Biobetters Biobetters ( also called biosuperiors ) is a term that is commonly used to refer to new molecular entities that are related to existing biologics but that are deliberately altered to improve duration of action , ease of administration , efficacy or safety . They are different than biosimilars , which do not have any clinically meaningful differences from the reference biologic . 8 , 9 With potential competition from biosimilars , reference product manufacturers may develop a biobetter for their original biologic in order to provide patent protection and sales of a new molecular entity that can compete with the reference biosimilar .
Critical quality attributes Slight differences between manufactured lots of the same biologic product are normal and expected within the manufacturing process . In controlling this within-product variation , critical quality attributes ( CQAs ) are evaluated to ensure that they fall within a range of acceptable variability . 10 This ensures that the variation does not adversely affect safety or efficacy . Important CQAs monitored include structure , glycosylation , biological activity , and process impurities . This assures that different batches or lots of a particular biologic are highly similar to another batch of the same biologic product . Similarly , when comparing a biosimilar to its reference product , CQAs are carefully examined during the regulatory process to help assure that no clinically significant differences occur . 11
Drift and evolution All manufacturing processes have inherent variability and although some is normal with biologics , any changes must be monitored and investigated . 12 Manufacturing processes can also change due to changes in : production materials , manufacturing site , regulatory requirements , changes in technology , filtration and purification process , pH levels , or inactive ingredients . Another source is the change in the manufacturing process itself to try to increase the yield of the target protein . Any of these potential changes could affect the activity of the drug . Occasionally , quality attributes of the biologic or biosimilar change over time without affecting the activity , which is referred to as drift or evolution .
Drift refers to unintended or unexplained change of the final product over the product ’ s lifetime . Drift might be a gradual or sudden change . Evolution is a deliberate process change to the final product such as removing certain inactive ingredients or changing a filtration process . It is important to note that through both drift and evolution , biologic products produced today are not exactly the same as products that were first FDA approved . One of the theoretical concerns raised regarding biosimilars is that over time the drift or evolution that can occur with both the reference product and the biosimilar could potentially be great enough to result in some clinically meaningful differences , even though no differences were noted at the time of product approval . 13
Extrapolation Extrapolation is a component of the biosimilar regulatory process where approval is granted for an indication held by the reference biologic that is not directly studied in a clinical trial with the biosimilar . Extrapolation is based on the assumption that the indications that are approved by extrapolation have the same mechanism of action and that the sensitivity of the population that is studied is appropriate . 14 For most biosimilars approved to date in the US and in Europe , the biosimilars have received the same indications as the reference product ( excepting those that are limited due to licensing exclusivity issues ) largely through extrapolation .
Immunogenicity Immunogenicity is a common concern with biologics that can be affected by their complex structure and the use of different cell lines and / or manufacturer changes . The FDA defines immunogenicity as the propensity of the therapeutic protein product to generate an immune response to itself and to related proteins or to induce immunologically-related adverse clinical events . 15 This can occur when a patient develops antibodies , often referred to as anti-drug antibodies ( ADAs ) or neutralizing antibodies , against the biologic product . These antibodies can either bind to and neutralize the biologic product , thus decreasing its efficacy , or elicit an immune response such as hypersensitivity reactions including anaphylaxis . This concern is important when developing biosimilar products and becomes a core feature to be investigated when seeking approval . 16
Interchangeability This refers to a status that may be granted to a biosimilar that is : “ expected to produce the same
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