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By: Jon S.B. de Vlieger, Daan J.A. Crommelin, and Vinod Shah

jon-de-vliegerNederland, Leiden, 14-07-2006 Prof. Daan J.A. Crommelin, Ph.D, oprichter and C.S.O. Octoplusvinod-shah







Biologics and non-biological complex drugs, including many nanomedicines, make up a significant portion of the products currently in different phases of development, under regulatory review, or already prescribed to patients. The first generic and similar versions of these products are now available for patients. Nevertheless, ongoing lively discussions between all parties involved illustrate the challenges associated with determining pharmaceutical and bioequivalence of these complex drug products.

Characterization of a product is key to a successful marketing authorization. During the 2016 AAPS Annual Meeting and Exposition in Denver, the symposium, Analytical Characterization of Complex Drug Products: Can We Keep Up with Complexity? dealt with questions related to the characterization of complex drugs. After a brief introduction to the topic, presentations were given on the current state of affairs in particle size measurement techniques in the nano/colloidal range and on novel approaches to understanding the pharmacokinetics of complex drugs through bioanalytical methods measuring drug release.

For biologics and their biosimilars, clear guidance policies are in place to aid the development of high-quality products. These guidance documents build on a stepwise comparison of the reference-listed drug and the similar version, starting with extensive physicochemical characterization up to clinical comparison studies. In essence, better preclinical characterization means that less clinical work is needed to show similarity. As a consequence, time and money are saved.

The Holy Grail in this quest for determining similarity is identifying the critical attributes. These critical attributes are those product characteristics that ensure efficacy and safety in humans. Differences in the critical attributes between two products directly imply differences in the in vivo performance. It also means that if these characteristics are the same, one can expect both products to perform the same in our patients.

To understand which product characteristics make up this set of critical attributes, physico-chemical characterization is important, as well as the availability of appropriate and validated in vitro and in vivo models. Only when one establishes the relationship between preclinical characteristics and in vivo performance, the critical attributes can be defined.

These insights are essential to understanding the interactions between nanomedicines and the biological environment, a topic that was also addressed during the AAPS symposium in Denver. From the presentations and the discussions afterwards, it became clear that much progress has been made in the development of sophisticated assays. However, it remains challenging to establish which differences in physicochemical characteristics of complex drug products are clinically meaningful. Similar to carpenters, they have, like us, a toolbox well-filled with sophisticated equipment. A skilled and experienced carpenter knows which tool is fit-for-purpose, and how to use it to obtain the best possible result matching the blueprint of the final design.  Thus, the message for us, pharmaceutical scientists, is, let’s master our toolbox like no one else, make sure we lay our hands on the blueprint, and that the final design meets all the necessary requirements!

Daan J. A. Crommelin, Ph.D., is emeritus professor at the department of pharmaceutics at Utrecht University and publishes extensively in the field of advanced drug delivery and pharmaceutical biotechnology. He was the scientific director of the Dutch Top Institute Pharma, a public private partnership currently known as Lygature. He is editor in chief of the AAPS Advances in the Pharmaceutical Sciences Series and Steering Committee member of the NBCD Working Group.
Vinod P. Shah, Ph.D., is a pharmaceutical consultant. He retired as a senior research scientist from FDA after 30 years of service in 2005. He was the scientific secretary for FIP from 2003 to 2011 and is a steering committee member of the  NBCD Working Group.
Jon S.B. de Vlieger, Ph.D., obtained his doctoral degree in bio analytical chemistry from the VU University in Amsterdam. In 2011 he joined Lygature, an independent not-for-profit organization based in the Netherlands that catalyzes the development of new medical solutions for patients by driving public-private collaborations. For Lygature, dr. de Vlieger coordinates several international public private partnerships, including the Non Biological Complex Drugs Working Group. He is a co-editor of the book on NBCDs in the AAPS Advances in the Pharmaceutical Sciences Series.