Standards and reference substances

 

Standards and reference substances play a central role in evaluating the quality of active pharmaceutical ingredients and finished products. These substances are used as anchor points and must therefore be handled and established with great care.

14.C.1 Definition of different standards and their areas of use

In (FDA, 1987) the FDA defines Reference standards as a particular lot or batch of an active pharmaceutical ingredient, which was specifically prepared either by independent synthesis or by additional purification of production material. A extensive set of analytical testst must then prove that the material is authentic and shows the highest purity reasonably attainable. Reference standards are normally used for structure elucidation and is the benchmark for working standards.

The FDA then proceeds to define (FDA, 1987) the working standard as an active pharmaceutical ingredient of established quality and purity, by comparison to the reference standard. The material is routinely used in the laboratory for analysing production batches of active pharmaceutical ingredients and drug products. A regular (e.g. annual) comparison with the reference standard will be necessary.

The pharmacopoeias use various terms. The figure 14.C-1 summarises these terms for the most important pharmacopoeias.

The pharmacopoeias specify that the CRS/BRS are only defined for the purpose stated in the monograph and that no guarantee can be made regarding further use.

For anorganic substances (e.g. for heavy metal determinations) the IUPAC has undertaken a further classification which is summarised in figure 14.C-2.

The procedure for characterising and establishing a new standard is set out in the Pharm. Eur. example (see figure 14.C-3). The manufacturer shall provide a sufficient quantity of the active pharmaceutical ingredient. More laboratories can be included depending on the test.

The same procedure can also be selected when defining a new primary standard (e.g. in the development phase). It must, however, be considered that impurities are calculated only once. If, for example, Toluol is defined as a residual solvent using GC, it should be ensured during the HPLC analysis that the Toluol peak value has not been integrated again. This also applies to anorganic impurities. When the assay was determined using two independent methods (e.g. HPLC and titration) and varying results were obtained, must also be clearly specified how to proceed.

Pharmacopoeia standards can be sourced directly. The most important addresses are listed in figure 14.C-4.

14.C.2 Handling, storage and stability

The handling of standards and reference substances must be established (in an SOP). The procedure to be applied for storage, monitoring and distribution must be set out (in this SOP). The responsible persons, who must be specially trained, should also be specified. Correct handling shall include, for example, withdrawal documentation, cleanliness and tempering (e.g. 30 minutes) of cooled standards.

Furthermore, it must also be specified whether or not the standard must first be dried before use, whether the loss on drying must be redetermined or if a different procedure is appropriate. Finally, the value (purity factor, content) chosen for the calculations must be specified.

The official pharmacopoeia standards may only be used for the purpose set out in the monograph. Since these standards are not only expensive but also supplied in small quantities only, making them sufficient for normally just one application, cleanliness and resourcefulness must be assured at all times. It is therefore advisable to use working standards (see chapter 14.C.1 Definition of different standards and their areas of use).

The regulations for storage of standards and reference substances vary according to the company. Some companies store all standards and reference substances in deep freezers, others go by the sensitivity of the substances and store them in a deep freezer, a refrigerator or under controlled conditions (temperature and humidity) and in special rooms. Practice has shown that it is best to pack the standards in small portions in suitable, individually labelled containers (vials).

The pharamcopoeias generally do not provide information on the handling of standards. Neither the USP nor the WHO give any information on stability. For Pharm. Eur. CRS no expiration date is specified, but an expiry date 6 months after receipt is assumed (if the product remains unopened). Once this date has expired, Pharm. Eur. should be consulted.

Different guidelines apply according to the company for primary standards (including in-house primary standards).

One guideline instructs as follows:

• 2 years uninterrupted upon receipt
• 1 year after opening
• a maximum of 2 further years once further tests have been carried out

Another procedure is regulated as follows:

• 5 years initially
• after annual inspections until the batch is used up

For working standards there are no specifications on maximum expiration dates. Quality is guaranteed through regular (e.g. annual) checks against the reference standard, provided that the deviations are kept within a defined range (e.g. maximum 2% deviation). The methods (selective) which are used for the checks and which are tailored to the type of working standard must be specified. For ampoule solutions, a content and purity determination is normally sufficient. For solid standards, a determination of the loss on drying is also recommended.

For company-made standards and reference substances all the details listed in figure 14.C-5 must be available: