More important pharmacopoeial norms

How to reconcile the endless variability of nature and the constant aspiration of people to standardise and classify something? It is possible with elegance. For some it is boring reading, and for some the awareness that behind every line there is learning from one’s own mistakes. One wonders why the European Pharmacopoeia is looking for an analysis of toxic cardiotonic glycosides in plantain? Which bureaucrat thought of that? And those who collect plants know how much beginners in picking plants can easily replace digitalis species with plantain. With fatal consequences.

Based on the accumulated knowledge, there are quality requirements for most medicinal plants and many preparations. If the preparation does not meet the quality requirement, it must not be used. 

There are a number of regulations, but the European Pharmacopoeia, which is issued bilingually (English and French), and regularly amended, is the main authority that dictates the quality requirements of herbal drugs and herbal preparations. The European Pharmacopoeia also provides very precise instructions on how to perform analytical techniques that confirm the quality. The content related to medicinal herbs can be divided into:

  • monographs of individual medicinal plants and/or plant extracts (e.g. chamomile flower, lemon fruit essential oil, arnica tincture, dry milk thistle extract)
  • general monographs for medicinal herbs and/or their extracts (e.g. herbal teas, tinctures, dry extracts)
  • general monographs for pharmaceutical forms (capsules, suppositories)
  • methods of analysis of medicinal plants (e.g. loss of water by drying, determination of ash, determination of tannins in drugs)

Unfortunately, most medicinal plants in Croatia do not meet the standards of the European Pharmacopoeia. The main problem is that each lot (batch) of medicinal herbs is often not analysed, and often not all analyses are performed according to the quality requirements of individual drugs. Often manufacturers perform only microbiological analyses, with no additional analyses required by the pharmacopoeia.

The reason for this is that most plants in our country are registered as food or food supplements, and the analysis of each lot of plants is not required, nor are the quality requirements in accordance with pharmacopoeial norms, i.e. they are not so rigorous. It is enough to establish health safety (most often microbiological safety, heavy metals and possibly pesticides), in order to comply with regulations.

There is considerable disagreement across the European Union about what is an herbal drug, what is an herbal medicine and what is a dietary supplement, but many more advanced countries such as France, Italy and Germany for herbal drugs accept quality criteria of either the European Pharmacopoeia or the National Pharmacopoeia, regardless of the purpose of the plant.

A good example is bearberry. The European Pharmacopoeia requires compliance with the requirements of the general standard for herbal teas, including in particular the examination of the microbiological load. However, the requirement of the pharmacopoeia is very clear: the plant must be tested for the content of anhydrous arbutine (which is the main active substance) and which must not be less than 7%, it is necessary to conduct macroscopic and microscopic identification and thin layer chromatography, and determine the content of foreign substances, leaves of a different colour from green, total ash, loss on drying. Only then can the plant be called by the pharmacopoeial name uvae ursi folium.

This is a message to everyone not to name products according to the pharmacopoeial name, without it being tested according to all the requirements of the pharmacopoeia.

In this part of the page you can view some important general monographs of medicinal plants, their preparations and extracts, and general monographs of pharmaceutical (medicinal) forms of plants and their extracts. The exact number of the monograph of the last, seventh edition (at the moment of writing this text) of the European Pharmacopoeia is given. Quality requirements for other individual medicinal plants can be found in individual monographs of medicinal herbs or essential oil.

It is very important to note that this is not a literal translation of the norm. Data are indicative only for quality requirements. Pharmacopoeia must be used for specific monographs.

Microbiological quality of herbal medicinal products for oral use 04/2010:50108


Microbiological testing of non-sterile products such as herbal medicinal products shall be performed in accordance with 2.6.12; 2.6.13 and 2.6.31 Ph Eur. TAMC (total number of aerobic bacteria) and TYMC (total number of yeasts and moulds) and other specific microorganisms are tested.

A) For herbal medicinal products containing only herbal drugs with or without excipients, which are prepared by hot water extraction methods (infusions and decoctions):

  • TAMC not more than 107 CFU/g maximum allowed number not more than 5×10 7 CFU/g
  • TYMC not more than 105 CFU/g maximum allowed number not more than 5×10 5 CFU/g
  • Escherichia coli not more than 103 CFU/g
  • Salmonella absence at 25

B) For herbal medicinal products containing herbal drugs and/or herbal extracts, with or without excipients, where the processing method (e.g. extraction) or pretreatment that reduces the number of microorganisms below the level specified in this category:

  • TAMC not more than 104 CFU/g or mL maximum allowable number not more than 5×104 CFU/g or mL
  • TYMC not more than 102 CFU/g or mL maximum allowable number not more than 5×102 CFU/g or mL
  • bile-tolerant microorganisms not more than 102 CFU/g or mL
  • Escherichia colia bsence in 1g or 1 mL
  • Salmonella absence in 25g or 25 mL

bakterijeC) For herbal medicinal products containing herbal drugs and/or herbal extracts, with or without excipients, where it can prove that the processing method (e.g. extraction with low percent ethanol or non-boiling water or concentration at low temperature) or in the case of herbal drugs, pretreatment which does not sufficiently reduce the number of microorganisms to achieve criterion B:

  • TAMC not more than 105 CFU/g or mL maximum allowable number not more than 5×105 CFU/g or mL
  • TYMC not more than 104 CFU/g or mL maximum permitted number not more than 5×104 CFU/g or mL
  • bile-tolerant microorganisms not more than 104 CFU/g or mL
  • Escherichia coli absence in 1g or 1 mL
  • Salmonella absence in 25g or 25 mL

Exceptionally for drugs/preparations where the stated limits cannot be achieved, other criteria can be determined by risk assessment.

Microbiological quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use 01/2011: 50104


The manufacturer must be aware that microbiological contamination can affect the therapeutic activity of the drug, and cause unwanted side effects. Therefore, individual forms must be tested by the microbiological techniques described in 2.6.12. and 2.6.13. For individual forms, the maximum acceptable number is shown in the following table:

Method of drug administrationTAMCTYMCIndividual microorganisms/Absence
Dry oral forms103102Escherichia coli/1g or 1 mL
Aqueous oral forms102103Escherichia coli/1g or 1 mL
Rectal use 103102-
Mucosa of the mouth, gingiva, skin, nose, ear 102101Staphylococcus aureus/1g or 1 mL
Pseudomonas aeruginosa/1g or 1 mL
Vaginally 102101Staphylococcus aureus/1g or 1 mL
Pseudomonas aeruginosa/1g or 1 mL
Candida albicans/1g or 1 mL
Transdermal102101Pseudomonas aeruginosa/1g or 1 mL
Inhalation102101Staphylococcus aureus/1g or 1 mL
Pseudomonas aeruginosa/1g or 1 mL
bile tolerant G(-)/1g or 1 mL
Special for oral forms * 104102bile tolerant G(-)/1g or 1 mL**
Escherichia coli/1g or 1 mL
Staphylococcus aureus/1g or 1 mL
Salmonella/10g or 10 mL

* for oral forms containing raw materials of mineral, vegetable or animal origin, for which antibacterial pretreatment is not possible and for which the competent authority accepts a TAMC greater than 103
** no more than 102

Plantae ad ptisanam– Herbal teas 01/2013:1435

According to the definition, herbal teas are one or more mixed herbs, intended for oral aqueous preparations that are prepared just before use.

  • Individual components must correspond to individual drug monographs, and in the absence of a specific monograph they must correspond to Ph Eur 01/2012:1433 Plantae medicinales.
  • The identity must be carried out in accordance with the requirements of the monographs.
  • Microbiological quality must comply with Ph Eur 04/2010:50108 Microbiological quality of herbal medicinal products for oral use.
  • Mass uniformity is performed by testing 20 randomly selected packages. A maximum of two units of twenty may deviate from the permissible percentage deviation of the average (declared) mass, and the deviation of these two units may not exceed the permitted percentage of deviation more than twice. Tolerances are: 15% for a unit weight of less than 1.5g; 10% for 1.5-2.0 and 7.5% for units weighing more than 2.0grams.

Praeparationes celeres ad ptisanam– Instant teas 01/2013:2620

Instant teas consist of one or more herbal preparations (mainly extracts with or without added essential oils), and are intended for oral aqueous preparations that are prepared just before use. They may contain excipients or added flavours. They are in the form of powder or granules, as larger packages or smaller dosage units. They are in accordance with the monographs Plantae medicinales praeparatae 07/2010:1434, Extracta 04/2008:0765 and Aetherolea 01/2008:2098.

  • The identity must be carried out in accordance with the requirements of the monographs.
  • Microbiological quality must comply with Ph Eur 04/2010:50108 Microbiological quality of herbal medicinal products for oral use.
  • Mass uniformity is performed by testing 20 randomly selected packages. A maximum of two units of twenty may deviate from the permissible percentage of deviation of the average (declared) mass, and the deviation of these two units must not exceed the permitted percentage of deviation by more than twice. Tolerances are: 15% for a unit weight of less than 1.5g; 10% for 1.5-2.0 and 7.5% for units weighing more than 2.0 grams.

Plantae medicinalis praeparatae– Herbal preparations 07/2010:1434

Herbal preparations are homogeneous products obtained by subjecting medicinal drugs to processes such as extraction, pressing, distillation, fractionation, purification, concentration or fermentation. Examples are extracts, essential oils, pressed juices, processed exudates, or herbal drugs themselves subjected to size reduction for a specific application.

Herbal teas must comply with the monograph Herbal teas 01/2013:1435.

Plantae medicinales– Herbal Drugs 01/2012:1433

Herbal drugs are mostly whole, fragmented (or broken), parts of plants, algae, fungi, and lichens, in unprocessed form, usually in dry but sometimes in fresh form. Certain exudates that have not undergone specific treatment are also considered herbal drugs. Herbal drugs are defined by a botanical scientific name according to the binomial system (genus, species, variety, author).

Whole signifies herbal drug that is not reduced in size, but is presented dry or undried, as collected, for example pomegranate, bitter or sweet fennel, Roman chamomile flower.

Shredded signifies that the herbal drug is reduced in size after harvest to facilitate handling, drying and/or packaging, such as rhubarb or passionflower.

Broken signifies herbal drug in which the more fragile parts have been broken during drying, packaging or transport (deadly nightshade leaf, chamomile flower, hop strobilus).

Cut signifies herbal drug that has been reduced in size by means other than by pulverisation, to the extent that the macroscopic identification described in the monographs can no longer be performed. When a plant is cut for specific use which results in homogenous herbal drug, for example for herbal teas, it then becomes a herbal drug preparation. A herbal drug complying with the requirements of a specific monograph and cut for the extraction process shall be compliant with its monograph except for macroscopic identification, unless a deviation from that rule is justified.

A herbal drug is obtained from cultivated or wild plant. Quality is defined by the process of collection, cultivation, harvesting, drying, shredding and storage conditions. It must be free of impurities, as far as possible, of soil, dust, dirt and contaminants such as fungi, insects and other animals. The plant must not be rotten.

If decontamination is carried out, it is necessary to prove that the plant ingredients have been preserved and that there are no harmful residues. The use of ethylene oxide is prohibited.

The plant must be:

  • Macroscopically and microscopically identified according to the monograph, and if necessary using other tests (for example thin layer chromatography)
  • Foreign substance according to 2.8.2. Unless otherwise prescribed, it must not contain more than 2% foreign matter.
  • Loss by drying according to 2.2.32.
  • Water in accordance with 2.2.13. if the drying loss is not reliable (plants rich in essential oils).
  • Pesticides according to 2.8.13. It must comply with the request.
  • Heavy metals according to 2.4.27, cadmium maximum 1.0 pp; lead maximum 5.0 ppm; mercury maximum 0.1 ppm.

If necessary, other important tests are performed:

  • Total ash according to 2.4.16.
  • Ash insoluble in hydrochloric acid according to 2.8.1.
  • Extractable substances.
  • Swelling index according to 2.8.4.
  • Bitterness index according to 2.8.15.
  • Aflatoxin B1 according to 2.8.18.
  • Ochratoxin A according to 2.8.22.
  • Radioactive contamination.
  • Microbiological contamination according to 5.1.8, or according to 5.1.4 (e.g. for skin use).

Extracta– Extracts 04/2008:0765

Extracts can be liquid (liquid extracts and tinctures), semi-solid (soft extracts and oleoresins) or solid (dry extracts), which are obtained from herbal medicines or animal substances, usually dry.

kvasciLabelling:

  • used herbal drugs or animal material
  • whether the extract is liquid, soft or dry, and whether it is a tincture
  • for standardised extracts, content of ingredients with known therapeutic properties
  • for quantified extracts, the content of ingredients (markers) used for quantification
  • ratio of initial and original extract (extract without excipients)
  • solvent or solvents used in the extraction
  • where applicable, state that the plant or animal substance is fresh
  • where applicable, state that the extract is purified
  • name and amount of excipient including stabilisations and antimicrobial preservatives
  • where applicable, percentage of dry residue

Extracta fluida– Liquid extracts

Liquid extracts are liquid preparations which are usually by one part mass and volume equivalent to one part of mass or volume of dry plant or animal substance. If necessary, they can be adjusted to suit the solvent or contents. They are obtained with ethanol of a certain concentration or with water, by the process of extraction of a plant or animal substance, or by dissolving a soft or dry extract (and which is obtained with a solvent of the same concentration as the solvent concentration for dry extract production). They can be filtered if necessary. A smaller precipitate may appear during standing, which is acceptable if the composition of the liquid extract has not changed.

Tests:

  • Relative density according to 2.2.5.
  • Ethanol for ethanol extracts according to 2.9.10.
  • Methanol and 2-propanol for alcoholic extracts according to 2.9.11, not more than 0,05% V/V for both solvents.
  • Dry residue according to 2.8.16.

Labelling, with the required labelling and ethanol content, if any, in V/V.

Tincturae– Tinctures

Tinctures are liquid extracts that are usually obtained using 1 part herbal drug or animal substance with 5 or 10 parts solvent. They are produced by maceration or percolation. For tinctures the following is examined:

  • Relative density according to 2.2.5.
  • Ethanol for ethanol extracts according to 2.9.10.
  • Methanol and 2-propanol for alcoholic extracts according to 2.9.11, not more than 0,05% V/V for both solvents.
  • Dry residue according to 2.8.16.

Tinctures are denoted by the ratio of starting material and solvent, or the ratio of starting material and tincture, and the percentage of ethanol in the final tincture.

Extracta spissa– Soft extracts

Soft extracts are semi-solid preparations obtained by complete or partial evaporation of the solvent used in the extraction. For soft extracts it is sufficient to determine:

  • Dry residue according to 2.8.16.
  • Residual solvents according to 5.4.

Oleoresina– Oleoresins

Oleoresins are semi-solid extracts consisting of a resin in solution with essential and/or vegetable oil and obtained by evaporating the solvents used to produce them. The monograph does NOT refer to natural oleoresins, but only to those obtained by extraction. For oleoresins the following is determined:

  • Water according to 2.2.13.
  • Residual solvents according to 5.4

Extracta sicca– Dry extracts

Dry extracts are solid preparations obtained by evaporating the solvent used for extraction. Dry extracts have no loss by drying greater than 5% m/m, unless otherwise specified in the monograph. For dry extracts the following is determined:

  • Water according to 2.2.13.
  • Dry residue according to 2.8.17.
  • Residual solvents according to 5.4.

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