technical_guide_for_the_elaboration_of_monographs_7th_editio(6)

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Method I only requires 2 mL of solution but is seldom prescribed except for substances that give highly coloured solutions;

Method II, which is more discriminating and therefore more frequently used, requires the larger volume of solution employed for the clarity test.

The results given by these 2 methods do not necessarily coincide so the one to be used is specified in the monograph.

The solution is described as colourless when it is less coloured than reference solution B9. When the solution is slightly coloured, the appropriate reference solution is given. When the shade of colour varies according to the samples, 2 or more reference solutions of the same degree of colour may be mentioned, or even only the degree of coloration without specifying the actual colour.

For material intended for parenteral use and for highly coloured solutions, especially when the use of Method I is contemplated, it is preferable to apply a limit of absorbance measured with a spectrophotometer at a suitable wavelength (usually between 400 nm and 450 nm). The concentration of the solution and the limit of absorbance must be stated. The conditions and limit must be based on knowledge of the absorbance curve in the range of 400 nm to 450 nm and on results obtained with appropriate samples, including stored and degraded samples, as necessary.

II.5.5. pH and Acidity or alkalinity

This test allows the limitation of acidic or alkaline impurities stemming from the method of preparation or purification or arising from degradation (e.g. from inappropriate storage) of the substance. The test may also be used to verify the stoichiometric composition of certain salts. Two types of test for protolytic impurities are used in the Ph. Eur.: a semi-quantitative titration experiment using indicators or electrometric methods to define the limits, the Acidity or alkalinity test; or a pH measurement.

pH measurement is included if the material has buffering properties, otherwise a titrimetric procedure is recommended.

The question of whether to prescribe an Acidity or alkalinity test or a pH measurement in a pharmacopoeial monograph can be decided on the basis of an estimation of the buffering properties of the material. To this end, a titration curve can be constructed for an aqueous solution (or, if necessary, an extract) in the intended concentration (10 to 50 g/L) of a specimen, preferably pure, of the substance to be examined, using 0.01 M hydrochloric acid and 0.01 M sodium hydroxide, respectively, and potentiometric pH measurement.

The inflexion point of the titration curve is the true pH of the solution and will, for a pure substance, be at the point of intersection with the pH-axis. The measure of the buffering capacity of the solution to be examined is the total shift in pH, (?pH), read from the titration curve as the result of adding on the one hand 0.25 mL of 0.01 M sodium hydroxide to 10 mL of the solution, and on the other hand 0.25 mL of 0.01 M hydrochloric acid to another 10 mL portion of the same solution. The buffering capacity is inversely proportional to the ?pH. For a sample that is not quite pure, carry out a parallel displacement of the titration curve so that the true pH of the solution is on the pH-axis before the ?pH is read from the curve.

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The magnitude of ?pH of the solution to be examined determines the choice of method for the limitation of protolytic impurities according to the following scheme. The classification is based upon the observation that the colour change for most indicators takes place over a pH range of 2 units.

Class A Class B Class C

?pH > 4 4 > ?pH > 2 2 > ?pH > 0.2

Acidity-alkalinity test utilising 2 appropriate indicators. Acidity-alkalinity test utilising a single appropriate indicator. Direct pH measurement.

The protolytic purity cannot be reasonably controlled. Substances that are salts consisting of ions with more than 1 acidic and/or basic function belong to this class and for these a pH measurement can contribute to ensuring the intended composition if the limits are sufficiently narrow.

Class D ?pH < 0.2

It is evident that by changing the concentration of the solution to be examined, the class of buffering properties as set out above into which the substance will fall can to some extent be altered, since the shape of the titration curve will then also be modified. The concentration range given above is not to be exceeded however, unless poor water solubility makes it unavoidable to use a more dilute solution.

In certain cases a test for acidity-alkalinity cannot be performed with the use of indicators due to coloration of the solution to be examined or other complications, and the limits are then controlled electrometrically. If on the other hand, the addition of standard acid/or base results in decomposition or precipitation of the substance to be examined, it may be necessary to prescribe a pH test regardless of the buffering properties.

If, for special reasons, as mentioned above, a pH measurement has to be prescribed for solutions with little or no buffering capacity, the solution to be examined is prepared with carbon dioxide-free water R. Conversely, the use of carbon dioxide-free water R for preparing solutions that have sufficient buffering capacity to warrant a direct pH measurement is not necessary since the required accuracy, which seldom exceeds 1/10th of a pH unit, will not be affected. When an acidity requirement corresponds to not more than 0.1 mL of 0.01 M sodium hydroxide per 10 mL of solution to be examined, the latter must be prepared using carbon dioxide-free water R. These considerations are to be borne in mind when prescribing the composition of solution S if it is to be used in a test for protolytic impurities.

II.5.6. Optical rotation (2.2.7.)

The optical rotation test, though sometimes useful for identification purposes, is mainly used as a purity test:

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either to assess the general purity of an optically active substance (a liquid or a solid in solution), by calculating the “Specific optical rotation” (title of the test);

or to limit the presence of optically active impurities in any optically inactive substance (racemate or racemic mixtures), provided that the specific optical rotation at 589.3 nm is sufficient to ensure adequate sensitivity. In this case the range normally given should be ? 0.10° to + 0.10° (covering the substances that are not true racemates). In this case the “Angle of rotation” (title of the test) of the liquid or of a solution of the solid, is

measured under defined conditions.

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It is usually more appropriate to control these impurities by chiral separation methods since the specific optical rotation is often insufficient to limit the presence of the unwanted enantiomer (distomer) in the presence of the active enantiomer (eutomer).

The test is not suitable for highly coloured or opalescent solutions (in the latter case a filtration can sometimes make the determination possible). The following aspects are taken into account in describing the test:

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the solvent, which depends on the solubility of the substance to be examined and the rotatory power in that solvent. In the case of non-aqueous solvents, their purity and especially their contents of water must often be carefully defined;

the concentration of the solution: it must be high enough to give a reliable reading of the angle of rotation;

the quantity of substance to be used, determined with sufficient accuracy (generally 1 %), as is also the volume to be obtained (given with 1 decimal figure);

the volume required which depends on the apparatus used, but since it rarely exceeds 25.0 mL, that volume is usually prescribed;

the degree of hydration or organic solvation of the substance must be taken into account in calculating the result;

the result is the mean of at least 5 measurements when evaluated visually, with an apparatus giving readings to the nearest 0.01°;

measured angles of rotation (rarely more than 2°) are given to 2 decimal places;

specific optical rotation values are given with 2 or 3 significant figures. Values less than 10 are given to 2 significant figures, while values of 10 and over are given to 3 significant figures;

composition limit for racemates or racemic mixture.

? ? ? ? ? ? ?

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The value of the optical rotation is calculated with reference to the dried or anhydrous substance

II.5.7. Absorption spectrophotometry (ultraviolet and visible) (2.2.25.)

The absorption of electromagnetic radiation may be used in purity tests as a limit test for certain impurities. The typical case is that of impurities that absorb in a region where the substance to be examined is transparent. It is then the absorbance of a solution of the substance to be examined that is measured. This test may be performed in the following ways:

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by direct measurement on the solution, where the absorbance measured is a maximum absorbance at a given wavelength, or over a wavelength range;

after carrying out a chemical reaction that forms, with the impurity, a substance that absorbs at a wavelength where the substance to be examined is transparent, a maximum value at the given wavelength being prescribed.

For measurements in the ultraviolet, it is advisable not to measure below 230 nm.

It is important to describe precisely the operational conditions to be observed, in particular the preparation of those solutions that are prepared by successive dilutions.

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II.5.8. Related substances

The policy on control of impurities is described in general chapter 5.10. Control of impurities in substances for pharmaceutical use and in the general monograph Substances for pharmaceutical use (2034). Monographs should be elaborated accordingly. Monographs are designed to take account of substances used in approved medicinal products in Member States and should provide adequate control of all impurities occurring in these substances, insofar as the necessary information and samples (substance and impurities) are available from the producers. Where the required information and samples are not provided for a substance synthesised by a given method, the monograph will not necessarily cover the corresponding impurity profile.

The provisions for related substances of the general monograph Substances for pharmaceutical use (2034) apply to all active substances covered by a Ph. Eur. monograph, unless otherwise stated. The following are given as exceptions in the general monograph: biological and biotechnological products, peptides, oligonucleotides, radiopharmaceuticals, products of fermentation and semi-synthetic products derived therefrom, to crude products of animal or plant origin or herbal products.

If an exception is to be made for some other substance, the following statement is included in the specific monograph: “The thresholds indicated under Related substances (Table 2034.-1) in the general monograph Substances for pharmaceutical use (2034) do not apply.” Monographs should include acceptance criteria for:

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each specified impurity;

unspecified impurities (previously referred to as “any other impurities”), normally set at the identification threshold; the total of impurities.

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Impurities to be controlled include: intermediates and by-products of synthesis, co-extracted substances in products of natural origin, degradation products. Monographs on organic chemicals usually have a test entitled “Related substances” (or a test with equivalent purpose under a different title), designed to control organic impurities. Inorganic impurities are usually covered, where applicable, by other tests. Residual solvents are covered by specific provisions [see below and in general chapter 5.4. Control of residual solvents and general monograph Substances for pharmaceutical use (2034)].

Genotoxic impurities. Based on the EMA Committee for medicinal products for human use (CHMP) Guideline on the limits of genotoxic impurities (CPMP/SWP/5199/02, EMEA/CHMP/QWP/251344/2006), the following pragmatic approach should be followed when elaborating or revising monographs. New monographs should be based on an evaluation for the presence of potentially genotoxic impurities (PGIs) during marketing authorisation according to the principles of the CHMP guideline or similar evaluation principles for non-EU member states. For active substances included in medicinal products authorised by the competent authorities before application of the CHMP guideline, the specifications as described in the dossier for marketing authorisation should be followed. Action is needed only where there is study data demonstrating genotoxicity of the impurity. The existence of structural alerts alone is considered insufficient to trigger follow-up measures. If a new synthetic route is used that may give rise to different PGIs or to higher levels of previously recognised PGIs then the evaluation by a

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Competent Authority should be used as the basis for the PGI in question.

Where an issue concerning a PGI is raised by a Competent Authority (notably for revision of a monograph or in comments on a Pharmeuropa draft), this will be dealt with on the basis of data provided to the European Pharmacopoeia Commission by the Competent Authority.

The policy described applies to substances for human use. Where a substance is used in veterinary medicine, the Competent Authority will decide for each particular case the requirements to be applied for PGIs.

The table shown below gives an outline of some common situations faced by groups of experts and suggested action.

Decision table for use during elaboration or revision of monographs

Status Action Substance included in a medicinal product authorised after application of the Monograph should be based on marketing authorisation(s). CHMP guideline*.

Substance included in a medicinal product authorised before application of No action needed, monograph based on marketing authorisation. the CHMP guideline*:

?

no PGI expected from synthetic route.

Substance included in a medicinal product authorised before application of No action needed during elaboration of monograph (based on the CHMP guideline*: marketing authorisation), no revision of existing monographs.

?

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PGI expected from synthetic route of 1st authorised product and subsequently authorised products (if any) have no expected PGI or same PGI as the 1st authorised product at same or lower level and no data showing genotoxicity.

Substance included in a medicinal product authorised before application of Monograph should be elaborated or revised based on evaluation the CHMP guideline*: by the Competent Authority.

?

?

PGI expected from synthetic route of an authorised product and data showing genotoxicity of an expected PGI.

Substance included in a medicinal product authorised before application of Monograph should be elaborated or revised based on evaluation the CHMP guideline*: of new PGI or high level of previously known PGI by the Competent Authority.

? PGI expected from synthetic route of 1st authorised product, and ? subsequently authorised products have a new expected PGI or same PGI as 1st authorised product at a higher level and ? data showing genotoxicity of an expected PGI. Substance included in a medicinal product authorised before issuance of the Monograph should be elaborated or revised based on evaluation CHMP guideline*: of new PGI by the Competent Authority.

? ?

?

PGI not expected from synthetic route of 1st authorised product, and

subsequently authorised product(s) have a new expected PGI and data showing genotoxicity of an expected PGI.

* or similar evaluation principles for non-EU member states

It should be noted that as of 1 January 2016 the new ICH guideline M7 assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk (EMA/CHMP/ICH/83812/2013) will enter into force and replace the current EMA guideline. Control of impurities. The most common and preferred method for control of organic impurities is LC; GC or CE may be the preferred method in some instances. Although there are still some monographs applying thin-layer chromatography, in the future this method should be reserved for

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