With biosimilars playing an increasingly prominent role in healthcare, maintaining a successful clinical supply chain is crucial, but the process is fraught with potential pitfalls. As with all biologics, the complexity of the manufacturing process can have an impact on the reliability of supply, and successfully maintaining product integrity and reliability through the supply chain can be difficult to master.

A biosimilar is an approved biologic medicine that it is similar in structure to the original ‘reference product’. However, unlike generic medicines, in which the active ingredients are identical to the small-molecule drugs reference, biosimilars exhibit fundamental differences in their complexity and development.

Crucially, a biosimilar must have no clinically meaningful differences in terms of safety and effectiveness from the original reference product. Thus, it presents the same issues in terms of supply and transportation as other biologic medicines.

Benefits and challenges

“Meeting this challenge involves understanding which reference product attributes are critical, and which manufacturing parameters need to be controlled to produce the desired product,” says Jeff Yant, executive director of global operations at California-based Amgen Biosimilars.

“This is difficult because biologics are particularly large and complex molecules, and they’re highly sensitive to complex manufacturing conditions. There have been instances when our initial processes did not produce medicines that matched reference product ranges for key quality attributes. These offsets can arise unexpectedly at many different stages of process development and manufacturing. In each of these cases, we decided to go back to the lab to recentre our process through further development work.

“These can sometimes be difficult decisions, especially when our data is on the edge of our predefined targets, because they often involve programme delays. But this is generally a better decision than proceeding into clinical trials with similarity risk,” he concludes.

Disruptions to the supply of biosimilars, and biologics in general, are not uncommon, particularly for oncology drugs. In order to avoid treatment delays and unplanned switching between medicines during the course of treatment, it is important to consider the robustness of the manufacturer’s supply chain when evaluating biosimilars. It is also important to consider a pharmaceutical company’s history of shortages and recalls related to quality concerns, and evaluate its capability to maintain adequate supply.

Yant says that Amgen’s biosimilars experience has contributed significantly to its understanding of how to manufacture biologics and manage them through the supply chain. “The conditions we choose for our biosimilar will certainly be different from those used to produce the reference product and from one biosimilar to another,” he says. “We need to understand and control how various conditions affect our biosimilars throughout cell line development, process development, tech transfer, manufacturing, release and distribution to ensure that the right product is delivered to patients reliably.

“Biosimilars will be different, because the reference product manufacturer’s cell bank and manufacturing conditions are all proprietary,” continues Yant. “Each biosimilar manufacturer will therefore make its own, unique choices for cell line and myriad process conditions.

“Consequently, the product it produces will be different from the reference product and from all other biosimilars. Understanding and routinely controlling these differences during manufacturing is a key differentiating factor for success.”

Biologics are particularly large and complex molecules, and they’re highly sensitive to complex manufacturing conditions.

Supply chains strategy

Perhaps the biggest challenge for biopharmaceutical companies in managing biosimilars supply is overseeing the transit of medicines through numerous countries and check-in points. Understanding the culture and dynamics of particular regions is crucial for protecting a product from criminal interventions including theft, redistribution and counterfeit operations.

Temperature control is another key issue, given that biosimilars are largely cold chain products and may be sensitive to fluctuations in temperature during transportation. This may present a challenge if the product needs to be carried by multiple contractors and if there are unexpected delays in the transit process; ‘contractor to contractor’ contracts and methodology is a key area of consideration.

“Amgen’s supply chain is based on the hard-won experience of supplying medicines to patients for over 35 years,” Yant comments. “Biosimilars have required a higher degree of nimbleness. For example, these products require that we monitor the reference products life-cycle management changes, and sometimes adjust our development and manufacturing strategies to stay competitive.”

Innovations in supply chain management now include high-grade product barcoding, state-of-the-art tracking devices and the hiring of specialist companies that monitor biosimilars throughout transportation. Manufacturers need a tightly honed and detailed project management strategy for supply that takes into account multiple factors.

It is often the key transfer points in the shipment process that are most vulnerable and require specific contingency and mitigation. Regulators often insist on a certain degree of transparency in supply chain processing, but biopharmaceutical companies also need to balance this with the critical need for the security and safety of the shipment, and the integrity and confidentiality of the company’s brand. This can be a hard line to maintain in a competitive global marketplace.

Understanding and routinely controlling these differences during manufacturing is a key differentiating factor for success.

Manufacturers need to make pharmacies and supply outlets aware if there is a potential risk of stolen biosimilars re-entering the market through counterfeit means. Discounted sales of pharmaceuticals via online pharmacies need to be monitored to check their legitimacy, and lot numbers and bar codes of stolen goods should be made available as a preventative measure against the products re-entering trade.

As well as the economic implications for manufacturers, stolen pharmaceuticals are at risk of being tampered with and of not being stored correctly, which can have dangerous implications for the patients taking them.

Future developments

The globalisation of the pharmaceutical industry has meant that manufacturers have had to address issues regarding the safety and security of their supply chains head-on, as the transit of medicines now involves crossing multiple terrains with the potential for major issues to arise.

The upside of this is that we can expect to see a more secure global supply chain developing, and a more efficient import and export process that guarantees the shipment of safe, high-quality biosimilars and other pharmaceuticals to patients.

Yant believes that increased competition in the biosimilars market may cause manufacturers to seek new opportunities for reducing manufacturing costs. This increase in competition will probably encourage the dual-sourcing of biosimilars from multiple locations and manufacturers, which will further increase the need for well-managed clinical supply chains that place safety and security at the top of their agenda.

Clinical supply chains and GMP

Good manufacturing practice (GMP) and good distribution practice (GDP) are of particular importance in the production and transport of biosimilars. The Medicines and Healthcare products Regulatory Agency (MHRA) outlines expected requirements for the manufacturing and delivering of drug supply, which can make successful management of the supply chain a challenge:

  • Controlling temperature and shipment integrity: to comply with regulations, a temperature monitor must be able to track and trace data at specific intervals throughout transit. However, this can be a complex and time-consuming process if multiple vendors and databases are involved, and if there is no centralised strategy for tracking and analysing data.
  • Increased costing versus wider patient pool: as global demand for biosimilar medicines increases, pharmaceutical companies are under pressure to reach a broader patient base in multiple territories. This brings with it the risks and costs of managing product life-cycle, cultural and regulatory issues, storage and packaging demands throughout an extended transit process.
  • Reliability of supply versus complexity of manufacturing: maintaining reliability of supply can be a huge challenge for the biologics and biosimilars market. Shortages of prescription medicines is a growing issue worldwide and, for biologics, the complexity of manufacture can be a major factor in meeting demand at patient level. Avoiding drug shortages through best practice is essential for avoiding drug shortfalls and maintain a competitive advantage.
  • Logistics of drug supply versus direct-to-patient (DtP): as the industry moves towards a more patient-oriented approach (particularly with regard to actioning clinical trials), the DtP model is a growing trend. Manufacturers must continue to overcome strategy, quality and cost issues to ensure viability and integrity in this developing global market.