18.3 Unrelated impurities in drug substances and drug products

18.3.1 Residual solvents

Levels of residual solvents in drug substances and derived drug products should be reduced as much as possible, and should meet product specifications, good manufacturing practices or other quality-based requirements.

The limits should comply with those in the EU/ICH guideline on residual solvents (Impurities: guideline for residual solvents ICHQ3C(R5) [EMA/CHMP/ICH/82260/2006]).

For residual solvents for which no ICH limit has been provided, permitted daily exposures can be calculated as outlined in the guideline, using adequate toxicological data.  These data should be generated using appropriate protocols, such as those described by:

• the Organisation for Economic Co-operation and Development (OECD)
• the United States Environmental Protection Agency
• the United States Food and Drug Administration (FDA) Redbook - Guidance for industry and other stakeholders – toxicological principles for the safety assessment of food ingredients.

18.3.2 Ethylene oxide and chlorohydrins

If the product or container is sterilised by treatment with ethylene oxide, the residue level for ethylene oxide and chlorohydrin should be controlled by the limits specified in the Committee for Proprietary Medicinal Products (CPMP)/ICH guideline on the use of ethylene oxide (Note for guidance on limitations to the use of ethylene oxide in the manufacture of medicinal products [CPMP/QWP/159/01]).

18.3.3 Metals

Residual metals used as process catalysts do not provide any therapeutic benefit and should therefore be restricted to meet safety-based and quality-based criteria.

The adopted guideline, Guideline on the specification limits for residues of metal catalysts or metal reagents (EMEA/CHMP/SWP/4446/2000), recommends maximum acceptable limits of metal residues (irrespective of their source) in drug substances and excipients. Guidance is also given on testing strategies, analytical procedures and reporting levels in excipients and drug substances.

18.3.4 Leachables and extractables

Chemicals leached from glass, plastic, metal or rubber components of medicine containers may cause adverse effects.

For applications to register a prescription medicine:

• identify the material, formulation code and manufacturer
• provide evidence of physicochemical and biological safety tests, and an assessment of the risks associated with patient exposure to the chemicals that may leach.

Where this evidence refers to a monograph of a recognised pharmacopoeia (e.g. United States Pharmacopeia (USP) <87>, Ph. Eur. 3.2.9):

• provide test certificates or reports to demonstrate compliance.

If a toxicological qualification of the leachables/extractables is required to be included in the dossier:

• provide full study reports or literature references.

18.3.5 Impurities in biological medicines

For biological medicines (biotechnology products), the residual level of process-related impurities and contaminants should be minimised and controlled.

Two components that should be considered for safety and tolerance reasons are residual host-cell deoxyribonucleic acid (DNA) and residual host-cell proteins.

18.3.5.1 Residual host-cell DNA

The level of cell-derived and plasmid-derived DNA should be not more than 10 ng per purified dose, in accordance with the recommendation from the World Health Organization (WHO) Expert Committee on Biological Standardization (Position statement on the use of tumourigenic cells of human origin for the production of biological and biotechnological medicinal products (CPMP/BWP/1143/00).

18.3.5.2 Residual host-cell protein

For biological medicines used chronically over a lifetime (e.g. human insulin, erythropoietin or factor VIII), the level of host-cell proteins should be not more than 10 parts per million.

For other biological medicines, the permissible level of host-cell proteins should be justified by:

• the minimum achievable level within methodological and statistical variation
• data from product manufactured for use in nonclinical and clinical studies.

A risk assessment of the effect of the proposed level may be required to justify the limit.

18.3.5.3 Other process-related impurities

The levels of other process-related impurities should be considered, as outlined in:

• Note for guidance on specifications: test procedures and acceptance criteria for biotechnological/biological products ICHQ6B (CPMP/ICH/365/96)
• Guideline on development, production, characterisation and specifications for monoclonal antibodies and related products (EMEA/CHMP/BWP/157653/2007).