5) the analysis of documentation of clinical trials - assessment of the report of clinical trials based on the protocol, the studied contingent of examinees and their quantity, method of distribution of examinees on groups of treatment, dose, methods of treatment, levels and methods of carrying out blind testing, type of control, technique of statistic analysis of the obtained data, compliance of researches to requirements of proper clinical practice;

6) assessment of safety and efficiency of medicine by results of clinical trials on the basis of the analysis of the observed complications, side effects, measures for their elimination, dose of medicine, concentration and their interrelation with safety and efficiency of medicine;

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