Hepatitis E Virus - Reflection Paper on Viral Safety

Recommendation

7/8 May 2024

Annex 2 & Co. - GMP Compliance for Biopharmaceuticals - Live Online Training
Regulatory Requirements and Practical Implementation

On 1 July the period of public consultations for the EMA Reflection paper on viral safety of plasma-derived  medicinal products with respect to Hepatitis E Virus (HEV) started.

HEV, a non-enveloped, single-stranded, positive-sense RNA virus, exists in different genotypes (1-4). It is normally transmitted by the faecal-oral route, in emerging countries mostly by contaminated drinking water. But current scientific results show that HEV (genotypes 3 and 4) has been found to be more prevalent in the human population of the industrialised countries than originally believed and detected not only in humans. It can be found in animals like swine, wild boar and deer too. So transmission by undercooked products by animal origin or contact with infected animals is possible.

HEV positive humans are often asymptomatic and therefore there is a risk for viraemic blood donations or transmission by transplants. HEV has been recognised as a transfusion transmissible agent since 2004, and transfusion-related cases have been documented in several countries (United Kingdom, France, Japan, Saudi Arabia, People’s Republic of China).  Subsequently, several regulatory documents with guidance information where published. The Ph. Eur. monograph for human plasma pooled and treated for virus inactivation (1646) was revised to include a test for HEV RNA (implementation date 1 January 2015). A WHO International Standard for HEV RNA has been established promoting the standardisation of HEV assays by nucleic acid amplification technology (NAT).

Some manufacturing processes includes inactiavatiom/removal steps for non-enveloped viruses. But the detection of HEV is tricky, because HEV is difficult to cultivate in cell culture and the information about susceptibility of HEV to virus inactivation/removal steps used in the manufacture of plasma-derived medicinal products is limited. If these steps are effective against HEV is still under investigation.

Related to the high number of open questions on that topic, an EMA Workshop on viral safety of plasma-derived medicinal products with respect to hepatitis E virus was held on 28-29 October 2014. The purpose of the workshop was to obtain further information on the safety of plasma-derived medicinal products with respect to HEV and to provide the basis for deciding what further action may be needed. Key questions that were addressed were:

• Clinical experience with HEV infections and transfusion-associated infections: How serious are HEV infections and which patient populations may be particularly at risk?
• HEV detection and epidemiology of HEV in blood/plasma donations
• Do serum antibodies against HEV significantly neutralise?
• Latest experience from studies on inactivation/removal of HEV: Which steps are effective to remove / inactivate HEV? Which model viruses can be used to assess that? Do we need more virus validation data?
• Risk assessment for plasma-derived medical products and implication for warning statements: Do we need risk assessments and/or warning statements?
• NAT testing will be required in the Ph. Eur. for SD plasma. Should this also be required for any other products?

The current draft edition of this reflection paper include the discussion and outcome of this workshop to the following headlines and contents:

• Transfusion-associated infections and clinical experience with HEV-infection
• HEV detection and epidemiology of HEV in blood/plasma donations
• Do serum antibodies against HEV significantly neutralise?
• Studies on inactivation/removal of HEV during manufacture of plasma-derived products
• Risk assessment for plasma-derived medical products

More details and the conclusions can be found directly in the "Reflection paper on viral safety of plasma-derived medicinal products with respect to hepatitis E virus"