important consideration with all biologics is unwanted immunogenicity as biologics are often manufactured in living cells of nonhuman origin. Unwanted immunogenicity may lead to a reduction or loss of efficacy, altered pharmacokinetics, general immune and hypersensitivity reactions, and neutralization of the natural endogenous counterpart.46 Immunogenicity of biosimilars would be expected to mirror those of the innovator biologic based on the similarity principle.47
1.6.4 Definition of Frequency of Adverse Effects
Pharmacists and doctors need to understand the accepted definitions of the frequency of adverse drug reactions. The Council for International Organizations of Medical Sciences (CIOMS), an international nongovernment organization established jointly by WHO and UNESCO in 1949, and its Uppsala Monitoring Centre, UMC, define48 the frequency of adverse reactions as:
Very Common (≥1 in 10); Common/Frequent (≥1 in 100 and <1 in 10); Uncommon/Infrequent (≥1 in 1 000 and <1 in 100); Rare (≥1 in 10 000 & <1 in 1 000); and Very Rare (<1 in 10 000).
1.6.5 Pharmacovigilance of Biologics
Any drug may produce adverse reactions, with varying levels of severity and frequency. Not all adverse reactions are, however, identified before the approval of a new drug, some only being observed during post‐marketing use when the drug is prescribed more widely to patients, as opposed to only clinical trial participants.
As part of the marketing authorization for biologics, the sponsor must submit a pharmacovigilance plan as part of a risk management plan (RMP) to the relevant authorities in accordance with EU regulations.49 Applicants seeking biosimilar approval also need to submit an RMP, as required for innovator biologics. The purpose of an RMP is to document the risk management system necessary to identify, characterize, and minimize a drug's significant risks. The plan should incorporate identified and potential risks outlining a plan for pharmacovigilance activities, to characterize and quantify clinically relevant risks, and to identify new adverse reactions and outline risk minimization measures.50
1.7 Manufacture, Delivery, and Naming Considerations
1.7.1 Post‐Translational Modifications (PTMs)
Biosimilars, like innovator biologics, raise challenges compared to SMDs, due to manufacturing complexity, presence of minor natural variations in the molecular structure (collectively known as microheterogeneity), and post‐manufacturing (post‐translational) modifications.51,52 The production of innovator biologics and biosimilars comprises numerous steps and minuscule differences in the product may result in different clinical outcomes. Consistent drug discovery and manufacturing paradigm are likely to minimize product variations. Besides, drift (unnoticed and unplanned deviations) and evolution (planned changes) may lead to divergence, which can also lead to product variability and different product attributes. Divergence means that the biosimilar and the currently marketed innovator differ from the originator product that was first approved and marketed and the innovator product that was used in the comparability exercise.53 Biotechnology process and manufacturing innovations, needed for regulatory reasons, production scale‐up, change in a facility or raw materials, and improving quality or consistency or optimizing production efficiency,54 may lead to a higher quality biologic.
Identifying and controlling PTMs and demonstrating biosimilarity require specific and sensitive analytical techniques. Pharmacists need to be familiar with such techniques and issues; these are discussed in Chapter 6.
1.7.2 Quality by Design Paradigm
Quality by design (QbD) is an approach that aims to ensure the quality of medicines by employing statistical, analytical, and risk‐management methodology in the design, development, and manufacturing of medicines. It focuses on the use of multivariate analysis, often in combination with the modern process and analytical chemistry methods, and knowledge‐management tools to enhance the identification and understanding of critical attributes of materials and critical parameters of the manufacturing process. This enhanced understanding of product and process is used to build quality into manufacturing and provide the basis for continuous improvement of products and processes.55
One of the goals of QbD is to ensure that all sources of variability affecting a process are identified, explained, and managed by appropriate measures. This enables the finished medicine to meet its predefined characteristics consistently.
The concepts behind QbD were introduced into international pharmaceutical guidelines between 2009 and 2012. EMA accepts applications that include QbD concepts.
1.7.3 Delivery Devices for Biologics
Converting a promising innovator biologic or biosimilar molecule into a pharmaceutical product presents numerous new challenges. For example, biologic medicines are highly viscous and formulated at high concentrations, which makes them more prone to aggregation. In addition, they need to be handled, packaged, stored, and transported carefully.56 These requirements are driving innovation in packaging and delivery device development as, increasingly, drug companies demand technologies that can protect and administer these high‐value medicines safely and conveniently.57
Historically, all biologic drugs were freeze‐dried and packaged in glass vials and administered, after reconstitution, using glass syringes. While most biologics are still packaged and delivered using glass, a growing number of biologics (including biosimilars) are packaged in plastic vials and administered using plastic syringes.
Devices for biosimilar administration are essential in quality use of medicine (QUM) considerations for biosimilars as for all biologics58; they may also have critical practical implications for patients. These devices, either prefilled syringes, pens, or pumps, are important for dosing accuracy and reproducibility as well as long‐term patient compliance and adherence. From a patient perspective, one would envisage that the device via which a biosimilar is administered must at least be able to match the innovator biologic's device for convenience and comfort. Inferior usability may also reduce treatment adherence and product uptake by patients. The design and user experience of the delivery device may also serve as a critical market differentiator between the innovator biologic and the biosimilar.
1.7.4 Naming and Labeling of Biosimilars
A critical question that is still eliciting much debate internationally is the naming convention for biosimilars; in other words, what should be their nonproprietary (noncommercial) name?
SMD generic medicines have the same nonproprietary names as their innovator medicines as the active ingredients in generics are identical to that in the innovator drugs. In contrast, biosimilars are not identical to innovator biologics. Giving all biologics, including biosimilars, different (distinguishable) nonproprietary names are consistent with the concept that no two versions of a biologic including a biosimilar are identical.59
Views on the naming of biosimilars fall broadly in two groups. The first is that since a biosimilar is highly similar to its innovator biologic, it should have the same name as the innovator. The other view is that for safety reasons, it is critical to have a unique name for each biologic, including a biosimilar so each biologic can be identified individually.59
Under the FDA's naming system, each biologic, innovator/reference product, and biosimilar receives a unique nonproprietary name;
