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calendary January 31, 2024

Related substances in the composition of drugs

Often in the specification of a regulatory document (ND) on quality you can find such a quality indicator as “Related substances”. What is this indicator? Why is it important and how is it standardized?

Related substances (e.g., precursor substances, certain degradation products) are variants of the molecular structure formed during manufacturing and/or storage that do not have properties comparable to the target product in terms of potency, efficacy, and safety. These impurities may be identified or unidentified.

The regulation of related substances is important due to their entry into the body and the ability of some of them to have a toxic effect on the human body. For example, N-nitrosamine compounds are potent genotoxic agents in mammals, and some of them are classified as probable human carcinogens.

Such compounds are formed, for example, when the storage conditions of ranitidine, a blocker of H₂-histamine receptors used to treat gastrointestinal diseases, in particular gastric ulcers, are violated.

Inclusion in the ND and standardization of the “Related substances” indicator should be carried out according to the following logic:

  1. If the active pharmaceutical ingredient is described in the State Pharmacopoeia of the Russian Federation, then control of impurities must be carried out in accordance with the pharmacopoeial monograph for the substance.
  2. In the absence of the monograph for a substance, the limits of control, identification and qualification of related substances are formed in accordance with the Pharmacopoeia General Monograph “Pharmaceutical Substances”, section “Related Substances” (Tables 1 and 2). In this case, the limits for the content of destruction products in the drug are calculated based on the maximum daily dose.

It is important to understand here that there are three “stages of control” and associated definitions regarding to related substances:

  1. Controlled limit - the limit above which an impurity must be controlled.
  2. Identification limit - the limit above which an impurity must be identified.
  3. Qualification limit – the limit above which the impurity must be qualified (i.e. its safety must be justified).

Depending on the concentration of the impurity in the drug, 1, 2 or 3 stages of control are carried out.

References:
  1. Decision of the Council of the Eurasian Economic Commission dated November 3, 2016 N 78 (as amended on October 20, 2023) “On the Rules for Registration and Examination of Medicines for Medical Use”
  2. https://doi.org/10.33380/2305-2066-2020-9-4-180-190
  3. https://pharmacopoeia.regmed.ru/pharmacopoeia/izdanie-15/1/1-1/rodstvennye-primesi-v-farmatsevticheskikh-substantsiyakh-i-lekarstvennykh-preparatakh/

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