A method for the determination of homogeneity (as well as resuspendability) of oral suspensions is described in the British Pharmacopoeia [2]. At first the suspension should settle, undisturbed, for 24 h. After shaking for 30 s 10 samples should be removed at a depth of 1 cm below the meniscus, while between every sample an additional 10 s shaking is performed. The sample size should match the usual dose unit. The doses are assessed individually according to the method specified in the individual monograph. The preparation complies with the test if each dose is between 85 % and 115 % of the average dose. The preparation fails to comply if more than one dose (out of 10) is outside these limits or if one individual dose is outside the limits of 75–125 % of the average dose.

Although, in practice, when dispersing solid substances with an ointment base several problems can arise (see Sect. 29.​3), the Ph. Eur. does not set quality requirements. At the design phase of a semisolid dosage form for cutaneous application in which an active substance is dispersed, the dispersion quality can be validated with, as in ‘dose unit’, an amount that approximately equals the minimal dose that is applied by the patient. After validation of the preparation method, the dispersion quality is usually monitored with an in-process control: spreading a sample between glass plates and controlling the absence of visible agglomerates.

The assessment methods and quality requirements for the microbiological purity of the finished products and raw materials have been harmonised worldwide since 2009.

The Ph. Eur. summarises the quality requirements for the microbiological purity of non-sterile preparations in monograph 5.1.4 ‘Microbiological quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use’. For raw materials quality requirements are described in individual monographs or in the general monograph ‘Substances for Pharmaceutical Use’.

Quality requirements regarding microbial enumeration tests and limit tests for specific microorganisms, see further Sect. 19.​6.​2.

For the methods of performing enumeration of microorganisms (TAMC and TYMC) see Sect. 19.​6.​3 and for specified micro-organisms see Sect. 19.​6.​4.

As part of the quality control of sterilised products the Ph. Eur. requires the performance of the test for sterility. The test for sterility as described in Ph. Eur. chapter 2.6.1 ‘Sterility’ is of relative value only, assuring only the actual units tested, see Sect. 19.​6.​1. In practice in some countries this can be replaced by validation of the sterilisation process or by validation of the aseptic method of preparation. For products with a short shelf life then it is not practical to obtain sterility testing results prior to product release and in these cases a parametric release process needs to be carried out. This process should consider all of the data available at the time of release, retrospectively obtained sterility testing results should be considered as part of the ongoing process validation. Process validation and end of session media transfer tests may be used in lieu of sterility testing where appropriate, for example where the final products are hazardous Sterile products with an extended shelf life, including those subjected to sterilisation and those made aseptically, should be subjected to a prospective sterility test and/or a batch specific media fill process validation. Parametric release may be carried out on condition that the competent authority has given approval. In the Dutch hospital pharmacy parametric release of sterilised preparations is a generally accepted by the professional group, in the UK it is generally only accepted where the product has a short shelf life. The conditions under which parametric release is carried out need to be well defined and controlled. The starting point for parametric release is the acknowledgement that tests and checks that are performed during the production process may give at least the same level of guarantee that the finished product corresponds to the specifications than when the finished product is tested, see also Sect. 34.​14.​1.

Quality requirements as to the effectiveness of the preservation are mainly relevant for preparations in dosage forms for multiple use. The Ph. Eur. thereby distinguishes preparations for parenteral and ophthalmic use, locally used preparations and oral preparations. The product has to undergo stress testing with various prescribed strains of micro-organisms. The quality requirements are defined as a decrease (or no increase) in populations at stated points in time. The Ph. Eur. describes in chapter 5.1.3 ‘Efficacy of antimicrobial preservation’ the determination methods of study. For effectiveness of preservation and minimal level of preservation, requirements are given. This differentiation is useful because some preparations are only marginally preserved. In those cases specific requirements are added to decrease the contamination risk, such as restricting the number of doses that can be removed or the in-use shelf life.

For dosage forms for parenteral administration the Ph. Eur. sets limits for bacterial endotoxins and pyrogens. For definition and difference see Sect. 19.​3.​4. Ph. Eur. chapter 2.6.14 ‘Bacterial endotoxins’ describes six different methods of which the LAL test (gel-clot-method) is the method of reference. On the condition that they are sufficiently validated the other methods may be used as an alternative to the gel-clot-method. See Sect. 19.​3.​4 for background information on these tests. Ph. Eur. describes an in-vivo test for the investigation of pyrogens in Ph. Eur. chapter 2.6.8 ‘Pyrogens’. This test is based on the measurement of the increase of body temperature of rabbits after intravenous administration of the substance to be analysed. Over the years this test is being replaced by the test for endotoxins, the LAL-test, with the exception of those products which interfere substantially with the LAL test.

Only a dissolved active substance can be absorbed in the bloodstream. To be able to dissolve the active substance first has to be released from the pharmaceutical form. The disintegration of oral dosage forms such as capsules and tablets and the disintegration of rectal and vaginal dosage forms such as suppositories are therefore important pharmaceutical parameters for the effectiveness of the medicine.

Ph. Eur. 2.9.1 ‘Disintegration of tablets and capsules’ describes the equipment and the method of analysis. The disintegration medium that has to be used as well as the quality requirements are specific for the dosage form and can be found in the appropriate monographs. The requirement for solid capsules is for example disintegration in water within 30 min.

For disintegration of suppositories the equipment and determination method are described in Ph. Eur. chapter 2.9.2 ‘Disintegration of suppositories and pessaries’. Fat suppositories have to melt within 30 min, water-soluble suppositories after 60 min.

These quality requirements are mainly tested in the design phase and probably repeated as a release control. Disintegration may however decrease on storage and hence it is recommended to include it in stability testing of the product. The quality requirements of the Ph. Eur. apply up to the expiry date.

Meeting the requirements for disintegration is a minimum condition for the release of the active substance from the dosage form. For solid dosage forms and dispersions (suspensions, most suppositories) the active substance still has to dissolve to be available for absorption (see Sect. 16.​1.​4).

The determination of the dissolution rate of the active substance from the dosage form is relevant for solid dosage forms and dispersions, especially when the substance is poorly soluble (see Sect. 16.​1.​4). Only dissolved substances are available for absorption. Ph. Eur. describes in chapter 2.9.3 ‘Dissolution test for solid dosage forms’ the equipment, the method of analysis and the interpretation of the determination of the dissolution rate of tablets and capsules. For suppositories it is described in Ph. Eur. chapter 2.9.42 ‘Dissolution test for lipophilic solid dosage forms’.

The general monographs for capsules, tablets and suppositories refer to the dissolution test when relevant. The Ph. Eur. describes for capsules and tablets different equipment, most important variants being the paddle-method and the basket-method. Next to these the flow-through-cell method is described, especially intended for the determination of the dissolution rate of poorly soluble substances.

With the paddle-method the product to be analysed is brought into a vessel with the prescribed dissolution medium, and mixing is performed by a blade attached to a shaft (the ‘paddle’).

With the basket method the product to be analysed is brought into a cylindrical basket that also provides the stirring.

The choice between both methods is to be made in the product design phase. Ideally these in vitro methods are meant to mimic the behaviour in the intestinal environment: in vivo. In practice the determination of the dissolution rate is meaningful as a tool in the design phase and as a means to monitor possible changes in (particle size of) raw materials and the production process. If changes are under control (no changes happen) then this test may not be required as part of the batch release specification.

The Ph. Eur. specifies (for information only and so not compulsory) that about the determination of the dissolution of a capsule or tablet the following points should be recorded: type of equipment; composition, volume and temperature of the dissolution medium, rotation speed, sampling times, sample volume and sampling method, method of analysis, acceptance criteria.

Ph. Eur. requires for conventional release preparations that the dissolved amount of active substance from every dosage unit after 45 min should be at least 80 % of the label claim. Other requirements apply to delayed-release and prolonged-release dosage forms.

Ph. Eur. doesn’t give requirements for specific medicinal products because it doesn’t describe products. The British Pharmacopoeia [2] and the United States Pharmacopoeia [3] describe dissolution rate requirements for almost all capsule and tablet products.

The British Pharmacopoeia [2] gives requirements for the dissolution rate of oral suspensions in the general monograph for ‘Unlicensed Medicines’. These quality requirements are similar to the advice of the Ph. Eur. for capsules and tablets. The dissolution rate of an oral suspension, being prepared in pharmacies for instance for patients with swallowing problems or for children, and how it compares to the comparable licensed oral dosage form, is an important consideration when designing such liquid medicines.

For the significance of the particle size of the raw material reference is made to Sect. 29.​2. For terminology and determination methods reference is made to Sect. 23.​1.​8.

The particle size is determined in the raw material. In the design phase the effective dispersion of agglomerates (see Sect. 29.​3) and possible particle growth during storage (see Sect. 18.​4.​2) have to be validated.

The Ph. Eur. sets quantitative requirements for the size of particles in finished products for suspension eye drops and eye ointments. Per 10 micrograms solid substance maximally 20 particles may be larger than 25 μm, maximally 2 particles larger than 50 μm and no particle larger than 90 μm. These quality requirements are valid until the expiry date.

For semisolid preparations with dispersed particles for dermatological use the Ph. Eur. specifies that care should be taken to control particle size to a suitable level during production. Also for liquid dosage forms with dispersed particles for oral use (oral suspensions) the Ph. Eur. gives an indication of controlled particle size.

The Ph. Eur. describes methods of analysis for the determination of visible and non-visible particles in parenteral dosage forms. Particles in parenterals, also called particulate contamination, consist of extraneous, mobile undissolved particles, other than gas bubbles, unintentionally present in the solutions. Because of their small mass and heterogeneous chemical composition they cannot be quantified with a chemical analysis method. Particles in parenterals can cause harm in patients, including phlebitis, emboli and granuloma formation.

Because most parenteral are made particle free by filtration through a membrane filter just before filling, the container has a relatively large influence on the final level of particles in the product. Anecdotally it appears from results of particle counting studies that infusions in glass usually contain more particles than those in plastic packaging materials. Also small units often contain more particles per unit volume than large ones [8–10].

For the determination of visible particles in parenteral dosage forms the Ph. Eur. describes a visual method under standardised conditions in chapter 2.9.20 ‘Particulate contamination: visible particles’. Here the background, the type and the intensity of the light source of the equipment are stated.

For the determination of sub-visible particles the Ph. Eur. describes two methods of analysis in chapter 2.9.19 ‘Particulate Contamination’. One method concerns the light obscuration particle count test and the second one the microscopic particle count test. The results of both methods are not always mutually comparable. For quantitative purposes the light block method is mainly used. The microscopic method can be used for viscous products or for those which are problematic in the light obscuration method

The light obscuration method is harmonised between the Ph. Eur., the United States Pharmacopoeia and the Japanese Pharmacopoeia, with regard to the equipment, the determination method, the number of units to be analysed and the quality requirements. For parenterals with a volume larger than 25 mL 10 separate units from a batch have to be counted. Parenterals with a volume smaller than 25 mL have to be combined to a minimal volume of 25 mL that will be counted.

The quality requirements are as follows:

In cases of small batches of product produced in pharmacies a random sample of 10 units can present a large proportion of the produced batch, meaning that quality control becomes very costly. The Ph. Eur. gives some latitude to use a smaller random sample than 10 units under certain conditions. With the aid of statistical analysis it is possible to derive the same level of quality assurance with a smaller sample size. Taking into consideration the uniformity/variability of the quantity of counted particles, the minimum sample size always has to be five units in order to achieve a sufficient level of assurance.

Particles that are unintentionally present are also relevant or ophthalmic preparations.

Only the Japanese Pharmacopoeia [4] and USP [3] set limits for levels of particles in eye drops. The Japanese Pharmacopoeia requires that eye drops after filtration and assessment with a microscope must have a maximum of 1 particle of 300 μm or larger per millilitre. The requirements of the USP are considerably stricter. Chapter 789 (Particulate matter in Ophthalmic Solutions) requires that maximally 50 particles of ≥10 μm and maximally 5 particles of ≥25 μm per mL eye drop fluid may be present. The method used is the light obscuration method.

The Ph. Eur. has set no specification, firstly because it is difficult to assess the risks posed by particles in eye drops. In general these risks are deemed to be very small to absent as is highlighted by the use of suspension eye drops. In Europe the United States specification is found to be too strict for all eye drops. According to reports the USP rationale is based on the concept that the acceptable particle load of ophthalmic preparations should be related to its use in a damaged eye or by means of an intravitreal or intracameral injection. In the latter case the presence of particles is considered totally unacceptable. However, there is no study that could be the basis of such a judgement.

Conversely the specification should consider what is practically achievable in the pharmaceutical industry with the so-called Blow-Fill-Seal (BFS) production process, cannot necessarily be extrapolated for the quality control of pharmacy made preparations. The USP requirement appears not to be based directly on the control of any apparent clinical risk. The USP standard leads to the monitoring of particle contents in BFS eye drops, performance of trend analysis and to investigate causes that lead to increased particle loads in that type of production process.

Physical tests including pH, relative density, optical rotation, refractive index, conductivity, viscosity and osmolality are generally used as in-process controls or as simple laboratory tests for the finished product.

pH requirements may be set for some medicines by the British, United States of Japanese Pharmacopoeia. If not a general rule is that the pH, in the case of a buffered system, is given to one decimal place and the limits for a preparation should be within ± 0.5 unit of the declared value. In practice a requirement immediately after release ± 0.1 unit is often achievable. However the requirement also has to cover the shelf life of the preparation. Values outside these limits could indicate a deviation of the declared composition or to significant product degradation.

Density requirements may also be set by the mentioned Pharmacopoeias, for the relative density of a liquid or solution. For alcoholic solutions such a requirement may be useful to determine whether the correct quality and the correct volume of ethanol have been used in the preparation process. The same is true for other preparations of which the density deviates strongly from water, for example because of the presence of dissolved substances. Preparations that, for example, contain a high percentage of sorbitol or glycerol are well characterised by their density and a determination of the density actually becomes an important identity criterion. The requirements for the relative density are not strictly defined, because the nature and amounts of the excipients may have a significant impact on the density of a product. As guidance a precision of maximally three decimal places may be appropriate, with limits of ± 0.020 unless there is practical information available that requires wider or stricter limits.

Optical rotation requirements may be found for some solution preparations.

This is a measure of the angle of rotation of plane polarised light and is often used as an identity criterion for certain materials, especially sugars. When these substances are present in a significant proportion in the final product and when few other excipients are present, the optical rotation can be used as a characteristic that gives quantitative information to the product concentration.

Refractive index is also generally used as identity criterion for various oils and sugars, but the technique can be used for multicomponent products such as parenteral nutrition solutions as well. In general the absolute scale is used for identification test purposes and the second sugar scale can be used for product analysis for either simple sugar solutions or complex mixtures.

A conductivity measurement is often used as a limit test, for example, when testing water for injection (see Sect. 27.​5.​2) but can also be used as part of the quality characteristics for other materials. The principle is to measure the resistance of a column of liquid in a conductivity cell. For water testing it is generally an in-process control.

The viscosity may be relevant for some pharmacy preparations, for example for gels or certain cutaneous liquids that have to be applied onto the scalp as well for eye drops especially those used for eye lubrication. A viscosity that is too low or too high may determine the therapeutic usability of a product. Similarly viscosity can be an important parameter for suspensions when viscosity should sufficiently high to reduce settling speed and sufficiently low to enable resuspendability. Hence a requirement for measurement of viscosity may be of added value to the quality or relevant products. For some products for example eye drops containing hypromellose the nominal viscosity should be stated on the label. Often viscosity is studied in the design phase of a formulation but it can also be used as a routine quality control test.

The osmotic value of a solution (see Sect. 18.​5) may be an important quality parameter for parenterals, but also for eye or nose drops which should, in principle, be isotonic. Values outside the physiologic limits point to a deviation in the declared composition. The osmolality will be studied in the design phase of the preparation and later often will only be checked as in-process control.

Medicinal plants are either cultured under controlled growing conditions, or collected from the wild under natural growing conditions (wild-crafted herbs).¹ Herbal raw material for herbal medicinal products is not referred to as a herbal active substance by the Ph. Eur. but as a herbal drug. Probably because it is not one ‘substance’ but usually is a mixture of plant material. The quality of herbal drugs as a raw material must be controlled according to pharmacopoeial standards. The Ph. Eur. includes as general monographs on herbals:

Quality-related problems are mostly associated with unregulated herbal drugs and include the (deliberate) inclusion of prohibited or restricted substances (e.g. admixture of synthetic actives, adulteration with toxic plants), contamination with toxic substances (e.g. heavy metals, residues) and incorrect declaration of constituents and content on the packaging labels.

The Ph. Eur. describes general methods of analysis to be applied to herbal drug products as well as more specifically dedicated methods (2.8. Methods in pharmacognosy). Identity tests must be specific for a particular herbal drug as adulterations and falsifications must be excluded. Macroscopic and microscopic evaluation and organoleptic assessment are important for the authentication of the botanical identity. In addition, simple chemical tests (colour reactions, precipitation reactions, chromatographic tests) are carried out. To assure a constant quality of the plant material and to compare different batches, analytical methods yielding a profile of the constituents are often applied. TLC-fingerprints are relatively easy to make and cheap, but GC- and HPLC-fingerprints are used as well.

Purity control of an herbal drug is not only relevant for the quality of a finished herbal medicinal product, but also for its safety. According to the Ph. Eur. herbal drugs are, as far as possible, free from impurities such as soil, dust, dirt and other contaminants such as fungal, insect and other animal contaminants and that they are not subject to decay.

Purity control limits contamination with pathogenic bacteria (Staphylococcus aureus, Escherichia coli, Salmonella-species, Pseudomonas aeruginosa, Clostridium-species and others), yeasts, moulds, microbial toxins (aflatoxins, endotoxins), toxic heavy metals (lead, cadmium, mercury, arsenic; e.g. from industrial emission), pesticide and herbicide residues, fumigants (ethylene oxide, methyl bromide, phosphine) and radionuclides. Furthermore, impurities with other plants parts (“foreign organic matter”) are limited. Moist levels must be below a certain maximum to avoid deterioration by microorganisms. Excreta of animals and dead insects must be absent. The ash value and acid-insoluble ash limits the amount of inorganic impurities (soil, sand).