BioPharm

www.biopharminternational.com April 2019 BioPharm International eBook 17 Outsourcing Resources Manufacturing improve patient care. To get these emerging medicines to patients who need them on a global scale, biotech and pharmaceutical com- p a n ie s, c ont r ac t d e ve lopme nt and manufacturing organizations (CDMOs), and other industry play- ers will need to find new ways to take these therapies from their current fledgling state to indus- trialized and efficient scaled-up ma nu fac t u r i ng processes. T h is will require building on current production "toolk its" to better meet the tailored manufacturing requirements of these next-genera- tion therapies. After nearly perfecting the pro- cess for developing the first gen- eration of large-molecule therapies, the future of biotechnology will depend on industry letting go of the "one-size-fits-all" approach to bioprocessing in favor of flexible manufacturing infrastructure with the capacity to support the devel- opment of a diverse field of new molecular formats. BRIEF HISTORY OF BIOPROCESSING Several decades ago, the pharma industry began developing large- molecule drugs, or biologics, using m Abs to t reat d isea se i n new ways and provide novel therapy options to patients. Approval of the first mAb for therapeutic use, Orthoclone OKT3 (muromonab- CD3), was in 1986, and, as of late February 2019, more than 95 mAbs or antibody-like products have been approved for therapeutic use since then. Initially, mAbs were of murine origin, but because murine mAbs have a short half-life, are immuno- genic in humans, and have a low efficacy due to a poor interaction with human effector f unctions, they were unsuitable as therapeu- tic entities. To reduce the immu- nogen ic it y issues a nd improve efficacy, the proportion of human sequence content was increased, initially through chimerization (e.g., infliximab) or humanization (e.g., daclizumab). The pharma and biotech industries are now discovering and designing more advanced, complex, and diverse proteins. Today, t herapeut ic m Abs a re typically fully human (e.g., pani- tumumab), and the industry has standardized the manufacturing processes for these drugs around a fed-batch process and mamma- lian cells, allowing for efficient, robust, and predictable output at large scales. Manufacturing has matured in several ways. First, achievable titer level—the main benchmark char- acterizing upstream manufacturing efficiency—has risen dramatically over the past two decades. Titer defines the amount of an expressed agent, generally a protein in aque- ous solution, relative to the vol- ume of liquid containing the agent, usually bioreactor volume. Higher titer levels generally mean that more product can be produced for a given bioreactor volume. Today, titer can exceed 10 g/L in some cases, a significant increase since 2000, when titer levels were less than 1 g/L (1, 2). Second, the time taken to pro- duce lead cell lines has dramati- cally shortened, from 104 weeks in the 2010 to approximately 15 weeks today. With the use of pools of stable clones rather than select- ing a single producer cell line, the time-to-start for protein produc- tion could be brought down to as little as five weeks. F i n a l l y, a s m A b t h e r a p i e s b e c o me e a s ie r to p r o d u c e at large scale, the cost of goods has decreased more than 1000-fold for certain processes. INCREASINGLY COMPLEX MAB FORMATS Mea nwh i le, biopha r maceut ica l advances are leading to the devel- opment of next-generation anti- body for mats beyond standard mAbs, with exciting implications for medical research and future treatment through new mecha- nisms or by increasing the efficacy of current modes of action. For example, protease inhibition, long considered to be only possible with peptides or small-molecule mimics (with associated off-target effects), is now increasingly targeted by antibody developers. Engineering the structure of the antibody to block the binding site and confer specificity for a particular protease opens up new potential treatment areas with lower toxicity (3). A nother emerg ing protein is the "multi-specific antibody," or fragments thereof. Designed to bind multiple different ligands, t hese mult i-specif ic ant ibod ies allow for the simultaneous attack on multiple disease pathways or components in a pathway, broad pathogen neutralization, or anti- body delivery to immune-privi- leged organs. Bispecific antibodies (bsAbs) are the most common sub- set of the family. A bispecific for- mat ta rget ing a single protein (double e pitop e bi nd i ng ) c a n improve antagonistic properties while using the bispecific format to target two different markers to improve specificity and potency with fewer side-effects on healthy

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