Pharmacovigilance Considerations for Biological Medicines

A biological medicine is a medicine that contains an active substance made by a biological process or derived from a biological source. Examples include recombinant proteins such as insulin, monoclonal antibodies, blood derived medicines and vaccines. A biosimilar is a biological medicine that is highly similar to an originator biological medicine that has already been authorised for use.

Manufacturers of biosimilar medicines must perform an extensive head-to-head comparability exercise with the originator medicine and demonstrate to regulators that the biosimilar medicine has similar quality, safety and efficacy to the originator medicine such that there are no clinically meaningful differences between the two. A biosimilar medicine will have the same non-proprietary name as the originator medicine. However a biosimilar medicine is not a generic equivalent of the originator medicine. This is because the active substance in each medicine has been shown to be highly similar but not identical.

Biological medicines typically consist of complex heterogeneous protein molecules. As a result there is often a degree of variability in the molecules of the active substance, even between different batches of the same medicine. The extent of variability allowed is controlled within strict limits. The production process of a biological medicine is specific to each manufacturer and can shape the quality, safety and efficacy profile of the medicine. In addition, any changes to the production process may result in changes in immunogenicity which may be difficult to predict. In the case of therapeutic proteins, the consequences of an immune reaction ranges from the transient appearance of antibodies without any clinical significance, to severe and life-threatening conditions. For these reasons traceability to product and batch level is extremely important. All biological medicines including biosimilar medicines, should be prescribed, dispensed and sold in a way where the product supplied to the patient is clearly identifiable. EU and national legislation also requires that adverse reaction reports for biological medicines contain the brand name and batch number of the medicine.

There are specific considerations related to the pharmacovigilance of biological medicines (see Table 1).

  • Biological medicines should be prescribed, dispensed and recorded by brand name.
  • Biological medicines have specific considerations such as immunogenicity, stability and manufacturing variability. As such, traceability to individual batch level should be ensured.
  • It is good practice to record the batch number of a biological medicine when dispensing (e.g. as part of the patient medication record).
  • All newly authorised biological medicines are subject to additional monitoring requirements. Healthcare professionals and patients should promptly report all suspected adverse reactions for such medicines.
  • The brand name and batch number should be included in any report of a suspected adverse reaction to a biological medicine. This enables reports to be traced back to the correct manufacturer and production process.
  • Suspected adverse reactions should be reported to the HPRA through the available reporting options.

Key Messages

  • Biological medicines pose a greater potential risk of immunogenicity compared to non-biological medicines
  • Sources of immunogenicity are multi-factorial and include product related factors (e.g. changes to 3D structure of protein during processing), treatment related factors (e.g. route of administration) and patient/disease related factors.
  • Changes in immunogenicity may be introduced due to changes in manufacturing processes and/or quality.
  • Changes in manufacturing processes are often required for biological medicines (e.g. change in source materials, purification processes etc.).
  • Changes are supported by a comparability exercise, where batches of the medicine produced before the change are rigorously compared to those manufactured after the change.
  • Manufacturing changes may impact product quality and subsequently affect efficacy and safety. It may not always be possible to predict immunogenicity as a result of a manufacturing change.
  • Biological medicines contain fragile proteins which are prone to denaturation. As a consequence biological medicines are less stable than their chemical counterparts.
  • After manufacture the stability of a biological medicine is assured by appropriate storage/handling, cold chain and good distribution practices.
  • Non adherence can affect the medicines quality and stability and may introduce immunogenicity or contamination.
  • Due to the aforementioned manufacturing variability and stability challenges, traceability to the individual batch number is essential in order to consider the potential impact of any suspected adverse reactions observed,
  • Consequently it is good practice to record brand name and batch number at all levels in the supply chain from manufacturer release, prescription, dispensing and patient administration.

Considerations related to pharmacovigilance of biological medicines

Manufacturing variability


Product traceability


Within the EU there is a well-developed pharmacovigilance framework for the monitoring, evaluation and prevention of drug-related adverse events. The safety of all biological medicines including biosimilar medicines is monitored closely on an ongoing basis during the post-approval phase, including continued benefit-risk assessment.



A medicine may be subject to additional monitoring if it is new to market or there is limited data on its long term use. The additional monitoring status will be indicated by the presence of an inverted black triangle () in the medicine’s product information (i.e. at the start of the Package Leaflet (PL) and the Summary of Product Characteristics (SmPC)*). All newly authorised biological medicines, including biosimilar medicines, are subject to additional monitoring for the first five years after authorisation. Healthcare professionals and patients should promptly report all suspected adverse reactions for medicines with this status, so new emerging information can be analysed efficiently.

*All product information (SmPCs and PLs) for biological medicines is available from or