Regulating Excipient Quality, No Mean Feat

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Regulatory bodies are taking a more stringent approach to excipient quality, but unlike guidance on GMP for APIs, those for excipients offer a framework only, meaning the onus lies with the manufacturer or supplier.

Editor’s Note: A version of this article was published in Pharmaceutical Technology Europe’s APIs, Excipients, and Manufacturing 2019 Supplement.

In recent years, regulatory bodies across the globe have been taking a more stringent approach to excipient quality. Within the European Union (EU) alone, regulatory guidance on the assessment of risk related to excipients was published in 2015 and required to be implemented by 2016 (1). However, these guidelines only offer a general framework from which pharmaceutical companies and excipient suppliers can look to develop their own appropriate ways of ensuring excipient quality.

To learn more about the European regulatory guidance, its implementation, potential impact on workloads, and best practices for companies and excipient suppliers, Pharmaceutical Technology spoke with Frithjof Holtz, advocacy and surveillance-life science regulatory management, Merck KGaA.

Regulating excipients

PharmTech: Could you elaborate on the EU regulations surrounding excipients and how these have developed over the years?

Holtz (Merck): The critical role of excipients in drug production has come into focus over the past few years. This has meant shaking off the long prevailing perception of excipients being passive additions to APIs. Now, regulatory authorities are calling for more stringent quality management in excipient production and use, leading to new requirements for both excipient suppliers and pharmaceutical manufacturers.

Regulating excipient quality, however, is no small task. More than 1000 different excipients are available, and only a small fraction is manufactured solely for pharmaceutical use. This heterogeneity and the resulting complexity have led to the European Commission’s (EC’s) approach to excipient quality. 

In 2011, the EU’s Falsified Medicines Directive established that pharmaceutical manufacturers must perform a formalized risk assessment for each excipient they use and determine its appropriate good manufacturing practices (GMPs). It also stated that the EC would develop guidelines offering direction on the risk management process and the appropriate level of GMP for excipients. Based on this directive, the EU excipient risk assessment guidelines were drafted in 2013 and published in March 2015 after intense discussion.

The guidelines apply not only to medicinal products produced in Europe but also for products manufactured outside Europe and intended for the European market. Since 21 March 2016, excipient users in the EU are legally mandated to implement GMP requirements, including comprehensive risk assessments for each excipient. 

The EU excipient risk assessment guidelines capture both the intended use and source of the excipients. Its main topics are described in chapter two to four, covering the determination of appropriate GMP based on type and use of excipient, the determination of an excipient manufacturer’s risk profile, as well as confirmation of application of appropriate GMP.

However, while regulations regarding GMP for APIs clearly define what is needed for compliance, the EU excipient risk assessment guidelines are-as the name suggests-not more than guidelines that offer tools and a framework but do not prescribe how to implement them. They neither provide detailed instructions nor a clear definition of appropriate GMP for excipients. This is the responsibility of the manufacturing authorization holder-and, evidently, no small task either. 

PharmTech: Why has the EC taken a risk‑based approach to excipient quality?

Holtz (Merck): A risk-based approach is the most logical way of assessing excipient quality. Some excipients pose much greater risks than others. Risks vary depending on the route of administration and the function of the excipient. An excipient used as filler, for instance a binder or colorant, might pose a lower risk than one used as a stabilizer or a vehicle for controlled release. Hence, the risk-based approach focuses on the harm posed by microbiological, chemical, or physical hazards.

Due to the risk excipients can pose to patients, robust excipient GMPs are needed. Increased attention to supply chains and more structured communication between excipient suppliers and drug manufacturers are essential in order to help reduce risks. Drug manufacturers should expect their suppliers to provide dossiers accompanying each excipient with information that, in turn, supports the drug manufacturer’s risk assessment. This can include data on production, testing, supply chain and quality systems, as well as information about alignment with regulatory guidelines.


Implications and potential aides for manufacturers

PharmTech: Are there significant workload implications for manufacturing authorization holders, and are there any solutions available to ease the workload? 

Holtz (Merck): It is important to understand that the EU excipient risk assessment guidelines offer a general framework. Developing a compliant risk assessment process and defining appropriate GMPs for all excipients is clearly the responsibility of the medicinal product manufacturer. However, there is no need for manufacturers and users of excipients to develop their own GMPs. Several well-established, voluntary industry standards can be used for guidance, such as the International Pharmaceutical Excipients Council-Pharmaceutical Quality Group (IPEC-PQG) GMP Guide, United States Pharmacopeia(USP) General Chapter <1078>, EXCiPACT, and NSF/IPEC/ANSI-363-2016. 


Take the IPEC-PQG GMP Guide as an example, it provides an in-depth description of a voluntary GMP guide for pharmaceutical excipients. Together with the IPEC Europe ‘how-to’ document on EU Guidelines on Risk Assessment for Excipientspublished in 2016, it gives a good initial guidance (2). The step-by-step document also offers a clearly arranged process overview of how to comply with the requirements outlined in the EU excipient risk assessment guidelines. In many cases, application of these standards is likely to be sufficient. However, a small number of excipients could potentially pose hazards to patients and require application of more thorough controls than those recommended in the voluntary standards.

Unfortunately, manufacturers and users of excipients are often still at a loss as to how exactly they should perform their risk assessment. Given the abundancy of excipients, a formalized risk assessment might even seem unmanageable. Also, the sheer number of supporting documents can be overwhelming, as helpful as they might be. So yes, the more stringent regulations have increased the workload of all parties involved. Performing excipient risk assessment in a structured manner requires a lot of effort and has significantly changed the daily work of excipient users and manufacturers. 

Although the voluntary industry standards are a great help, they are not binding, but based on best industry practices, offering guidance and facilitating implementation. As described before, excipient suppliers and pharmaceutical manufacturers are still facing the complicated task of putting these standards into practice.

As a result of these complexities, Merck has developed the Emprove program (3). The intention of the program is to simplify processes and to help drug manufacturers master the challenges of timely information, structured communication, and ‘inspection-friendly’ documentation. Dossiers, which are available 24/7 online and backed by comprehensive support, cover the relevant EU guidelines, with constant reference to the respective chapters. Additional information, such as a quality self-assessment and detailed supply information, is also included in the dossiers. Regarding excipient risk assessment, the tools and information help to efficiently implement a compliant and sustainable risk assessment process, which makes pharmaceutical manufacturers optimally prepared for inspections.

Best practices

PharmTech: Do you have any best practices for companies to successfully prepare for excipient risk assessment inspections?

Holtz (Merck): Absolutely, a few months ago, we [at Merck] conducted a real-life case study to simplify the task and to enable effective learning through practical experience. We began by selecting medicinal products to identify all relevant excipients and their respective use. This selection resulted in a total of 24 excipients for inclusion in our investigation and assessment.

Based on the EU guideline, we then compiled criteria for manufacturing and supply, as well as application. This led to the definition of five different quality areas: quality management system (QMS), manufacturing of excipients, supply chain, route of administration, and function of the excipient. Based on these initial considerations, we conducted the case study in four distinct steps.

The first step focused on supplier qualification. The EU guidelines were translated into a supplier questionnaire. The incoming information was harmonized and bundled in a spreadsheet. 

Next, we developed an excipient risk ranking template covering all elements of the EU guidelines. It provides a risk score (low, medium, and high) for each individual excipient for each criterion as well as the overall risk score. As recommended by the EU guidelines, we used International Council for Harmonization (ICH) Q9 Quality Risk Management as guidance for risk prioritization (4).

Finding an appropriate procedure for risk prioritization of the responses was by far the greatest challenge. Here, suppliers can actively contribute to a good risk assessment process by following established guidelines, fulfilling information needs and providing timely documentation, ideally bundled in packages and transmitted electronically.

Step three determined the supplier risk, based on the previous definition of minimum requirements derived from the IPEC-PQG GMP Guide and EXCiPACT. 

Finally, a risk profile for each supplier was created based on a gap analysis. The goal was to find effective mitigation options, such as an update of the quality assurance agreement or intensified incoming goods control.

All 24 excipients were classified as medium risk. It is important to note that this classification represents an overall ranking, as explicitly required by the guidelines. This means that excipients might show high single risks-which need to be closely looked into-but are still classified as medium risk overall. The high single risks showed that storage monitoring and packaging are important considerations regarding the excipient’s source, whereas dosage form, permanent intake, and function are predominant regarding the excipients’ use.

The gap analysis at the supplier end resulted in 14 excipients classified as low, and 10 as medium risk. The identified gaps include a potential for microbiological or endotoxin/pyrogen contamination-with the mitigation option to perform additional quality control testing in the manufacturing authorization holder’s laboratory. Other identified gaps concerned environmental control and control of storage/transportation conditions including cold chain management and packaging integrity.

One of the main challenges we recognized in conducting our analysis was in obtaining meaningful data. Supplier data input to our survey was sometimes incomplete, contradictory, not as requested or not delivered in a unified format. Also, data transfer and dealing with large spreadsheets was an error-prone and time-consuming task. More clearly defined instructions for suppliers might be able to solve this challenge. 

Another major challenge we encountered is providing a sustainable risk assessment process that can be easily incorporated into daily business to keep it up to date. However, it is important to note that the risk assessment cannot replace regular audits, since the information provided by suppliers and manufacturers does not necessarily reflect the degree of compliance in daily work.


Future predictions

PharmTech: What do you believe the excipient suppliers and pharma manufacturers should anticipate in terms of regulatory guidance and required compliance for quality of excipients in the near future?

Holtz (Merck): I see two important areas. The first is multicompendial compliance. Unfortunately, pharmacopeial harmonization has not led to the expected results. Manufacturers and users of excipients still need to cross-validate pharmacopeial standards, as long as the industry is lacking a standardized approach. The industry needs to develop a best practice that is accepted by regulatory authorities. This would enable companies to align their internal procedures for compliance with multiple compendia.

Second, novel excipients are prevented from being introduced in the EU due to the absence of an excipient master file system. Major regulatory environments such as Japan, US, Canada, and China, have design master file-type systems in place and treat novel excipients as APIs, requiring comprehensive manufacturing, quality, and safety data. In Europe, however, there is no way to directly submit confidential information for an excipient in a centrally authorized product. A regulatory pathway that guarantees the protection of confidential manufacturing know-how for novel excipients would encourage innovation.


1. EU, “Guidelines of 19 March 2015 on the Formalized Risk Assessment for Ascertaining the Appropriate Good Manufacturing Practice for Excipients of Medicinal Products for Human Use,” Official Journal of the European Union, 58 10–13 (2015).
2. IPEC Europe, “‘How-To’ Document: Guidelines of 19 March 2015 on the Formalized Risk Assessment for Ascertaining the Appropriate Good Manufacturing Practice for Excipients of Medicinal Products for Human Use (OJ 2015/C 95/02),” Guide, (Brussels, 2016). 
3. Merck, “The Emprove Program,” Regulatory Support Information, [Accessed 19 August 2019].
4. ICH, Q9 Quality Risk Management (ICH, 9 November 2005).