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PHARMACOPOEIA

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APPROVED BYDecision of the Board ofthe Eurasian Economic CommissionNo. 100 dated August 11, 2020PHARMACOPOEIAof the Eurasian Economic Union

21. GENERAL NOTICES

3101000000-20191.1. General ProvisionsThe provisions of Section 1. General Notices applyto all the texts of the Pharmacopoeia of the EurasianEconomic Union.The Pharmacopoeia of the Eurasian EconomicUnion is a set of regional requirements and regulationsthat establish the maximum allowable quality level ofmedicinal products in the pharmaceutical market of theEurasian Economic Union. The Pharmacopoeia of theUnion is the abbreviated name of the Pharmacopoeiagiven in the texts. In some cases, the word"Pharmacopoeia" may be used to indicate thePharmacopoeia of the Union.The official texts of the Pharmacopoeia of theUnion include general notices, general chapters,monographs, and annexes, which are published inRussian.Monograph is a document that sets out therequirements and statements of the Pharmacopoeia fordrugs, excipients and other articles as well as tests andtheir methods.Monographs can be general or individual.General monograph is a monograph thatestablishes general requirements and regulations for thequality and packaging of medicinal products, excipientsand other articles, as well as tests, their methods, andreagents used.Individual monograph (monograph) is apharmacopoeial monograph that sets specialrequirements for the quality of specific medicinalproducts, excipients and other articles.The reference to a monograph and/or its section inthe texts of the Pharmacopoeia means that the drugs,excipients and other articles meet the requirements ofthis monograph. References to monographs in the textsof the Pharmacopoeia are shown using the monographtitle and reference number in italics.-The requirements of the Pharmacopoeia for medicinalproducts must be met throughout their valid shelf life.Pharmacopoeial monographs do not regulate shelf lifeof medicinal products in opened packages and/or theirquality specifications, which must be approved by thecompetent authority. Any other materials (activepharmaceutical ingredients, excipients, etc.) must meetthe requirements of the pharmacopoeial monographthroughout their period of use. The shelf life and thetime which the shelf life is calculated from must beapproved by the competent authority based onexperimental results of stability tests.The requirements of pharmacopoeial monographsmay be mandatory, advisory, and informative. Therequirements of monographs are mandatory unlessotherwise specified in 1. General Notices or generalmonographs. General chapters become mandatory ifthey are referenced in the monograph, except in caseswhere the reference is advisory or given for information.Active pharmaceutical substances, excipients, drugproducts and other auxiliary materials described inmonographs are intended for human use and veterinaryuse, unless a monograph gives instructions for use inonly one of these fields.Quality Systems. The quality standards establishedin the monographs apply to drug products, excipientsand auxiliary materials only if they are produced interms of the relevant quality system. The quality systemmust ensure that drugs, excipients and auxiliarymaterials always meet the requirements of the standardsof the Pharmacopoeia.Alternative Procedures. All tests and proceduresdescribed are the official methods upon which thequality standards of the Pharmacopoeia are based.Subject to approval by the competent authority,alternative procedures may be used for quality controlof medicinal products.

4Alternative methods included in the manufacturer'squality specifications and/or quality regulatorydocuments must ensure that an unequivocal decisionshould be made as to whether drug compliance with thestandards of the monograph would be achieved if theofficial procedures were used. The alternativeness ofproposed procedures is confirmed by validation testsusing the same validation characteristics as in the caseof pharmacopoeial procedures. Analytical proceduresshould be validated in accordance with the requirementsstated in General Chapter Analytical ProceduresValidation. In the event of doubt or dispute, thepharmacopoeial analytical procedures are aloneauthoritative.Confirmation of compliance with requirementsof the Pharmacopoeia. (1) Drug, excipient or auxiliarymaterial is considered to be of pharmacopoeial gradeonly if it meets all the requirements of thecorresponding monograph. This requirement does notmean that the manufacturer must perform all the testsdescribed in the monograph when evaluatingcompliance with the Pharmacopoeia before the productis released to the market. The manufacturer may obtainassurance that a medicinal product is of Pharmacopoeiaquality on the basis of its design, together with itscontrol strategy and data derived, for example, fromvalidation studies of the manufacturing process.(2) An advanced approach to quality control couldutilise process analytical technology and/or real-timerelease testing (including parametric release) strategiesas alternatives to end-product testing alone. Real-timerelease testing in circumstances deemed appropriate bythe competent authority is thus not precluded by theneed to meet with the Pharmacopoeia requirements.(3) Reduction of animal testing: the Pharmacopoeiais dedicated to phasing out the use of animals for testpurposes by replacing, reducing and refining tests inaccordance with the provisions set out in the EuropeanConvention for the Protection of Vertebrate Animalsused for Experimental and Other Scientific Purposes.In proving compliance with the Pharmacopoeiarequirements as indicated above (1), manufacturers mayestablish additional systems to monitor consistency ofproduction. With the agreement of the competentauthority, the choice of tests performed to assesscompliance with the Pharmacopoeia requirements whenanimal tests are prescribed, is established in such a waythat animal usage is minimised as much as possible.Qualification of Materials. Some materials,requirements to which are described in monographsmay be produced with different quality depending ontheir intended use. Unless otherwise specified in themonograph, its requirements apply to all qualifications(categories, forms, brands, classes) of materials. Insome monographs, for example, on excipients, a list offunctional characteristics of the material that areimportant for its use may be provided as additionalinformation. In addition, the monograph may provideprocedures for determining one or more of thesecharacteristics for information. The informative oradvisory nature of data on excipients is indicated in thegeneral chapter Functional Characteristics ofExcipients.Validation of Pharmacopoeial Procedures. Thetest methods given in general and individualmonographs are validated in accordance with goodscientific practice and modern recommendations for thevalidation of analytical procedures. Unless otherwisespecified in the general and individual monographs,validation of an analytical procedure is not required.Implementation of Pharmacopoeial Procedures.When implementing a pharmacopoeial procedures, theuser must assess (verify) whether and to what extent thesuitability of the procedure under the actual conditionsof use needs to be demonstrated according to therelevant monographs, general chapters and qualitysystems. The assessment of the pharmacopoeialprocedure suitability and the extent thereof should becarried out in accordance with the requirements stated inGeneral Chapter Verification of PharmacopeiaProcedures.

5Conventional Terms. The term "competentauthority (organisation)" means the body (organisation)vested with the authority for making decisionsconcerning the issue of drug circulation.The expression "unless otherwise justified andauthorised" means that the monograph requirementshave to be met, unless the competent authorityauthorises a modification to or an exemption from theserequirements where justified in a particular case.In certain monographs or other texts, the term"suitable" and "appropriate" are used to describe areagent, micro-organism, test procedure, etc. If criteriafor suitability are not described in the monograph,suitability is demonstrated to the satisfaction of thecompetent authority.The following key terms and definitions are used inthe Pharmacopoeia.Medicinal product (drug) is any substance orcombination of substances that come into contact withthe human body and may be used in or administered tohuman beings with a view either to treating, preventing,or restoring, correcting, or modifying mmunological, or metabolic action or to making amedical diagnosis.Drug preparation means a drug in a dosage form.Dosage form is the state of the medicinal productcorresponding to the methods of its administration andapplication and ensuring the achievement of the desiredeffect.Substance for pharmaceutical use means asubstance intended for the production and manufactureof drug preparations.Active pharmaceutical ingredient is a substance forpharmaceutical use containing active ingredient(s) ofchemical, plant, animal, or human origin.Excipient (auxiliary substance) is any substance forpharmaceutical use that is not an active substance forthe given drug preparation and intended to create adosage form with specific properties.References to regulatory documents. Monographsand general chapters may contain references todocuments issued by regulatory authorities of theUnion. These references are provided for informationfor Pharmacopoeia users. Inclusion of such a referencedoes not modify the status of the documents referred to,which may be mandatory or for guidance.102000000-20191.2. Other Provisions Applying toGeneral Chapters and MonographsSubstance quantity. In tests with numerical limitsand quantitation procedures, the quantity stated to betaken for examination is approximate. The amount ofsubstance actually used, which may deviate by notgreater than 10% from that stated in the monograph, isaccurately weighed or measured and the result iscalculated from this exact quantity. In tests where thelimit is not numerical, but usually depends uponcomparison with the behavior of a reference substancein the same conditions, the quantity stated in themonograph is taken for examination. Reagents are usedin the prescribed amounts.Substance quantities are weighed or measured withaccuracy according to the indicated degree of precision.For weighings, the precision should correspond to 5units after the last figure stated (for example, theweighed amount of 0.25 g is to be interpreted as 0.245 gto 0.255 g). The measurement of volumes is carried outas follows. If the figure after the decimal point is 0 orends in 0 (for example, 10.0 mL or 0.50 mL), therequired volume is measured using a pipette, avolumetric flask, or a burette. Otherwise, a graduatedmeasuring cylinder or a graduated pipette may be used.Volumes stated in microlitres are measured using amicropipette or microsyringe.

6However, in certain cases, the precision with whichsubstance quantities are stated does not meet to thenumber of significant figures stated in a specifiednumerical limit. The weighings and measurements arethen carried out with a sufficiently improved e should comply with Class A requirements ofthe appropriate International Standard issued by theInternational Organisation for Standardisation (ISO). Itis allowed to use the volumetric apparatus of accuracyClass 1 according to the appropriate standard of amember state of the Union, provided that thereplacement of Class A volumetric glassware with thatof Class 1 does not increase the value of the extendeduncertainty of the test result.Unless otherwise prescribed in the monograph,analytical procedures are carried out at a temperaturebetween 15 C and 25 C.Unless otherwise prescribed in the monograph,comparative tests are carried out using identical tubes ofcolourless, transparent, neutral glass with a flat base; thevolumes of liquid prescribed are for use with tubeshaving an internal diameter of 16 mm; tubes with alarger internal diameter may be used provided thevolume of liquid used is adjusted (see chapter 2.1.1.5).Equal volumes of the liquids to be compared areexamined down the vertical axis of the tubes against awhite background, or if necessary against a blackbackground. The examination is carried out in diffuselight.Any solvent required in a test or quantitation inwhich an indicator is to be used is previouslyneutralised to the indicator unless a blank test isprescribed.Water Bath. The term "water bath" means a bathof boiling water unless water at another temperature isindicated in the monograph.Other methods of heating may be substitutedprovided the temperature is near to but not higher than100 C or the indicated temperature.Drying and ignition to constant mass. The terms"dried to constant mass" and "ignited to constant mass"mean that two consecutive weighings do not differ bygreater than 0.5 mg, the second weighing following anadditional period of drying or of ignition respectivelyappropriate to the nature and quantity of the residue tobe dried or ignited.Where drying is prescribed using a desiccator or invacuo, it is carried out using the conditions described inGeneral Chapter. Loss on drying.Reagents. The proper conduct of the analyticalprocedures described in the Pharmacopoeia and thereliability of the results depend, particularly, upon thequality of the reagents used. The specifications ofreagents are given in General Chapter Reagents. It isassumed that reagents of analytical grade are used, forsome reagents, tests to determine suitability are includedin the specifications.Solvents. Where the name of the solvent is notstated, the term "solution" implies an aqueous solution.The term "water" means purified water. Where theuse of water is specified or implied in the analyticalprocedures described in the Pharmacopoeia or for thepreparation of reagents, water complying with therequirements of the monograph Purified water is used,except that for many purposes the requirements forbacterial endotoxins (Purified water in bulk) andmicrobial contamination (Purified water in containers)are not relevant. The term "distilled water" indicatespurified water prepared by distillation.The term "ethanol" without qualification meansanhydrous ethanol. The term "alcohol" withoutqualification means 96% ethanol (V/V). Other dilutionsof ethanol are indicated by the term "ethanol" or"alcohol" followed by a statement of the percentage byvolume of ethanol (C2H6O) required.Expression of content. In defining content, theexpression "percent" is used according to circumstanceswith one of three meanings:

7- mass percent (m/m, mass in mass) expresses thequantity of grams of substance in 100 grams of the finalproduct;- volume percent (V/V, volume in volume)expresses the number of millilitres of substance in 100millilitres of the final product;- mass/volume percent (m/V, mass in volume)expresses the number of grams of substance in 100millilitres of the final product.The expression "parts per million" (or ppm)and "parts per billion" (or ppb) refers to mass in massunless otherwise specified in the monograph.Quantities of liquid substances and solutions usedin the preparation of mixtures can be expressed asvolume in volume (V/V).Temperature. Where an analytical proceduredescribes temperature without a figure, the generalterms used have the following meaning:In a deep-freezebelow -15 CIn a refrigeratorbetween 2 C and 8 CIn a cold/cool placebetween 8 C and15 CWarmbetween 40 C and50 CHotbetween 80 C and90 CWater bath temperaturefrom 98 C to 100 CIce bath temperature0 C103000000-20191.3. General Chapters and GeneralMonographsThe names of general chapters and generalmonographs are given in Russian. In some cases (forexample, in general monographs on drug dosage forms),additional names in Latin are allowed.General Chapters. General chapters of thePharmacopoeiamayincludeseveralgeneralmonographs grouped by types of objects of thestandardisation of the Pharmacopoeia, types of tests andtheir methods, the nature of requirements, etc. Forexample, general chapters may contain generalmonographs on physical and chemical test methods,biological test methods, packaging and packagingmaterials, reagents, etc.Generalmonographs.Substancesforpharmaceutical use, drug preparations, and other articlesthat are the subject of an individual monograph are alsorequired to comply with relevant general monographs.General monographs apply to all substances andpreparations within the scope of the Definition sectionof the general monograph, except where a preamblelimits the application, for example to substances andpreparations that are the subject of an individualmonograph of the Pharmacopoeia.General monographs on dosage forms apply to allpreparations of the type defined. The requirements arenot necessarily comprehensive for a given specificpreparation and requirements additional to thoseprescribed in the general monograph may be imposedby the competent authority.General monographs and individual monographsare complementary. If the requirements of a generalmonograph do not apply to a particular product, this isexpressly stated in the individual monograph.Packaging (containers). Materials used forcontainers are described in General ChapterPharmacopoeia of the Union. General names used forpackaging materials, particularly plastic materials, eachcover a range of products varying not only in theproperties of the principal constituent but also in theadditives used. The test procedures and limits formaterials depend on the formulation and are thereforeapplicable only for materials whose formulation iscovered by the preamble to the specification. The use ofmaterials with different formulations, and the testprocedures and limits applied to them, are subject toagreement by the competent authority.

8The specifications for containers in GeneralChapter Pharmacopoeia of the Union have beendeveloped for general application to containers of thestated category. However, in view of the wide variety ofcontainers available and possible new developments,the publication of a specification does not exclude theuse, in justified circumstances, of containers thatcomply with other specifications, subject to agreementby the competent authority.Reference may be made within the monographs ofthe Pharmacopoeia to the definitions and specificationsfor containers provided in chapter Packaging. Thegeneral monographs for pharmaceutical dosage formsmay, under the heading Definition and Production,require the use of certain types of container. Certainother monographs may, under the heading Storage,indicate the type of container that is recommended foruse.104000000-20191.4. MonographsA monograph may include the following sections.TITLESMonograph titles are in Russian and there are Latinand English subtitles.In the titles of monographs on substances forpharmaceutical use, the international nonproprietaryname (INN) is indicated, and in its absence, thegenerally accepted name of the active substance. Ifnecessary, it is supplemented with the name of the anionor cation and the degree of hydration.In the names of monographs on drug products, thedosage form is additionally indicated.RELATIVE ATOMIC AND MOLECULAR MASSESRelative atomic masses and relative molecularmasses are indicated in monographs on substances forpharmaceutical use.The relative atomic mass (Ar) or the relative molecularmass (Mr) is shown, as and where appropriate, at thebeginning of each monograph. The relative atomic andmolecular masses and the molecular and graphicformulae are given for information.CHEMICAL ABSTRACTS SERVICE (CAS)REGISTRY NUMBERSChemical abstracts service (CAS) registry numbersare included for information in individual monographs,where applicable, to provide convenient a

"Pharmacopoeia" may be used to indicate the Pharmacopoeia of the Union. The official texts of the Pharmacopoeia of the Union include general notices, general chapters, monographs, and annexes, which are published in Russian. Monograph is a document that sets out the requirements and statements of the Pharmacopoeia for