Biosimilars & Biobetters
Biologicals are a fast growing segment of the pharmaceutical market and over 30 branded biologics with sales in excess of $50 billion are facing or have exhausted patent expirations. That represents a significant business opportunity to develop Biosimilars.
Biosimilars – A Quality by Design Concept
Biosimilar development is not without challenges. The complexity of the problem equates with the complexity of the molecule. Biosimilar manufacturing can be expensive because the candidate needs to be fully characterized in comparison with the innovative biomolecule, pharmacology and toxicology studies need to be conducted, then the requisite clinical trials need to be designed and executed. Unlike with small molecule generics, the process of developing and commercializing a Biosimilar can take upwards of 7 years or even longer.
When one develops an innovative protein, they can define their own criteria. However, when making a Biosimilar, the product and process developed have to meet much tighter regulatory standards. Biosimilar companies will need to provide a significant amount of analytical, physical, and clinical evidence to demonstrate that it is highly similar to the innovator.
A number of biosimilars have been approved and launched in Europe. Despite the fact that the European Medicines Agency developed some general guidance in 2005, which is currently under revision, and has since released other guidelines for manufacturing requirements and analytical specifications for specific biological types, and the International Conference on Harmonization (ICH) published its Q6b quality guidelines that describe test procedures and acceptance criteria for biologics, the development of a Biosimilar remains a hot topic of discussion.
Meanwhile, in the U.S., the 2009 Biologics Price Competition and Innovation Act (BPCIA) helped provide the industry with the legislative pathway to approval of Biosimilars, and the FDA published an article in 2011 that provided some insight into how those guidelines might actually play out. For the FDA Guidelines, please click here. In short, the FDA seems to be implementing the concept of Quality by Design (QbD), which is a systematic and science-driven approach demanding the application of process understanding (process parameters and process controls) and product knowledge (product specifications and product quality attributes) to present a “totality of evidence” required to confirm sufficient similarity.
Common Challenges in Characterization
Goodwin Biotechnology will design your approach for characterization and comparability studies of the Innovator Drug Product and your Biosimilar Drug Candidate.
A Biosimilar needs to have quality attributes that are very similar to the innovator product. Therefore, it is critical to characterize the reference product very thoroughly so that the targets for identity and purity profiles are understood. Then, similarity can be established by conforming to the known quality standards and established reference standards. In the event that uncertainties are identified, they will have to be evaluated for potential clinical significance to ensure similarity and possibly interchangeability.
At Goodwin Biotechnology, we offer a wide array of analytical assays to demonstrate adequate comparability, in addition to full characterization and stability studies that are essential in testing of Biosimilars and in providing a side-by-side comparison to the Reference Innovator Drug Product. Key considerations that must be addressed include identity (primary, secondary, tertiary and quaternary structure), purity, potency, safety and immunogenicity.
Strategic approaches toward performing comparative characterization of a Biosimilar versus an innovator product involves:
- Consideration of factors in Biosimilar comparability evaluation
- Biochemical characterization (product and process knowledge)
- Non-clinical characterization (relevant species model)
- Clinical characterization (severity of condition; heterogeneity of patient population; feasibility of trials design [e.g., the number of patients])
- Consideration of elements to successful Biosimilar comparability
- Product knowledge –critical quality attributes: what matters and why; structure-function understanding; product stability profile; historical ranges and leveraging innovator supplement ranges
- Process understanding – critical process parameters; link between process parameters and critical quality attributes; where are the sources of variability
Because the Biosimilar will be based upon the formulation composition of the existing innovator product, a risk analysis will be used to establish which variables and unit operations are likely to have the greatest impact on product quality. Critical Quality Attributes may include aggregates formation, sub-visible particles, visible particles, certain sugars (e.g., fucose, galactosylation, etc.), host cell protein, residual DNA, among others. Further risk assessment on the product formulation composition may be performed. This may include pH, antibody concentration, detergent concentration, buffer salt concentration, primary container, raw material impurities, sugar (e.g., mannitol, sucrose) concentration, and other considerations.
Analytical Assays that may be selected for side-by-side comparability testing with the innovator drug include:
A Biobetter May Be a Prudent Approach
- Biobetters vs Biosimilars
- Why Not a Biobetter?
Biobetters are proteins that are biosuperior when compared to the innovative biological, based on a protein modification (molecular or chemical) that may translate into an improvement over the reference protein product.
Whether your goal is to develop a Biobetter or after the comparative characterization work has been completed, and it becomes clear that your protein is not suited to be a Biosimilar, perhaps a Biobetter strategy should be pursued.
At Goodwin Biotechnology, we can partner with you to develop a strategically sound approach that is designed to cost-effectively produce a high quality Biobetter as rapidly as possible.
Biobetter strategy improvements/modifications can be made by protein or glycol-protein engineering:
- Start with the same gene sequence
- Utilize the same or different vector
- Use the same or different host cell
Another strategy is to leverage our unique and unrivaled expertise in the research, development, validation and multi-gram GMP manufacture of bioconjugates. Goodwin Biotechnology has many years of experience and multiple patents pending in protein modifications through chemical conjugation of cancer drugs, protein toxins, bifunctional ligands and metal chelates (for radio-isotope labeling), antibodies and other biological molecules onto monoclonal antibodies and recombinant proteins. The conjugates are then used for diagnostic and/or therapeutic purposes. The benefits of bioconjugation and protein modification are:
- Earlier and improved diagnosis
- Greater cell kill
- Lower patient toxicity
- Reduced Cost of Goods
Goodwin also has both the expertise and experience in protein modification utilizing either chemical conjugation or enzymatic digestion. Antibody modification through enzyme digestion is another Goodwin Biotechnology staff specialty. The production of Fab and F(ab’)2 fragments and their subsequent purification can be achieved to a client’s specifications. These processes are GMP compliant and scalable to multi-gram lot sizes for clinical applications.
Where Goodwin Shines: A Case Study of the Development of a Biosimilar Commercial Product
Biosimilar commercial product; Upstream and Downstream activities included the completion of many upstream development production Batches (up to 200L Bioreactor Scale) in GMP facility and development of a complex Five (5) Column purification Process.
Biosimilars Regulatory Strategy
We will work with you and the relevant regulatory group(s) to develop a strategy to identify regulatory pathways and gain regulatory approval of your Biosimilar in accordance with the requirements of the FDA, EMEA, WHO, DCGI, and / or others.
For more information on the following guidelines, click on the link below:
Based on the challenges of a Biosimilar, it is critical to have pre-submission meetings with the relevant agency or agencies to discuss the approach, then maintain open communications for frequent consultation throughout the development process.
What Clients Say
We work with a number of companies around the world to advance our portfolio of drug candidates, and one of our primary collaborators highly recommended Goodwin Biotechnology based on the track record they had on a number of their projects that Goodwin Biotechnology had worked on over the last six years.
Your Biosimilar or Biobetter
To learn how Goodwin can help with your Biosimilar or Biobetter, Contact Us