Regulatory requirements for quality risk management

The risk-based approach of all facilities, procedures, and processes used in the production of medicinal products is a globally central GMP requirement and an important component of quality risk management. The EU GMP guidelines, taking into account ICH Q9, apply to all member states of the European Union and the UK. In addition, Annex 11 and GAMP 5 regulate the requirements for IT security. This means that risk assessments must be carried out for your equipment, cleaning procedures, starting materials, transport, manufacturing processes, quality control, quality assurance procedures, as well as for computer-based systems and, of course, product specifications.

Our experts have carried out highly successful risk-based qualification and validation of plants and processes in the pharmaceutical industry for many years and prepare risk analyses on a daily base.

Based on the complete documentation, we prepare risk analyses using FMEA (Failure Mode and Effects Analysis). All GMP-relevant critical components of the plant and process steps, possible sources of error and their risks are described and critical process steps for product quality and process stability are identified.

We define necessary steps and actions for qualification and validation and summarize them in a risk analysis report. If required, we can use this report as the basis for a risk analysis workshop to discuss the relevant quality and process aspects with your responsible specialists.

Of course, other well established risk-assessment procedures can also be used, such as brainstorming, the Ishikawa diagram, or a hazard analysis according to Hazard Analysis Critical Control Points (HACCP).

In 2018, nitrosamine contaminants were found in several antihypertensive medicines. As a result, EU regulators recalled medicines and banned the use of active ingredients from certain manufacturers.

To ensure the quality of medicines and protect patients, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) requires companies to develop control strategies to ensure that nitrosamines are not present or below the permitted limits.

This example shows the importance of a risk-based specification definition as a basis for developing an appropriate control strategy. It also shows that an incorrectly or incompletely performed risk analysis can lead to significant problems.

However, nitrosamines are not the only mutagenic impurities that can result during the production of active ingredients, pharmaceutical excipients, and the processing of finished pharmaceuticals.

To minimize these risks, increasing regulatory requirements are being implemented.

ICH Guideline Q3D on elemental impurities has been extended in 2022. Similarly, the ICH Guideline ICH Q3C on residual solvents is being updated to incorporate toxicological assessment using permitted daily exposure (PDE) levels. ICH Guideline M7 on mutagenic impurities was updated in April 2023 and adopted by the European Commission in September 2023. End of 2023, ICH Q2(R2)/Q14 was released, which puts strong emphasis on risk management processes during analytical method development and further increased requirements for the control strategy and quality control of medicinal products.

In this context, you should ask yourself the following questions:

Are your investigations on the impurity profile/contamination level of raw materials and finished pharmaceuticals up to date?

Are the process-related risks reflected in the specification of your products?

If you cannot answer those questions with a clear "yes", it is time to act now!

Valicare can support you in complying with these mandatory regulatory requirements.

We start with a risk analysis to identify whether and which critical impurities could have been formed during the process and with the raw material. If desired, we limit this check to the nitrosamine impurities.

Based on the results of the risk analysis, the determined impurity profile and the regulatory requirements, we advise and support you in the development of a control strategy to reduce the risk of critical contamination.

Considering the complete product life cycle approach, we propose a suitable specification for your product and develop an efficient test strategy to enable extensive control.

This approach will enable you to meet current and expected regulatory requirements and ensure the quality of your product with regard to critical impurities.

More information about nitrosamines can be found here and on the EDQM website.

If you have any questions about risk-based specification determination, please contact us!