Pharmacovigilance of Biologics Under Scrutiny

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology-10-02-2016, Volume 40, Issue 10
Pages: 18-20

Regulators are tightening up on post-marketing monitoring of biological medicines to detect deficiencies caused by manufacturing problems, particularly those stemming from post-authorization changes in the manufacturing process.

The European Union introduced a guideline (1) in August 2016 on the monitoring of the safety of biological medicines on the market amidst industry worries about the ability of regulators to deal with quality deficiencies due to manufacturing variations in biopharmaceuticals. Manufacturing standards can have a bigger impact on the post-marketing safety and efficacy of biological medicines than those of chemically synthesized pharmaceuticals with which different producers can achieve a uniform quality.

“[With biologicals], the manufacturing process--including choice of cell line, raw or starting materials, fermentation and purification process, final formulation--is as much a determinant of the product’s quality as the active substance,” states the guideline (1). “Minor changes in any manufacturing step can affect the product quality and subsequently its safety and efficacy.” As a result, the guideline, published by the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA), constantly highlights the need to find the “root cause” of a suspected adverse drug reaction (ADRs) by tracing the product back not only to its manufacturer but also to its batch and the individual medicines within it.

Lack of traceability 

The guideline applies to reference biological medicines, biosimilars, and related biological products such as interferon and faction VIII. Traceability is the vital tool for discovering what could be responsible for the lapse in quality during the manufacturing that has impacted the safety and efficacy of the medicine on the market. It has become even more important in the wake of a rise of approximately 50% in the reporting of suspected ADRs in Europe, a large proportion of them relating to biologicals.

In 2014, biologicals accounted for 42% of 181,000 side-effect reports on centrally approved medicines in the EU or 27% of all suspected adverse reaction reports. Yet, the pharmaceutical industry has been protesting about the weaknesses of the traceability system operated by the European regulatory network, headed by EMA and the regulatory authorities of 28 EU member states represented by the HMA.

Dissatisfaction with the standards of traceability, especially tracking medicines back to the batch and product stages of their manufacture, was evident in the industry’s comments during a public consultation on the last draft of the guideline (2) before the issue of its final version. Comments (3) made during the consultation were published with the guideline.

The European Federation of Pharmaceutical Industries and Associations (EFPIA), Europe’s main trade association for research-based drug companies, and its sister biotechnology organization, European Biopharmaceutical Enterprises (EBE), welcomed the guideline’s emphasis on the importance of batch traceability. “But overall, [it] does not appear to acknowledge the sheer practical challenges of obtaining batch numbers when a suspected ADR is reported for any product and especially biological medicinal products where the reporter may not even be aware of the batch number,” the two organizations said (3), referring to medicines such as insulin, which had been on the market for decades, but also more recent products.

The current pharmacovigilance legislation

Marketing authorization holders have had a low response rate to repeated requests to the ADR reporter, usually a healthcare professional, for batch data. This has often been due to hospital supply difficulties resulting in substitution so that the prescribers did not know that the patient had been dispensed a biosimilar rather than the original brand, according to EFPIA and EBE. Because of differences in member state regulations on issues such as substitution and hospital prescribing, EFPIA and EBE doubted whether the EU’s present pharmacovigilance legislation on post-marketing surveillance of medicines could provide an adequate traceability system, especially for biologicals.

“Until there is a consistent system in place across the EU that reliably tracks batch numbers of medicines dispensed to patients and follows this throughout the entire treatment pathway, it is unrealistic to expect such information to be collected via current routine pharmacovigilance activities,” the two organizations said (3).

The EU’s current pharmacovigilance (PV) legislation (4) was approved in 2012 with EMA being made responsible not just for monitoring centrally approved medicines but coordinating the whole PV system in the EU and the three non-EU states of Norway, Iceland, and Liechtenstein. EMA also maintains various central databases storing information on ADRs both in Europe and worldwide.

Member states of the EU have been criticized for delaying the transposing of the PV legislation into their national laws with some holding back the transfer to 2014. In addition, the publication of PV guidelines on a range of aspects of the legislation has been slowed down.


The European Association for Bioindustries (EuropaBio) has, for example, urged that the biologicals guideline should only come into effect with other relevant guidelines whose revision has yet to be finalized, particularly dealing with risk management of known and potential safety issues. In addition to the issue of manufacturing variability and traceability, the guideline pinpoints other major challenges with pharmacovigilance of biologicals, such as immunogenicity and stability of the medicines during distribution. Nonetheless, EMA and HMA have made few significant changes in the guidelines following the comments during the public consultation, despite the increased burden on the industry in dealing with the big rise in ADR reports.

In the final version of the guideline, the need for MAHs to give details of numbers/codes of batches and their geographical distribution in safety update reports, particularly after changes to manufacturing processes, has been deleted. But it does refer to batch information as being “required data” when MAHs assess new ADRs needing further investigation. The guideline also mentions the necessity to obtain information on batch numbers when MAHs submit or update risk management plans particularly in cases of batch-specific matters.


Recording ADRs

The importance of healthcare professionals and patients giving batch and product data when reporting ADRs is stressed even more strongly in the guideline’s final version. EMA and HMA are hoping that the increased transparency of the PV system will encourage the two groups to become more active in post-authorization surveillance.

The guideline suggests that information on the manufacturing process for biologicals and its variability should be communicated to not just healthcare professionals but to patients as well. Medicines for Europe, formerly the European Generic and Biosimilar Medicines Association (EGA), said that regulatory authorities should consider as an “essential step” the continuous training of professionals on the new PV rules on recording of ADRs and related product information.

The European industry as a whole has been calling for more consistency in the application of pharmacovigilance by the EU’s member states. More uniformity has been particularly important in areas where there seems to be a clash between the PV responsibilities of MAHs to find the “roots causes” of ADRs and the freedom for countries to take their own initiatives in post-marketing surveillance.

“It is important to have a clear separation between activities falling under member state responsibilities and expectations of the marketing authorization holder in terms of traceability,” an EFPIA spokesman told Pharmaceutical Technology. He points out that the guideline stresses that different products with the same international non-proprietary name (INN) should be “readily distinguished so safety issues can be traced to a product, batch, location, or patient.”

Pharmaceutical packaging regulation

Yet member states will be able to exempt hospitals and other healthcare facilities from certain safety features under an EU pharmaceutical packaging regulation (5) due to come into effect in early 2019. The regulation, which is part of the EU’s Falsified Medicines Directive (FMD) to combat counterfeiting of pharmaceuticals, stipulates that individual medicines should have a 2D matrix serialization barcode containing a “unique identifier,” consisting of a product code, serial and batch numbers, and expiry date. The packaging safety features scheme will be an ‘end-to-end’ system under which the serialization and other data on each pack can be verified by a pharmacist with a scanner at the dispensing point.

The regulation is seen by both regulators and industry as a possible effective means of tackling traceability problems with biologicals. “[Yet] member states can exempt healthcare institutions--including hospitals and in- and out-patient clinics--from the obligation to verify safety features on the packaging, including the unique identifier,” says the EFPIA spokesman. “It needs to be understood that the traceability will depend upon the way each member state implements the (regulation).”

Due to manufacturing variability between a growing number of biosimilars and their reference products and increases in changes of manufacturing processes, an effective PV system covering biologicals throughout their lifecycle will become even more vital. A high level of efficient traceability will be a crucial part of that.


1. EMA and Heads of Medicines Agencies (HMA), Guideline 
on good pharmacovigilance practices (GVP)--Product- or 
Population-Specific Considerations II: Biological medicinal products, EMA/168402/2014 (London, Aug. 4, 2016). 
2. EMA and Heads of Medicines Agencies (HMA), Track-change version following public consultation of Guideline 
on good pharmacovigilance practices (GVP)--Product- or 
Population-Specific Considerations II: Biological medicinal products. EMA/168402/2014 (London, Aug. 4, 2016). 
3. EMA, Comments received from public consultation on 
good pharmacovigilance practices, GVP--EMA/168402/2014 
(London, Mar. 3, 2016). 
4. European Union, Implementing Regulation 520/2012. 
The performance of pharmacovigilance activities provided 
for in Regulation 726/2004 and Directive 2001/83/EC (Brussels, June 19, 2012).
5. European Commission, Delegated Regulation 2016/161, 
supplementing Directive 2001/83/EC, Detailed rules for 
the safety features appearing on the packaging of medicinal products for human use (Brussels, Oct. 2, 2015).

Article Details

Pharmaceutical Technology
Vol. 40, No. 10
Pages: 18–20


When referring to this article, please cite it as S. Milmo, "Pharmacovigilance of Biologics Under Scrutiny,” Pharmaceutical Technology 40 (10) 2016.