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DECISION OF BOARD OF THE EURASIAN ECONOMIC COMMISSION

of May 10, 2018 No. 69

About approval of Requirements to research of stability of medicines and pharmaceutical substances

(as amended of the Decision of Board of the Eurasian economic commission of 30.06.2020 No. 86)

According to article 30 of the Agreement on the Eurasian Economic Union of May 29, 2014, Item 2 of Article 3 and article 6 of the Agreement on the single principles and rules of drug circulation within the Eurasian Economic Union of December 23, 2014 and Item 3 of the list of acts of the Eurasian economic commission on questions of regulation of the total markets of medicines and medical products within the Eurasian Economic Union for 2017 - 2019 (No. 15) the Board of the Eurasian economic commission solved appendix to the order of Board of the Eurasian economic commission of May 17, 2017:

1. Approve the enclosed Requirements to research of stability of medicines and pharmaceutical substances.

2. This Decision becomes effective after 6 months from the date of its official publication.

Chairman of Board of the Eurasian economic commission

T. Sargsyan

Approved by the Decision of Board of the Eurasian economic commission of May 10, 2018 No. 69

Requirements to research of stability of medicines and pharmaceutical substances

I. General provisions

1. These Requirements are developed according to the Agreement on the single principles and rules of drug circulation within the Eurasian Economic Union of December 23, 2014 for the purpose of establishment of procedure for research of stability of medicines and pharmaceutical substances in state members of the Eurasian Economic Union (further respectively - state members, the Union) in addition to provisions of Rules of registration and examination of the medicines for medical application approved by the Decision of Council of the Eurasian economic commission of November 3, 2016 No. 78 (further - Rules of registration and examination), the Rules of proper production practice of the Eurasian Economic Union approved by the Decision of Council of the Eurasian economic commission of November 3, 2016 No. 77.

2. Requirements to researches of stability of biological medicines are established by the Rules of carrying out researches of biological medicines of the Eurasian Economic Union approved by the Decision of Council of the Eurasian economic commission of November 3, 2016 No. 89.

3. These Requirements are applied when planning and carrying out researches of stability of pharmaceutical substances and medicines on their basis, and also in case of creation of the registration file. At the same time biological (including biotechnological) origins these Requirements are applied to pharmaceutical substances and medicines in the part which is not contradicting requirements of Chapter 8 of Rules of carrying out researches of biological medicines of the Eurasian Economic Union. And also to the medicines received on their basis, these Requirements are applied to radio pharmaceutical, vegetable pharmaceutical substances in the part which is not contradicting requirements to the researches of stability of radio pharmaceutical and vegetable pharmaceutical substances and medicines determined by the Eurasian economic commission (further - the Commission).

4. The purposes of carrying out researches of stability are data acquisition about change of quality of pharmaceutical substance or medicine eventually under the influence of different factors of the environment (temperature, humidity and light), and also establishment of recommended storage conditions and the period prior to repeated researches of stable pharmaceutical substance, period of validity of unstable pharmaceutical substances or medicines.

II. Determinations

5. For the purposes of these Requirements concepts which mean the following are used:

"the choice of extreme options (breketing)" (bracketing) - scheduling of research of stability so that tests only with extreme (extreme) values of certain factors among in all temporary points of control used when carrying out complete researches were exposed to research. The plan assumes that stability of tests with intermediate values of factors among is equated to stability of tests with extreme values;

"this, in addition confirming stability" (supporting stability data) - data which are not the specification on stability obtained during formalized (standardly carried out according to requirements imposed to these researches) researches. Such data in addition prove analytical techniques, the offered period prior to repeated researches or period of validity, and also storage conditions;

"expiry date of the validity (storage duration)" (expiratio№date) - the date specified in marking of container of pharmaceutical substance or medicine and designating the end of the period during which (inclusive) in case of storage in the established conditions they will meet the approved specifications and after which they cannot be used;

"date of repeated researches" (re-test data) - date after which it is necessary to conduct repeatedly researches of stable pharmaceutical substance for confirmation of its compliance of the specification and, respectively, suitability for production of certain medicine;

"date of production of series" - date of accomplishment of the first transaction, including mixing of active pharmaceutical substance with other components of medicine. For the medicines consisting of one pharmaceutical substance in primary package, initial date of packing (filling of primary package) is considered date of production;

"long-term researches" (long term testing) - research of stability of physical, chemical, biological, biopharmaceutical and microbiological characteristics of pharmaceutical substance or medicine for the purpose of determination of the period prior to repeated researches for the confirmation of earlier fixed term of the validity and (or) storage conditions specified in information on medicine;

"acceptable deviations in storage conditions" (storage conditio№tolerances) - acceptable fluctuations of temperature and relative humidity in technical means for storage in case of the formalized stability researches;

"significant change of medicine" (significant change of the drug product) - one of the following changes:

5 percent change of content or discrepancy to eligibility criterions on activity (potency) (when using biological or immunological methods);

exceeding of eligibility criterion of product of degradation;

discrepancy to eligibility criterions on appearance, physical properties and functional characteristics (for example, on color, separation of phases, capability to resuspending, on balling up (sealing), durability, delivery of one dose when actuating). Some changes of physical properties in the conditions of the accelerated researches are allowed (for example, softening of suppositories, melting of creams);

discrepancy to eligibility criterion on PH value (in the presence of this indicator in the specification);

discrepancy to eligibility criterion in case of dissolution of 12 units of the dosed medicine (in the presence of this indicator in the specification);

"significant change of pharmaceutical substance" (significant change of the API) - change after which pharmaceutical substance ceases to meet specifications;

"researches of forced degradation (decomposition)" (forced degradatio№testing studies) - the researches directed to deliberate degradation of test. If other is not proved, such researches should be conducted in case of development of pharmaceutical substance, data of researches are used for assessment of general photosensitivity of material in case of development of technique and (or) for clarification of ways of its degradation (decomposition);

"climatic zones" (climatic zones) - zones, division into which is based on the prevailing annual climatic conditions;

"room temperature" - usual conditions of the environment;

"critical change of medicine or pharmaceutical substance" - the change influencing efficiency, safety and (or) quality of medicine or pharmaceutical substance;

"material balance" (mass balance) - the amount of the weight received in case of quantitative determination, and the mass of products of degradation (decomposition), determined to estimate is how close the received amount to 100 percent from reference value taking into account admissible error within analytical technique;

"matrix planning", "matrix method" (matrixing) - plan development of research of stability so that only the chosen part from total quantity of tests was analyzed at a given time taking into account all combinations of factors. At the subsequent stages of control it is necessary to research other set of tests from total quantity taking into account all combinations of factors. The plan assumes that stability of the researched tests is identified with stability of all tests of time at present. Shall be revealed distinctions in tests for the same medicine, including the distinctions covering different series, different dosage, the different size of identical type of packaging and corking elements and if it is necessary, the "container-packing" systems (are considered);

"multidose packaging" - primary package of medicine which allows to select consistently medicine doses from total quantity of the doses containing in this packaging without changing at the same time safety, concentration, quality and microbiological purity of the rest of medicine;

"new pharmaceutical substance", "new molecular structure" (new molecular entity) - the pharmaceutical substance containing molecule of the new chemical which is absent as a part of any registered medicine including new salt, ether or derivative (with non-covalent bond) the pharmaceutical substance permitted for use;

"trial series" (pilot scale batch) - the series of pharmaceutical substance or medicine made on industrial equipment according to the technology used in case of full-scale serial production (or by means of its modeling). Trial series for firm dosage forms for intake, as a rule, constitutes at least 1/10 amounts of industrial series or 100 000 units of the dosed dosage form (depending on the fact that it is more);

"relative humidity" - the relation of partial pressure of vapors of water in gas (first of all, in air) to the equilibrium pressure of saturated steam at this temperature;

"primary series" (primary batch) - series of pharmaceutical substance or medicine which is used in the formalized stability researches for establishment of the period prior to repeated researches or establishment of period of validity and data about which stability join in the registration file. The amount of primary series for pharmaceutical substance shall be at least an amount of trial series. For medicine amounts of 2nd or 3rd series shall be at least amounts of trial series, the amount of 3rd series can be less on condition of its representativeness concerning critical production stages. Primary series can be and industrial;

"the period prior to repeated researches" (re-test period) - the period before carrying out repeated researches during which stable pharmaceutical substance meets specifications of quality and is suitable for production of medicine in case of observance of the storage conditions declared in the master file of pharmaceutical substance included in the registration file of medicine. After this period series of pharmaceutical substance, held for use in medicine production, it is necessary to research repeatedly on compliance of the specification and then to use without delay. Series of pharmaceutical substance is allowed to be researched repeatedly, different parts of series can be used after each repeated research until they continue to meet specifications;

"the medicine use period" (utilizatio№period of medicinal product) - the period during which it is allowed to use medicine in multidose packaging after the first opening of primary package with preserving the quality established in the specification;

"confirmatory researches" (confirmatory studies) - the researches conducted for determination of characteristics of photostability in the standardized conditions established by these Requirements, the Pharmacopoeia of the Union or pharmacopeias of state members. Such researches are conducted for determination of the precautionary measures required in case of production or preparation of pharmaceutical substance or development of composition of medicine for light impact reduction, and also need of use of light-tight packaging and (or) special marking. For confirmatory researches series (series) should be chosen according to instructions for the choice of series for the long-term and accelerated researches described in Sections III and IV of these Requirements;

"semipermeable packagings (containers)" (semi-permeable containers) - containers which allow to get to the solvent (usually to water), but interfere with loss of dissolved substance;

"preliminary period of validity" (provisional shelf-life) - the period of validity established temporarily based on satisfactory results of the accelerated researches and the available data of long-term research of medicine in the "container-packing" system intended for realization;

"intermediate researches" (intermediate testing) - the researches conducted at temperature of 30 °C and relative humidity of 65 percent, directed to moderate increase in the speed of chemical degradation or physical changes of pharmaceutical substance or medicine which are dolgosrochno planned to be stored at temperature of 25 °C;

"industrial series" (productio№batch) - the series of pharmaceutical substance or medicine of industrial scale made in the production room with use of production equipment as it is specified in the registration file of medicine;

"the series subjected to stability researches according to the obligation" (commitment batches) - industrial series of pharmaceutical substance or medicine which researches of stability are begun or ended after registration according to the obligation undertaken by the applicant during procedures according to Rules of registration and examination and specified in the registration file;

"the specification on release", "the specification in case of release" (release specification) - the list of indicators of quality, methods of their determination and eligibility criterions by means of which quality of medicine at the time of release is determined;

"the specification on period of validity (storage duration)" (shelf life specification) - the list of indicators of quality, methods of their determination and eligibility criterions to which there shall correspond pharmaceutical substance or medicine during the term of their validity";

"period of validity", "storage duration" (shelf life, expiratio№dating period) - the period during which medicine shall meet specifications in case of proper storage in the conditions specified on packaging;

"stable substance" (stable substance) - the pharmaceutical substance meeting specifications in case of its storage at temperature of 25 °C and relative humidity of 60 percent or at temperature of 30 °C and relative humidity of 60 percent (65 percent) within 2 years and also at temperature of 40 °C and relative humidity of 75 percent within 6 months;

"stressful researches of medicine" (stress testing of the medicinal product) - the researches conducted for impact assessment of more adverse conditions, than condition of the accelerated storage researches, and including researches on photostability and researches of the parameters specific to certain dosage forms;

"stressful researches of pharmaceutical substance" (stress testing of the API) - the researches conducted for establishment of the characteristics of stability inherent to pharmaceutical substance. Such researches are part of strategy of development and are, as a rule, conducted in case of more adverse conditions, than the accelerated researches;

"the existing pharmaceutical substance" (existing API) - pharmaceutical substance which is part of the medicine registered in the territory of the Union;

"the accelerated researches" (accelerated testing) - the researches planned for the purpose of acceleration of chemical degradation or physical change of pharmaceutical substance or medicine by means of creation of adverse conditions of storage and which are part of the formalized program of research of stability. Such data in addition to results of long-term researches of stability are used for assessment of more remote chemical effects in the conditions of not accelerated researches, and also for impact assessment of short-term variations from the storage conditions specified in marking which can arise when transporting. Results of the accelerated researches not always allow to predict physical changes;

"storage conditions" - optimum parameters of the environment (temperature, humidity of air, the light mode, etc.) and rules of the address (protection measure from spoil, etc.), preserving quality of medicine or pharmaceutical substance, necessary for providing;

"the formalized research program of stability" - the documented research program of stability which includes number of researches (storage conditions), same for this chemical group of pharmaceutical substances and medicines;

"the formalized research" - the research which is standardly carried out according to requirements imposed to it;

"extrapolation" - method of receipt of information on future data based on the available data.

For the purposes of these Requirements the concept "substance for pharmaceutical use (use)" is applied in the value determined in the Information reference book of the concepts applied within the Eurasian Economic Union in the field of drug circulation, No. provided by the Recommendation of Board of the Eurasian economic commission of May 2, 2017 12, the concept "pharmaceutical substance" - in the value determined by the Agreement on the single principles and rules of drug circulation within the Eurasian Economic Union of December 23, 2014.

III. Researches of stability of new pharmaceutical substances

1. General provisions

6. In this Section information on stability of new pharmaceutical substances which should be specified in the registration file is considered.

Provisions of this Section are not applied in case of creation of statements for registration of medicine with the simplified registration file, statements for modification of the registration file, statements for receipt of permission to conduct of clinical trials, etc.

Data on stability of pharmaceutical substance are integral part of system approach to assessment of its stability.

7. Stability of pharmaceutical substance is established by her producer based on results of researches of stability and is necessary for determination of the period prior to repeated researches of stable pharmaceutical substances or period of validity of unstable pharmaceutical substances.

8. Before carrying out researches by the producer (applicant) the program of research of stability of pharmaceutical substance including types of the planned researches (stressful, accelerated and long-term), the choice of series, the description of the "container-packing" system, the researched characteristics, analytical techniques, frequency of researches, storage conditions is constituted.

2. Stressful researches

9. Stressful researches of pharmaceutical substance can help to identify probable products of degradation that helps to establish ways of degradation and stability inherent to molecule, and also to validirovat capability of analytical techniques to determine stability. Carrying out stressful researches depends on specific features of pharmaceutical substance and type of medicine.

10. For confirmation of the identified products and ways of degradation the data published in scientific literature can be in addition provided. The separate research of certain products of degradation can not be necessary if it is proved that they are not formed in the conditions of the accelerated or long-term researches. If there are no such data, then it is necessary to conduct stressful researches.

11. Stressful researches are conducted on one series of pharmaceutical substance. Such researches include researches of influence of temperatures exceeding temperature in case of the accelerated researches with its consecutive increase on 10 °C (for example, 50 °C, 60 °C, etc.), humidity influences (for example, relative humidity of 75 percent and above), and also if necessary oxidation and photolysis. If pharmaceutical substance represents solution or suspension, during the research of stability it is necessary to estimate their capability to hydrolysis in wide interval of pH.

12. Photostability assessment - integral part of stressful researches. Conditions of researches on photostability are described in the Section V of these Requirements.

13. Establishment of ways of degradation, and also development and validation of the corresponding analytical techniques requires research of products of degradation in stressful conditions. However if these or those products of degradation in the conditions of the long-term and accelerated researches are not formed, independently they are not required to be researched.

14. Results of stressful researches make integral part of information provided to authorized body of state member in the registration file of medicine.

3. Choice of series

15. The data received during the formalized stability researches need to be provided at least for 3 primary series of pharmaceutical substance. In case of production of trial series of pharmaceutical substance it needs to be received in the same way synthesis, and also with use of method and the production technology imitating final process which will be used for production of industrial series.

16. Quality of pharmaceutical substance in general for the series subjected to stability research shall be representative concerning product quality which will be made in industrial scale. It is allowed to represent other proving data.

4. "Container-packing" system

17. Researches of stability shall be conducted concerning the pharmaceutical substance packed with use of the "container-packing" system which is used in case of storage and realization of this pharmaceutical substance or by its imitation.

5. The specification on release and the specification on period of validity

18. The research of stability includes research of such properties of pharmaceutical substance which are subject to changes in the course of storage and, most likely, will influence quality, safety and (or) efficiency. The research shall cover, when applicable, physical, chemical, biological and microbiological indicators. It is necessary to use validirovanny according to the management on validation of analytical techniques approved by the Commission, the analytical techniques testimonial of stability. Need and amount of the researches which are subject to repeating depend on results of validation researches.

19. Techniques of researches shall allow to determine authentically content of pharmaceutical substance and products of its degradation in mix with each other.

20. Specifications shall establish techniques of researches, admissible limits of content of impurity and products of degradation of pharmaceutical substance.

These admissible limits, and also the quality and quantity physical, chemical, biological and microbiological characteristics of pharmaceutical substance and their acceptable deviations brought in the specification should be determined based on profile of degradation of pharmaceutical substance.

6. Frequency of researches

21. When carrying out long-term researches the frequency of researches shall provide establishment of profile of stability of pharmaceutical substance. Frequency of researches of pharmaceutical substance which offered period prior to repeated researches constitutes at least 12 months in long-term storage conditions, as a rule, constitutes each 3 months within the first year, each 6 months within the second year, and then annually during all offered period prior to repeated research.

22. In the conditions of the 6-month accelerated research it is necessary to use at least 3 temporary points, including initial and final (for example, 0, 3 and 6 months). If as a matter of experience developments it is expected that results of the accelerated researches, most likely, will border on criteria of significant changes, then it is necessary to conduct expanded researches by addition of tests in final temporary point or by inclusion of the fourth temporary point in the protocol of research.

23. If owing to significant change by results of the accelerated storage it is necessary to conduct researches in intermediate storage conditions, it is recommended to conduct 12-month research at least in 4 temporary points, including initial and final (for example, 0, 6, 9 and 12 months).

7. Conditions of researches

24. Pharmaceutical substance needs to be researched in the conditions (with the corresponding acceptable deviations in storage conditions) allowing to study its thermal stability and if it is necessary, sensitivity to effect of moisture. Conditions and duration of researches are chosen so that to correspond to conditions and the period in case of storage, realization and the subsequent use.

25. The devices used when carrying out researches shall control storage conditions within the corresponding ranges described in these Requirements. Storage conditions shall be traced and registered the used devices or the researcher. Short-term changes of conditions because of opening of door of the device for storage are accepted as inevitable. In case of variation from storage conditions in view of defect of the device of effect shall be established and entered in the report if it is supposed that it affected results of research of stability. Effects of variations which exceed acceptable deviations in storage conditions within more than 24 hours shall be analyzed.

26. At the time of filing of application on registration of medicine in authorized body (organization) of state member long-term researches shall be conducted within at least 12 months with use of quantity of the series specified in Item 15 of these Requirements and proceed during all expected period prior to repeated researches or period of validity. The additional data on results of researches of stability collected during the registration period are represented to authorized body of state member. The data obtained in case of accelerated and if it is necessary, in case of intermediate researches, can be used for assessment of short-term variations from the storage conditions specified in marking (it can occur when transporting).

27. Conditions of researches of pharmaceutical substance in case of long-term, accelerated and if it is necessary, intermediate researches are given in tables 1 - 3.

28. General rules.

Table 1

Conditions of the researches "General Rules"

Research

Research conditions (temperature and relative humidity)

The minimum duration of research of stability at the time of filing of application about registration (month)

Long-term <*>

25 2 °C and 60 5%, or 30 2 °C and 65 5% <**>, or 30 2 °C and 75 5% <**>

12

Intermediate <***>

30 2 °C and 65 5%

6

Accelerated

40 2 °C and 75 5%

6

--------------------------------

<*> The choice of storage conditions for the accelerated researches is based on risks assessment. Researches in case of adverse conditions can be alternative to research at temperature of 25 2 °C and relative humidity in 60 5% or temperature in 30 2 °C and relative humidity in 65 5%.

<**> It is carried out in case of drug circulation in the countries of the climatic zones III and IV determined in appendix No. 1 to these Requirements.

31. If other is below not provided, the data received in case of storage in refrigerating conditions need to be estimated according to subsection 9 of this Section.

32. If in the conditions of the accelerated researches in period between the 3rd and 6th months of researches significant change is observed, the offered period prior to repeated researches or period of validity is determined on the basis of the data obtained in real time in the conditions of long-term researches.

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