General monographs

Question 1

Considerations for solvents used in API

Answer 1

If solvents are used during production, they are of suitable quality. In addition, their toxicity and their residual level are taken into consideration. If water is used during production, it is of suitable quality.

Question 2

What is important for elemental impurities in API?

Answer 2

The identity of elemental impurities derived from intentionally added catalysts and reagents is known, and strategies for controlling them should be established using the principles of risk management.

Question 3

What are Nitrosamines and how should they be treated?

Answer 3

N-Nitrosamines As many N-nitrosamines are classified as probable human carcinogens, manufacturers of active substances for human use are expected to evaluate the potential risk of N-nitrosamine formation and contamination occurring throughout their manufacturing process and during storage. If the risk is confirmed, manufacturers should mitigate as much as possible the presence of N-nitrosamines – for example by modifying the manufacturing process – and a control strategy should be implemented to detect and control these impurities.

Question 4

API tests - polymorphism

Answer 4

If the nature of a crystalline or amorphous form imposes restrictions on its use in preparations, the nature of the specific crystalline or amorphous form is identified, its morphology is adequately controlled and its identity is stated on the label.

Question 5

API tests - related substances

Answer 5

Unless otherwise prescribed or justified and authorised, organic impurities in active substances are to be reported, identified wherever possible, and qualified.

Question 6

API tests - elemental impurities

Answer 6

Permitted daily exposures for elemental impurities (e.g. as included in the ICH Q3D guideline) apply to the medicinal product. Individual monographs on substances for pharmaceutical use therefore do not contain specifications for elemental impurities unless otherwise prescribed.

Question 7

API tests - residual solvents

Answer 7

Where a quantitative determination of a residual solvent is carried out and a test for loss on drying is not carried out, the content of residual solvent is taken into account for calculation of the assay content of the substance, the specific optical rotation and the specific absorbance.

Question 8

API tests - micro

Answer 8

Individual monographs give acceptance criteria for microbiological quality wherever such control is necessary. Depending on the nature of the substance and its intended use, different acceptance criteria may be justified.

Question 9

API tests - sterility

Answer 9

If intended for use in the manufacture of sterile dosage forms without a further appropriate sterilisation procedure, or if offered as sterile grade, the substance for pharmaceutical use complies with the test for sterility

Question 10

API tests - endotoxin

Answer 10

The substance for pharmaceutical use complies with the test for bacterial endotoxins if it is labelled as a bacterial endotoxin-free grade or if it is intended for use in the manufacture of parenteral preparations or preparations for irrigation without a further appropriate procedure for the removal of bacterial endotoxins.

Question 11

API tests - pyrogens

Answer 11

If the test for pyrogens is justified rather than the test for bacterial endotoxins and if a pyrogen-free grade is offered, the substance for pharmaceutical use complies with the test for pyrogens. The limit and analytical procedure are stated in the individual monograph or approved by the competent authority. Based on appropriate test validation for bacterial endotoxins and pyrogens, the test for bacterial endotoxins may replace the test for pyrogens.