Q_and_A_IconNandini Kashyap of Cambridge Healthtech Institute recently spoke with Dr. Joel Richard of MedinCell about immunogenicity risk of aggregates and particulates in protein and the analytical and risk assessment trends industry is following. Dr. Richard is the keynote speaker at the 5th Annual Detection and Characterization of Particulates and Impurities which is taking place on January 15-16, 2019 in San Diego, CA where he will be delivering his talk on “Aggregates and Particulates in Protein Formulation: Orthogonal Characterization Methods for a Data-Based Immunogenicity Risk Assessment”. This conference is being organized as part of the 18th Annual PepTalk which runs from January 14-18, 2019 in San Diego, CA.

KEYNOTE PRESENTATION

Aggregates and Particulates in Protein Formulation: Orthogonal Characterization Methods for a Data-Based Immunogenicity Risk Assessment

Joël Richard, PhD, Head, Technical and Pharmaceutical Operations, MedinCell

Aggregation remains a considerable challenge in the manufacturing, stability behavior and delivery of liquid protein formulations. Orthogonal biophysical techniques make it possible to characterize protein structure alteration and the subsequent mechanism of formation of sub visible aggregates and particulates, which are among the most striking issues suspected to trigger immunogenic reactions upon repeated subcutaneous administration. Clinical impact regarding potential safety issues will also be discussed, as identified by regulatory agencies.

SPEAKER BIO

Dr Joël Richard is currently Head of Technical & Pharmaceutical Operations at MedinCell (Montpellier, France). He is leading all the pharmaceutical development and non-clinical pharmaco/toxico-kinetic activities of the company, specialized in the development of Long-Acting Injectables. (LAIs), using the proprietary technology BEPO®. Dr Richard has 30 years of experience in chemistry and biopharmaceutical R&D, including several global senior positions in various Biotech and Pharma companies, such as:

  • Senior Vice President, Pharmaceutical Development – Peptides in Ipsen (France),
  • Vice President, Drug Product Development in Ipsen (France),
  • Director, Pharmaceutical Development in Serono and Merck Serono (Italy, Germany),
  • Vice President Research, and Europe R&D Director at Ethypharm (France),
  • COO at Mainelab (France), a drug delivery company he co-founded, which was specialized in developing solvent-free processes for protein delivery systems.

Since 1996, Dr Richard has focused his research activity on new formulation technologies and drug delivery systems (such as microspheres, nanosystems, gelling systems, chemically-modified proteins, supercritical fluid technology . . .), especially for injectable peptide and protein formulations. Dr Richard has graduated from Ecole Normale Supérieure (Cachan, France). He has got a PhD in Materials Science from University of Paris, France, and the “Habilitation à Diriger les Recherches” degree in Chemistry from University of Bordeaux I. He has published 68 peer-reviewed scientific papers, 8 book chapters and 2 review editorials in various fields (colloids and interfaces, drug delivery systems, supercritical fluids, protein formulations, nanoparticles, . . .). He is the author of more than 140 international communications and 55 patent families.

1. Can you tell us about yourself and about your role at MedinCell?

I have a 30-year experience in R&D including more than 20 years in biopharma R&D with various senior leadership positions in Pharmaceutical Development of biopharmaceutical products in different companies (Serono, Merck, Ipsen …). I have just joined MedinCell a few months ago, after 10 years in Ipsen. I am really excited about MedinCell and my new role in the company. I am leading all the product development activities of the company, which are focused on Long Acting Injectables (LAIs) using a proprietary technology (BEPO®).

2. What are you most passionate about and major obstacles in your field of research?

I am highly passionate about novel formulations of proteins, designed for specific functionalities like e.g. prolonged action or targeting. Long acting formulations of proteins have not been successful on the market in the past two decades. There are still a lot of challenges related to the poor compatibility of most of the biologics with novel formulation processes, due to the presence of water-solvent interfaces, high temperature exposure or use of excipients that induce strong denaturation and aggregation of proteins. The key challenge in the field remains to design protein-friendly formulation processes for long acting formulations.

3. What are the most effective ways to deal with the aggregates and particles that pose immunogenic risk?

In the last ten years, Agencies have put a strong focus on aggregates and particulates in the micron range, since their presence in a formulation of proteins significantly increase the immunogenicity risk. For instance, the USP information Chapter <1787> “Measurement of Subvisible Particulate Matter in Therapeutic Protein Injections” recommends the measurement of 2-10 μm subvisible particle concentrations and the use of “orthogonal” methods to characterize these subvisible particles. It underlines the need to distinguish and when possible identify extrinsic (e.g. fibers) and intrinsic (e.g. silicone oil) particles from other inherent protein-containing particles. In the same way, the Guideline on Development, Production, Characterisation and Specifications for Monoclonal Antibodies and Related products published by the EMEA has stated that “[the] formation of aggregates, subvisible and visible particulates in the drug product […] should be investigated and closely monitored on batch release and during stability studies. In addition to the pharmacopoeia test for particulate matter, other orthogonal analytical methods may be necessary to determine levels and nature of particles.” So, as a summary, beyond the regulatory and compendial requirements for measurements of subvisible particle concentrations, the thorough characterization of the aggregates and particulates is key to evaluate the immunogenicity risk. In addition, biopharmaceutical companies have to anticipate and predict protein aggregation propensity in the early stages of formulation development using relevant “orthogonal” biophysical methods.

4. What are some of the industry trends and where is the field headin in coming years and what will revolutionize this field of research?

In the field of aggregation propensity prediction, the paradigm has changed in the past ten years. Traditional approach used to be based on forced degradation and accelerated stability experiments that made it possible to evaluate aggregation a posteriori, after weeks and months. The new idea is to predict aggregation from day 1, based on the thermodynamic linkage between structural protein stability and aggregation that can be exploited to predict aggregation propensity. Denatured or partially denatured state of proteins is a critical determinant of long-term stability. Formulating proteins means to try to maximize the population of protein molecules in the native state, minimize the population of (partially) denatured conformations, as well as to minimize the rate of aggregate formation. To anticipate and predict the protein aggregation propensity, we need then to characterize the very early structural modification steps of proteins using the appropriate set of relevant biophysical characterization methods. Then with regards to minimizing the aggregation propensity, it is vital to be able to identify and characterize early modifications of the higher order structures (HOS) of proteins - secondary and tertiary structures. Circular Dichroism (CD), Fluorescence techniques, Raman spectroscopy can bring very helpful information in this perspective. Th second point is that there are many different types of physical interactions between protein molecules in solution that determine the colloidal stability, which can be characterized by implementing the right techniques. For example, it is key to understand the influence of electrostatic and hydrophobic interactions, characterizing the surface charge of the proteins and developing the models that help improve this understanding. Zeta potential measurements, Dynamic and Static Light Scattering (DLS and SLS) experiments can support a better understanding of protein-protein interactions and protein interactions with other formulation components. Finally, Isothermal Chemical Denaturation (ICD) experiments can bring key information on the aggregation process, and whether it involves proteins in their native state, or conversely proteins in the denatured state.

5. Why have you chosen to speak at 5th Annual Detection and Characterization of Particulates and Impurities conference at PepTalk and what are you looking forward to at 2019 gathering? What can audience expect from your talk?

I have chosen to speak at 5th Annual Detection and Characterization of Particulates and Impurities conference at PepTalk, because I would like to share my views on the early prediction of protein aggregation propensity with the best experts in the field that will for sure also attend this major conference in the field and get challenged by them on the proposed methodology. In addition, in attending PepTalk I am sure that I will get the best opportunities for networking, discussing key issues of protein formulation, characterization and analysis, and getting high value, expert opinions in so many different areas of protein science.

6. Do you have any closing remarks?

As usual, PepTalk and the 5th Annual Detection and Characterization of Particulates and Impurities conference show a really great scientific programme and impressive speaker panel. So, I am really excited by attending this major event in the field and eager to meet with strong, highly recognized experts in the field of protein science, more particularly protein formulation and stability. I would like to thank you for inviting me and giving me the great opportunity to deliver a keynote lecture at PepTalk 2019.