When Excipients Become a Safety Concern in Pharmacovigilance

When assessing medicine safety, most people focus on the active ingredient. But what happens when a potential safety concern involves an excipient instead? The EMA’s review of Rifadin highlights why excipient safety matters and what pharmacovigilance teams should consider when new regulatory concerns emerge.

Why Excipients Matter More Than We Think

Active ingredients produce the intended therapeutic effect, but excipients also play an important role in medicines. They help maintain stability, improve solubility, preserve products, and support other features such as taste and ease of use.

However, the term “inactive ingredient” does not mean that a substance can never raise safety concerns. Its effects may depend on its properties, concentration, route of administration, and the patient’s characteristics.

For pharmacovigilance (PV) professionals, this creates an important consideration. Excipient safety deserves attention when new information may affect a medicine’s overall benefit–risk balance. Regulatory concerns can also lead to changes in product information, formulation requirements, or marketing authorisation status.

Understanding these issues helps PV teams recognise relevant developments and work with other departments to assess their potential impact.

The Rifadin Case and the Regulatory Review

In June 2026, the European Medicines Agency (EMA) initiated a referral procedure for Rifadin 20 mg/ml oral suspension and syrup. These medicines contain rifampicin, an antibiotic used to treat tuberculosis and other serious infections.

The review focuses on diethanolamine (DEA), an excipient in these formulations. DEA helps distribute the active substance evenly throughout the liquid and supports the formulation’s stability.

The concern relates to the DEA’s potential carcinogenic properties. Studies in rodents raised questions about the effects of long-term exposure to high doses. EMA notes that these doses greatly exceeded the exposure people would normally receive from medicines containing DEA.

The agency will assess whether this concern affects the benefit–risk balance of the specified Rifadin formulations. Its review will help determine whether the medicines can retain their current authorisations or require regulatory changes.

The case illustrates how an excipient can become the focus of a regulatory assessment, even when the active substance itself is not the main concern.

Why Does the Review Cover Only Specific Formulations?

The scope of the Rifadin review matters. EMA is assessing the 20 mg/ml oral suspension and syrup, not every medicine that contains rifampicin.

The excipient plays a specific role in these liquid formulations. Other rifampicin medicines come in different forms, including capsules and infusion preparations. The same referral does not automatically apply to these products simply because they contain the same active substance.

This distinction matters when companies interpret regulatory announcements. A concern with one formulation does not necessarily indicate the same risk across all products containing the same active ingredient.

Marketing authorisation holders (MAHs) should therefore check the exact product, strength, pharmaceutical form, and authorised indications when assessing a regulatory development. This approach helps teams identify affected products without making assumptions about the wider portfolio.

From an Excipient Concern to Regulatory Action

The Rifadin referral follows earlier regulatory action. In 2019, the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) asked MAHs to assess risks associated with DEA.

The group called on companies to reformulate affected medicines without the DEA or explain why they could not replace the excipient.

According to EMA, the current review began because the company marketing the specified Rifadin oral suspension and syrup had not submitted a proposal for a new formulation without a DEA.

This history shows how a regulatory concern can develop over time. An initial request may require companies to assess the available evidence, explore formulation changes, and explain their decisions to regulators.

For MAHs, receiving a regulatory notice is only the first step. Teams must understand the requirements, assign responsibilities, track deadlines, and provide the evidence needed to support their response.

Effective follow-up helps companies avoid treating important regulatory communications as isolated events.

How Regulators Assess the Benefit–Risk Balance

The presence of a potential hazard does not automatically mean that a medicine has an unfavourable benefit–risk balance. Regulators must consider the available evidence and the implications for patients who depend on the treatment.

In the Rifadin procedure, the Committee for Medicinal Products for Human Use (CHMP) will evaluate the issue and adopt an opinion. The European Commission will then issue the legally binding decision applicable across the EU. Depending on the assessment, regulators may maintain the marketing authorisation, introduce changes, suspend it, or revoke it.

The Rifadin case also highlights the need to communicate scientific uncertainty carefully. Animal studies can raise important safety questions, but their findings require careful interpretation in the context of human exposure.

PV and regulatory professionals should distinguish between a potential hazard, evidence of actual risk under the conditions of use, and the conclusions regulators reach after reviewing the available data. This distinction supports accurate communication and helps prevent premature conclusions about a medicine’s safety.

What Should Pharmacovigilance Teams Do?

PV teams may not lead formulation development or quality investigations, but they still need to understand regulatory developments that could affect their products.

A structured approach can help teams assess these developments and coordinate the appropriate response.

First, monitor relevant regulatory communications. Check whether a notice concerns a product in your portfolio, and confirm its exact formulation and the scope of the procedure.

Second, assess the potential impact on existing safety information, risk management activities, and other PV responsibilities. The appropriate response will depend on the nature of the concern and any resulting regulatory requirements.

Third, document the assessment and any follow-up actions in accordance with company procedures. Even when a development requires no immediate PV action, a clear record of the rationale supports traceability.

Finally, involve the relevant departments when the concern extends beyond PV responsibilities.

The goal is not to classify every excipient concern as a safety signal. Instead, PV teams should recognise relevant information, assess its implications, and direct it to the people who can act on it.

Why Cross-Functional Collaboration Matters

Excipient-related concerns often require input from several departments. PV, Regulatory Affairs, Quality Assurance, pharmaceutical development, and manufacturing each bring different expertise to the assessment.

Quality and pharmaceutical development teams can assess formulation characteristics and explore possible alternatives. Regulatory Affairs can interpret authorisation requirements and coordinate submissions. PV teams can evaluate relevant safety information and determine whether the development affects their responsibilities.

Clear communication becomes especially important when regulators set deadlines or request a formal response. Companies should assign responsibilities, agree on next steps, and support decisions with appropriate evidence.

The Rifadin case shows why organisations need processes that connect regulatory intelligence with internal product knowledge. Without this coordination, teams may identify an important announcement but fail to assess its relevance or complete the necessary follow-up. A clear process helps turn regulatory information into timely, documented action.

Excipients and Product Information

Not every excipient concern leads to a referral or a change in marketing authorisation. Some issues require companies to update product information under existing regulatory rules.

In the EU, specific excipients with a known action or effect require appropriate declarations in medicine labelling and package leaflets. The European Commission’s guideline and annex identify relevant excipients and explain what information companies should include.

EMA also updates its guidance when new evidence changes the information that patients and healthcare professionals need. MAHs must review these changes and follow the applicable requirements and deadlines for updating product information.

PV teams should monitor these developments alongside individual safety signals. Changes to excipient information may require coordination with Regulatory Affairs and other departments, even when the development does not involve a new adverse reaction signal. This broader view helps companies identify regulatory changes that may affect their products and determine which teams need to respond.

Practical Lessons for Marketing Authorisation Holders

The Rifadin referral offers several practical lessons for MAHs.

First, consider excipient safety throughout a medicine’s lifecycle. New evidence and changing regulatory expectations may lead authorities to reassess an established formulation.

Second, connect regulatory monitoring with impact assessment. Identifying an announcement is not enough. Companies must determine which products it affects and whether they need to take action.

Third, define responsibilities across PV, Regulatory Affairs, Quality, and pharmaceutical development. Clear ownership helps teams assess concerns, justify decisions, and track required actions.

Finally, communicate risks in proportion to the evidence. A potential hazard does not automatically establish a confirmed clinical risk. Likewise, a procedure involving a single formulation should not be generalised to all medicines containing the same active substance.

These principles help companies make informed decisions and keep patient safety at the centre of their regulatory activities.

Key Takeaways

The Rifadin case shows that regulatory concerns can extend beyond a medicine’s active ingredient. Excipients serve important purposes, but new evidence may prompt regulators to reassess their safety.

PV teams should monitor relevant developments, understand their scope, assess potential implications, and collaborate with colleagues in other departments. Not every excipient concern represents a safety signal, and not every regulatory review leads to changes in a medicine’s authorisation.

However, every relevant development deserves an appropriate assessment and clear documentation.

Effective pharmacovigilance requires more than monitoring adverse reactions. It also requires awareness of the wider regulatory environment and an understanding of how new information can affect medicines throughout their lifecycle.