ORDER OF THE GOVERNMENT OF THE REPUBLIC OF KAZAKHSTAN

of July 14, 2010 No. 712

About approval of the Technical regulation "Requirements to Safety of Medicines"

For the purpose of implementation of the Law of the Republic of Kazakhstan of November 9, 2004 "About technical regulation" the Government of the Republic of Kazakhstan DECIDES:

1. Approve the enclosed Technical regulation "Requirements to Safety of Medicines".

2. This resolution becomes effective after six months from the date of the first official publication.

 

Approved by the order of the Government of the Republic of Kazakhstan of July 14, 2010, No. 712

Technical regulation "Requirements to Safety of Medicines"

1. Scope

1. This Technical regulation (further - the Technical regulation) is developed for the purpose of implementation of the Law of the Republic of Kazakhstan of November 9, 2004 "About technical regulation" and establishes requirements to medicines.

2. Subjects to regulation of this Technical regulation are the medicines entering the Single commodity nomenclature of foreign economic activity of custom union.

3. Provisions of the Technical regulation extend to the health care subjects performing pharmaceutical activities irrespective of their form of business.

4. Products types falling under action of this Technical regulation and their codes according to the Single commodity nomenclature of foreign economic activity of custom union (further on tekstukoda of FEACN CU) are specified in appendix 1 to this Technical regulation.

5. Classification of medical immunobiological supplies is given in appendix 2 to this Technical regulation.

6. Do not treat subjects of the Technical regulation:

1) the medicines used in veterinary science;

2) radionuclides in the form of the isolated sources;

3) whole blood, plasma or blood cells of human origin;

4) means on ensuring industrial safety, fire safety, explosion safety, chemical safety and safety of other types in case of production of medicines, requirements to which are regulated by other regulating documents.

7. Features of drug circulation, containing the drugs, psychotropic substances and precursors which are subject to control in the territory of the Republic of Kazakhstan are regulated by the legislation of the Republic of Kazakhstan in the field of drug trafficking, psychotropic substances and precursors.

8. Treat dangerous factors (risks) arising in the course of lifecycle of medicines:

1) loss of quality characteristics under the influence of factors of external environment;

2) availability as a part of incompatible active agents;

3) availability as a part of prohibited to application in the Republic of Kazakhstan painting and excipients;

4) contamination (pollution) of medicines;

5) lack of reliable information about medicine.

9. Identification of medicines is carried out for the purpose of determination of identity of products of the regulating documentation on medicine and information specified in the instruction on medical application, way:

1) visual survey;

2) establishments of identity of the name of medicine;

3) establishments of these certified testing;

4) establishments of identity of properties (physical, chemical, biological and others) and methods of their measurement;

5) identity of information on medicine presented in the marking form on packaging, the instruction on medical application, the certificate of conformity;

6) determinations of the FEACN CU code.

2. Terms and determinations

10. In this Technical regulation the concepts regulated by the legislation in the field of technical regulation and in the field of health care and also the following terms and determinations are used:

1) allergenic products - the medicines of mainly natural origin containing components which can cause or provoke allergic diseases;

2) vaccines - the medicines containing antigenic substances capable to induce specific and active immunity at the person against the infectious agent or toxin, or the antigen received from them;

3) validation - documentary confirmation of the fact that the processes which are carried out within the established requirements can effectively be performed also with the reproduced results;

4) medicine angro-product - medicine, in large packing, intended for production, production, packing, processing, final packaging and marking;

5) medicine development - scientific search, carrying out preclinical (not clinical) researches of perspective substances regarding their safety, preclinical (not clinical) researches of ready dosage forms, clinical trials and receipt of permission to production;

6) medicine balk-product - the dosed medicine which passed all stages of engineering procedure, except for final packaging;

7) medicines - the means representing or containing pharmacological the active agents intended for prevention, diagnostics and treatment of diseases, and also change of condition and functions of organism: medicinal substance, medicinal raw materials of natural origin, medicinal angro-and balk-products, medicines, medical immunobiological supplies, parapharmaceutics;

8) medicine packaging - means or complex of the means providing their protection against damages and losses, and also protecting the environment from pollution.

Packaging consists of primary (internal) and secondary (outside) package:

primary (internal) package is the packaging which is directly adjoining to dosage form;

secondary (outside) package is packaging in which medicine in primary package is located;

9) the trade name of medicine - the name under which medicine is registered;

10) immune serums - the medicines containing the immunoglobulins of the person or animals received by means of different technologies;

11) preclinical (not clinical) research - chemical, physical, biological, microbiological, pharmacological, toxicological and other pilot scientific research or series of researches on studying of the tested substance or physical impact, means, methods and technologies of prevention, diagnostics and treatment of diseases, for the purpose of studying of specific action and (or) safety for health of the person;

12) clinical trial - the research with participation of the person as the subject conducted for identification or confirmation of safety and efficiency of means, methods and technologies of prevention, diagnostics and treatment of diseases;

13) number of series - the digital, alphabetic or alphanumeric reference allowing to identify specifically series of medicine and to determine the complete sequence of production and control operations;

14) sticker (sticker) - the additional label on packaging containing information on medicine in the state and Russian languages;

15) marking - the texts, trademarks, symbol and drawings bearing information for the consumer and applied on labels, counterlabels, kolyeretka, labels, stickers (stickers) medicine packaging;

16) the trademark - the designation registered in the Republic of Kazakhstan serving for difference of medicines, products of medical appointment and medical equipment of one producers from homogeneous products of other producers.

3. Conditions of drug circulation in the market

11. In case of drug circulation the requirements to safety of medicines regulated by this Technical regulation shall be observed.

12. Realization of medicines is not allowed:

1) the medicinal substances which did not undergo state registration in the Republic of Kazakhstan, except for made in the conditions of the Proper production practice;

2) expired;

3) non-compliant to the requirements of this Technical regulation;

4) without certificate of conformity;

5) health workers in the medical organizations, except as specified stipulated by the legislation the Republic of Kazakhstan;

6) through warehouses of temporary storage of medicines;

7) without recipe of the doctor, provided for leave according to the recipe;

8) revealed counterfeited, counterfeit;

9) without complete and reliable information for the consumer (marking, the instruction on medical application).

4. Requirements to safety of medicines

13. Medicines shall:

1) to conform to requirements for the indicators given in the List of characteristics (indicators) which are subject to control in case of certification of medicines according to appendix 3 to this Technical regulation;

2) to have optimum dosage form;

3) to contain compatible components, safe active and excipients;

4) to conform to requirements of the State pharmacopeia of the Republic of Kazakhstan (further - GF RK) and the pharmacopeias recognized acting in the Republic of Kazakhstan, or standards of the organization;

5) to have safe taroukuporochny system (inertness of materials, hermeticity and functionality) providing stability of ready medicine during fixed term of the validity under the regulated conditions;

6) to be supplied with necessary amount of information on the safety of ready medicine specified in the instruction on medical application and when marking packaging;

7) to be stable during expiration date;

8) to be applied on medical indications, taking into account contraindications, cautions, interaction with other medicines;

9) to be stored in the conditions providing compliance of physical and chemical, pharmacological properties.

5. Requirements to safety of process of development of medicines

14. In case of development of new medicine:

1) safety of medicine by implementation of proper assessment of the potential risks influencing efficiency and quality in case of its impact on human body shall be ensured;

2) optimum solutions on reduction of harmful effects of ready medicine by human body are chosen.

15. The researches (testing) planned and performed in the course of medicine development shall determine indicators (characteristics) influencing safety of the developed medicine. Results of researches (testing) shall clearly demonstrate safety of medicine.

16. At development stage the package of measures for safety includes the following:

1) the structure of active agent, including configuration, conformation and possible isomerism of molecule, shall be proved by modern methods of research definitively;

2) by ratio evaluation methods "structure activity" the molecule fragments responsible for toxicity manifestation shall be established;

3) the most important physical and chemical characteristics of active agent influencing its safety shall be determined;

4) the profile of impurity of new medicinal substance shall be established on the basis of scientific assessment of chemical reactions of synthesis, and also mix of the impurity brought from raw materials and possible products of decomposition; in case of change of the scheme of synthesis of medicinal substance the profile of impurity shall be established repeatedly;

5) based on the analysis of chemical structure of impurity and the subsequent researches (testing) for genotoxicity the connections potentially capable to manifestation of genotoksichny properties shall be revealed (azoxyconnections, nitroso compounds, connections, similar to aflatoxin and others);

6) the initial substances and materials used for receipt of active agents shall have the degree of chemical purity answering effective objectives for active components of biological origin - biological (microbiological, virologic, prion) purity;

7) if as initial substances the substances known for toxic properties are used (for example, genotoksikant and (or) carcinogens), then any available options of receipt of new medicinal substance which are not leading to residual toxic impurity, except for lack of alternative ways of synthesis, or impossibility of use of other initial substances shall be considered;

8) in case of impossibility of complete removal of toxic impurity from medicinal substance decrease in residual impurity to admissible (acceptable) level as a result of the made technical efforts shall be guaranteed (for example, cleaning stages);

9) in the course of receipt of new medicinal substance the organic solvents of 1 class of toxicity regulated by the Directive of the International conference on harmonization of technical requirements to registration of medicines for application for the person (International Conference on Harmonization of technical Requirements for Registration of Pharmaceuticals for Human Use) (ICH) "Classification of residual solvents by risk degree "Guidelines on impurity shall not be used: residual solvents" Committee on patent medicines (Committee for Proprietary Medicinal Products (CPMP) CPMP/ICH/283/95, except as specified their applications in production of highly effective medicines;

10) techniques of testing of new medicinal substance shall be validirovana;

11) regulation of content of impurity in new medicinal substance (related impurity, residual solvents, heavy metals and others) shall be carried out on the basis of toxicological assessment of impurity;

12) regulation of related impurity shall be carried out not only on content of the identified impurity, content of neintifitsirovanny impurity, but also the amount of impurity;

13) regulation of residual solvents shall be carried out according to requirements of GF RK in all cases of their application in the course of receipt of medicinal substance;

14) stability of active components of live attenuirovanny vaccines and anatoxins shall be studied for version exception in initial virulence strain or toxin;

15) stability of new medicinal substance shall be confirmed according to the established requirements in the stressful, accelerated and long-term testing;

16) stability of substances of biological origin shall be studied in testing under intermediate conditions and long-term testing;

17) testing of photosensitivity of new medicinal substance shall be integral part of stressful testing;

18) the recontrol period for steady substances and the storage duration for unstable substances, including substances of biological origin, shall be established based on results of long-term testing of stability;

19) special requirements to storage of the light-sensitive substances, substances which are easily hydrolyzed under the influence of moisture of air, substances which are not subject to freezing shall be developed.

17. At stage of pharmaceutical development the package of measures for safety includes the following:

1) in case of introduction in compounding of new active agent compatibility and pharmacological efficiency and as a result of its safety in ready dosage form shall be proved;

2) if there is need of introduction in compounding of medicine of new excipients, their safety in the form of net substance and as a part of ready dosage form shall be proved;

3) new excipients shall not worsen medicine pharmacokinetics indicators;

4) doses, methods of introduction and dosage form of the developed medicine shall exclude the risks of manifestation of side effects, complications and toxic action connected with incompatibility of doses, methods of introduction and dosage form with physiological parameters of the person;

5) the production technology of medicinal substance, ekstsipiyent, ready dosage form shall be fulfilled taking into account exception of risk of pharmaceutical incompatibility, above-standard content of microbes, viruses and pyrogens, prion safety.

18. Process of development of medicine shall be валидирован that assumes forming of documentary drawn up proofs providing high degree of confidence that as a result of process the product which is completely meeting safety requirements for the person will be made.

19. Validation process includes development of the protocol, expanded and frequent sampling, planning of testing with emphasis on establishment of uniformity within one series, consecutive improvement of quality of medicine is at least, than in three series, the analysis of all variations, the test report with reasons, demonstration of opportunities of new medicine.

20. In case of development of medicine proper management of the procedure of development of medicines which is systematic process of assessment, control, the message, overview and implementation of the adjusting actions shall be effective.

6. Requirements to safety of process of carrying out preclinical (not clinical) researches of medicines

21. Preclinical (not clinical) researches are conducted for the purpose of assessment of safety of new biologically active agent or ready medicine from it.

22. Preclinical (not clinical) researches are conducted at development stage of medicinal substances and development stage of ready dosage form.

23. At stage of preclinical (not clinical) researches the package of measures for safety includes systematization, data analysis and assessment:

1) toxicity of substance and ready dosage form in case of single introduction;

2) toxicity of substance and ready dosage form in case of repeated introduction (subacute and chronic);

3) reproductive toxicity (fertility, embrio-and fetotoksichnost, teratogenecity, peri-and post-natal toxicity) substance and ready dosage form;

4) genotoxicity of substance and ready dosage form;

5) mutagen potential of substance and ready dosage form;

6) cancerogenic potential of substance and ready dosage form;

7) toksikokinetik of substance and ready dosage form;

8) pharmakodinamik of substance and ready dosage form for the purpose of identification of undesirable side effect;

9) local portability of substance and ready dosage form, including phototoxicity, irritant action, local hypersensitivity;

10) possibilities of development of accustoming and/or syndrome of cancellation of drugs in case of use of substance or ready medicine;

11) risk of insufficient pharmacological efficiency of substance and ready medicine;

12) risk of reversion in initial toxic form of nontoxic biological component;

13) risk of pharmaceutical and pharmacological incompatibility with other medicines.

24. As guarantee of reliability of results of preclinical (not clinical) researches serves observance of the rules of the preclinical (not clinical) researches in the Republic of Kazakhstan approved by the order of the Minister of Health of the Republic of Kazakhstan of November 19, 2009 No. 745, and also which are carried out according to the international rules of proper laboratory practice.

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