The sensitivity of modern detection methods increased considerably during the last years. The development includes that the detection limits of adventitious agents decreased considerably too. In 2010 EMA became aware of some scientific publications which presented new information regarding the possible presence of nucleic acid sequences from endogenous2 and adventitious3 viral agents in a few batches of different live attenuated viral vaccines tested by a new analytical technique. A team of US scientists used a polymerase chain reaction (PCR) combined with pyrosequencing with the aim to determine whether low levels of nucleic acids e.g. originating from adventitious viruses “were introduced during the attenuation or manufacture of eight live viral vaccines”.
Some batches of live attenuated vaccines tested by the research team had tested positive for either sequences of endogenous avian leukosis virus (ALV), or endogenous simian retrovirus (SRV), or porcine circovirus 1 (PCV-1). In view of the above, the Executive Director of the EMA presented on 13 April 2010 a request for a CHMP (Committee for Medicinal Products for Human Use) opinion under Article 5(3) of Regulation EC (No) 726/2004.
CHMP outlined the following opinion:
"1. Whilst the presence of endogenous ALV and SRV DNA fragments is potentially linked to the cell lines used for the manufacture of the individual vaccines, the finding of PCV-1 DNA pointed towards the presence of non-endogenous viral DNA. The Committee is therefore asked to assess if there is any potential public health concern arising from all the findings described in the article.
2. It is understood that as more hi-tech analytical methods become available, new findings may reveal in medicinal products presence of substances at very low concentrations and/or hard to detect that were thus far not picked up because of limitations of the analytical instruments/methods declared and authorised in the marketing authorisation dossier. Specifically, the Committee is asked to indicate if the new test method described above applied to identify viral genomic nucleic acid fragments should be considered, if validated, for the development/qualification and/or routine testing of biological medicinal products, and particularly live attenuated vaccines. Recognising the limitations of this novel method, and in order to conclude on the presence or absence of specific risks, the Committee is also asked to consider whether additional tests would be needed to conclude on the presence of replication competent endogenous and adventitious viral agents.
3. The Committee should indicate if there is a need to update existing guidance related to the testing and elimination of such substances in the context of development and/or testing of live attenuated vaccines.
4. Depending on the outcome of these investigations, the Committee should consider the need for appropriate guidance for other vaccines and other biological products."
Earlier in 2012, EMA published an "Assessment Report for Art 5(3) procedure: Detection by a highly sensitive new PCR technique of genomic fragments from endogenous and adventitious viral agents in live attenuated vaccines". Based on the scientific discussion of the outlined questions and after evaluation of all available data, CHMP considered that the finding of these viral sequences do not raise any public health concern. CHMP comments this conclusion in detail and announced to further handle these new sensitive detection methods in contact with other authorities: "The issues identified by the Committee are common to regulators worldwide. The CHMP has started a dialogue with other authorities, including the US Food and Drug Administration, the World Health Organisation and the European Directorate for the Quality of Medicines, to start working towards a common approach for the use of metagenomic testing in biological medicines. A common road map will be sought whenever possible."
More details can be found in the "Assessment report for Art 5(3) procedure:Detection by a highly sensitive new PCR technique of genomic fragments from endogenous and adventitious viral agents in live attenuated vaccines".
Axel H. Schroeder
ECAs RMM Working Group