What To Do About Process Drift In Your Biosimilar's Reference Product

By Ki Tae Bong, vice president and head of process development, Samsung Bioepis

Since the emergence of recombinant technology in the 1980s, biopharmaceuticals have transformed the way patients are treated, fundamentally shifting medical treatment from symptom management to targeted treatment.¹ Biologics – mostly monoclonal antibodies – have revolutionized the treatment of wide-ranging conditions that were once considered unmanageable, including rheumatoid arthritis, cancer, diabetes, and many others.² They are continuing to evolve and next-generation biologics such as antibody-drug conjugates, CAR T cell therapies, and gene therapies are now leading the growth of the biologic market.

Unlike small molecules, biologics are a complex mixture of active molecules, produced in living cells, which can be sensitive to manufacturing conditions.³ With every biologic, there is an inherent degree of structural heterogeneity in proteins due to the biosynthetic processes that living organisms use to produce proteins.⁴ Because biologics are so sensitive to changes in external conditions, they need to be tightly monitored for any variations in quality throughout different stages of the manufacturing process from lab scale to commercial manufacturing, as well as during process modifications, which often occur in the post-marketing phase for life cycle management of a product. Regulators require manufacturers to conduct “comparability” assessments for pre- and post-manufacturing changes in order to ensure that manufacturing changes do not result in clinically meaningful differences that can impact patients’ health.⁵

Comparability And Biosimilarity

Biosimilars began to be developed in the mid-1990s as the patent exclusivity for early blockbuster biological medicines began to expire.⁶ The goal was to provide more affordable, high-quality alternatives, leading the European Medicines Agency (EMA) to create the first dedicated regulatory pathway for biosimilars in 2005.⁷ Biosimilarity — a regulatory and scientific term defining that a biological medication (a biosimilar) is highly similar to an already approved biologic medication — is fundamentally rooted in the concept of comparability.⁸ It uses the same scientific principles — extensively comparing structural and functional attributes to a reference product — originally developed to prove that manufacturing changes in a single biologic have no adverse impact on safety or efficacy.

Development of a biosimilar requires a stepwise approach, and it begins with thorough analytical and functional evaluation of the reference product’s profile, also referred to as “product characterization.” In order to define the critical quality attributes (CQAs) – quality targets for physical, chemical, biological, or microbiological properties – a large number of reference products are collected and analyzed for a lengthy period of time, sometimes over 150 lots.⁹ Interestingly, biosimilar development often leads to discovery of quality drifts in certain lots of the reference biologic. In most cases, quality changes are noncritical, but some drifts were found to impact CQAs such as glycosylation, purity, and potency, which can affect the safety and efficacy of the biologic therapy.

This was the case of trastuzumab, where the manufacturer found a downward drift in antibody-dependent cellular cytotoxicity (ADCC) activity in certain lots of the reference product with expiry dates from August 2018 to December 2019. It was important to analyze what caused this downward drift because ADCC is one of the clinically relevant mechanisms of action for trastuzumab, and the biosimilar manufacturer needed to justify that the biosimilar was comparable to the reference product with consistent ADCC activity, glycosylation, and Fc binding. Further analysis found a downward drift in the proportions of afucosylated glycans and an upward drift in the levels of high-mannose gylcans in the reference product, and a follow-up to the Phase 3 study that lasted five years found that the biosimilars were comparable to the reference product and there was no clinically meaningful difference in cardiac safety and long-term efficacy.¹⁰

In order to mitigate heterogenicity risks in biosimilar development, three things need to be considered:

Extensive characterization of the reference biologic

When evaluating quality attributes, every quality attribute needs to be accounted for. A deviation in one quality attribute can potentially impact the quality of a biosimilar’s clinical profile. Many of the quality attributes are directly or indirectly linked to clinical effects such as safety, immunogenicity, efficacy, and pharmacokinetics (PK).

There are two aspects of characterization: structural and functional. Structural characterization confirms that the molecule has the correct primary structure, three-dimension fold, and purity level where impurities are contained within safe, comparable limits. Functional characterization confirms that the structural similarity translates into equivalent biological activity (e.g., binding to receptors, antibody-dependent cell-mediated cytotoxicity).

Once manufacturers set the quality target with early-stage batches, it is important to maintain the consistent quality throughout clinical batches, PPQ batches, and commercial batches. For every stage of development, manufacturers should collect samples of products to confirm analytical and functional comparability to the reference product and maintain the tightest specification of quality throughout the whole life cycle.

Stringent quality target control & risk-based assessment

In order to produce high-quality biosimilars, manufacturers need to implement a tollgate system with stringent quality targets. Biosimilars move on to the next phase of development depending on the "go" or "no-go" decision made at each tollgate, and only the highest-quality biosimilar candidates that meet or exceed the quality target can pass each stage of screening.

As part of the risk-based assessment, manufacturers sometimes tier up quality attributes, and tiers are determined by their relevance to clinical impact, such as efficacy, PK, pharmacodynamics, safety, and immunogenicity. To increase the product quality and lower the risk of variation, biosimilar manufacturers should tightly control their quality targets and take into consideration the largest historical data of the reference to derive the most stringent quality range.

Utilization of advanced quality by design (QbD) approach

Manufacturing consistency and process capability are important parts of the QbD approach. This includes maintaining consistent product specifications during in-process testing (specifications of the biosimilar candidate in different stages of development) and lot release testing (specifications of the finished product), as well as stability testing, which is essential for checking any degradation during storage of the product.

As analytical technologies continue to evolve, manufacturers adopt new assays that are more sensitive and accurate in assessing product quality. With advancements in artificial intelligence, many manufacturers are now testing or utilizing digital twins to achieve higher efficiency and optimization of process development. A digital twin is a dynamic virtual replica of a physical biopharmaceutical manufacturing process, such as a bioreactor or purification system, that uses real-time data to simulate, predict, and optimize production. By creating a "living" computer model that parallels the physical process, manufacturers can test changes and predict product quality in silico before applying them in the real world.

The Future Of Biosimilar Development

The ultimate goal of biosimilar development – which is to establish biosimilarity to the reference product – does not change, and biological development will continue to move toward greater sensitivity, accuracy, and precision. Thorough and extensive characterization of the reference product, as well as consistent quality management throughout the entire process development, will continue to be the key success factors for any biosimilar development. The difference will be determined by how much manufacturers achieve time/cost efficiency and process optimization by using advanced analytical tools, methods, and digital resources that are currently available.

References:

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About The Author:

Ki Tae Bong, Ph.D., is vice president and head of process development at Samsung Bioepis, where he has worked since its founding. Throughout his tenure, he has received roles of increasing responsibility, working as a senior engineer, principal scientist, and director before his current executive role. He received his Ph.D. in engineering from the Sungkyunkwan University.