What are the Requirements for Testing for Impurities in the Pharmaceutical Industry?

In the pharmaceutical industry, the handling of impurities, in particular the control via suitable analytical methods and the reporting requirements, is clearly regulated. The main requirements are set out in the ICH Q3A(R2) and ICH Q3B(R2) guidelines. Accordingly, the pharmaceutical manufacturer must meet the following requirements.

Reporting and control of degradation products

One of the key requirements stipulates that all degradation products observed during manufacture and stability testing must be systematically recorded and evaluated.

In particular, the following is required:

• the systematic recording of all relevant degradation products from manufacturing and storage
• the consideration of possible degradation pathways, including interactions with excipients and packaging materials
• the comparison of development and production batches to identify changes in the impurity profile
• the justification for exclusions (e.g. when impurities are not classified as degradation products)

A key component is the application of thresholds:

• Reporting threshold
• Identification threshold
• Qualification threshold

These thresholds depend on the maximum daily dose and define the point at which:

• a contaminant must be reported,
• must be structurally identified and
• must be toxicologically assessed.

Particularly important: All degradation products above the identification threshold must be identified, provided this is technically feasible.

In addition, the following are required:

• the development of specific analytical methods for potentially toxic impurities, even below the thresholds
• a scientific justification for alternative thresholds (e.g. in the case of specific manufacturing conditions)

Overall, this results in a risk-based approach in which patient safety and product quality are central.

Analytical methods

The requirements for analytical methods used to assess impurities are defined as follows:

All analytical methods must:

• be validated (in accordance with ICH Q2(R2)),
• be suitable for the intended purpose,
• be specifically selective/specific for degradation products, i.e. they must be capable of clearly distinguishing between
  - degradation products
  - active substance
  - process impurities
  - excipients
  clearly from one another.

Furthermore, the limit of quantification (LOQ) must be below or equal to the reporting threshold.

The following applies to documentation:

• All peaks in chromatograms must be identified and explained.
• Differences between development methods and commercial methods must be explained.

Overall, the ICH Q3B(R2) guideline requires sophisticated, robust and traceable analytical procedures as the basis for the control of impurities.