Risk Assessment

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

Our employees have carried out the risk-based qualification and validation of plants and processes in the pharmaceutical industry highly successfully for many years. Therefore, they prepare risk anaylsis successfully 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. On request, we conduct a risk analysis workshop based on this report in order to discuss the quality and process-relevant aspects with your respective responsible specialists.

Of course, other risk-assessment procedures that have been tried and tested by you can also be used, e.g., brainstorming, the Ishikawa diagram or hazard analysis according to Hazard Analysis Critical Control Points (HACCP).

In 2018, nitrosamine contaminants were found in a number of blood pressure medications. Based on animal studies, N-nitrosodimethylamine (NDMA) is classified as a suspected human carcinogen.

EU regulators recalled medicines and banned the use of active ingredients from certain manufacturers. To ensure the quality of medicines and protect patients, the CHMP (Committee for Medicinal Products for Human Use of the EMA) requires companies to develop control strategies to ensure that nitrosamines are not present or are below the permitted limits.

The example shows the importance of a risk-based specification definition as a basis for developing an appropriate control strategy and 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, the current discussion suggests that increasing regulatory requirements will be implemented in the coming years.

ICH Guideline Q3D on residual solvents has been extended in 2022. ICH Guideline M7 on mutagenic impurities was finally published in April 2023, but adoption by the European Commission is still pending. In 2024, new versions of ICH Guidelines Q2 and Q14 are expected with further increasing requirements for the control strategy and quality control of affected 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 the products?

If you cannot answer those questions clearly with "Yes", then it is time to act!

Valicare can support you in complying with these regulatory requirements, which are already mandatory!

We start with a risk analysis in order to weigh up whether and which critical impurities could have been formed during the process and with the raw material used. 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.

With this approach, you will meet current and expected increasing regulatory requirements and ensure the quality of your product with regard to critical impurities.

More information about nitrosamines can be found in the blog article and in the research "Nitrosamines in active ingredients and finished pharmaceuticals".

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