A guide to pharma EU risk assessments

Frithjof Holtz, advocacy & surveillance life science regulatory management at Merck KGaA offers a practical view on the implementation of the EU Excipient Risk Assessment Guidelines. 

They are often inconspicuous, but just as often indispensable: excipients are far more than passive additions to active pharmaceutical ingredients (APIs). Their critical role in drug production has become the focus of many debates – and of regulatory authorities who are demanding more stringent quality management in excipient production and use.

Whether speaking of anti-adherents or binders, a high quality of the more than one thousand different excipients is essential for drug and patient safety. Regulatory authorities are increasingly demanding stricter quality management in excipient production and use, which affects both excipient suppliers and pharmaceutical manufacturers. Since March 2016, excipient users in the EU are legally mandated to implement GMP requirements of the EU Excipient Risk Assessment Guidelines.

However, while regulations regarding GMP for APIs clearly define what is required for compliance, the EU guidelines never intended to be more than their name suggests: guidelines offering tools and a framework. From the manufacturing authorisation holder’s point of view, the guidelines are lacking a clear implementation prescription. They neither provide detailed instructions nor a clear definition of appropriate GMPs for excipients. This remains the responsibility of the manufacturing authorisation holder and can be quite a challenging task.

The EU guidelines and their challenges

The good news is that no one needs to develop their own GMPs from scratch. In fact, they can follow several well-established, voluntary industry standards such as USP General Chapter 1078, EXCiPACT and NSF/IPEC/ANSI-363-2016, or the IPEC-PQG GMP Guide. Together with the IPEC Europe “how to“ document, the latter gives a good initial guidance. It offers a clearly arranged step-by-step overview of how to comply with the EU Excipient Risk Assessment Guidelines, which will be sufficient in many cases.

But what about those excipients that could potentially pose hazards to patients? They certainly require application of more exhaustive control mechanisms. Moreover, the voluntary standards are not binding, which often confronts manufacturers and users of excipients with nearly unsurmountable challenges as to how exactly they should perform their risk assessment. The large number of excipients that need to be formally assessed, as well as the scope of the supporting documents can also be quite overwhelming.

Learning from real experience

To simplify the task and to enable effective learning through practical experience, Merck conducted a real-life case study based on a defined number of pharmaceutical products and excipients. The initial question was “what do medicinal product manufacturers need to consider during risk assessment?” Two lists of criteria, i.e. from the manufacturing or supply perspective and from the application point of view, identify risks related to excipients based on the EU guidelines.

Based on these lists, five different quality areas were defined for risk assessment: quality management system, manufacturing of excipients, supply chain, route of administration and function of the excipient. Prior to the actual assessment process, the medicinal products were examined in order to identify all excipients and their respective use. In the end, 24 excipients were investigated and assessed in a step-by-step approach.

A four-step assessment process

The first step consisted in translating the EU guidelines into a supplier questionnaire to assess the supplier qualification. The incoming information was harmonised and bundled in a spreadsheet. Next, the team developed an excipient risk ranking template covering all elements of the EU guidelines, using ICH Q9 Quality Risk Management as guidance. The template provides a risk score from low to medium to high for each individual excipient, both regarding each single criterion as well as the overall risk score.

According to the previously defined minimum requirements derived from documents such as the IPEC GMP Guide and EXCiPACT, the supplier risk was determined in step three. The final step consisted in creating a risk profile for each supplier based on a gap analysis. The goal was to identify effective mitigation options, such as an update of the Quality Assurance Agreement or intensified incoming goods control.

Results and further challenges

In the overall ranking, none of the 24 assessed excipients were classified as high-risk. However, excipients can still have high single risks, for instance regarding storage monitoring and packaging, dosage form and permanent intake, which need to be closely looked into. The gap analysis at the supplier end led to 14 excipients classified as low, and 10 as medium risk. The identified gaps included a potential for microbiological or endotoxin/pyrogen contamination, which can be mitigated through additional quality control testing in the manufacturing authorisation holder’s laboratory. Other gaps concerned environmental control and control of storage/transportation conditions including cold chain management and packaging integrity.

While translating the relevant points from the EU guidelines into a supplier questionnaire was already rather complex, finding an appropriate procedure for risk prioritisation proved to be the largest challenge. The sheer amount of data was overwhelming. Here, suppliers can contribute to a good process by following established guidelines, fulfilling information needs and providing timely documentation, ideally in electronically transmitted packages. Once defined, the risk assessment process must be transferred into daily business and kept up to date.

A way out of the assessment maze

A good excipient risk assessment procedure contributes decisively to product and patient safety – and facilitates regulatory inspection processes for excipient manufacturers and users. However, the more stringent regulations have also increased the workload for manufacturing authorisation holders: as the case study shows, a structured excipient risk assessment process requires a large amount of resources. Cross-functional teams, an open and structured communication between drug manufacturers and excipient suppliers are just as important as a strong commitment and awareness from management.

Online programmes such as Merck’s Emprove provide further support. Tried and tested tools including comprehensive documentation packages simplify processes and help drug manufacturers master the challenges of timely information, structured communication and “inspection-friendly” documentation. The dossiers cover all relevant EU guidelines with clear references to the respective chapters. This way, the tools help to efficiently implement a compliant and sustainable risk assessment process – and offers pharmaceutical manufacturers a way out of the assessment maze.