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Article / Nov 01, 2015

In-depth Process and Product Expertise

Pharma's Almanac – A Nice Insight Supplement, Q4 2015 Edition

In-depth Process and Product Expertise – This is Key to CDMO Support of Orphan Drug and Breakthrough Therapy Development & Commercialization

As older blockbuster drugs lose patent protection and generic competition increases, many pharmaceutical companies are focusing discovery efforts on therapies with the potential to treat multiple niche populations. Increasingly, innovative small and emerging pharma firms are developing new drug candidates with orphan or breakthrough therapy status that are ultimately licensed or sold to large brand manufacturers. These companies rely heavily on contract manufacturing and development organizations (CDMOs) that can provide in-depth scientific expertise and achieve under rapidly accelerated timelines the development of cost-effective, robust, reliable processes that consistently yield high-quality products.  

Until recently, most pharmaceutical firms were not interested in the development of small-volume drugs due to fears of limited returns. With the age of the blockbuster drug now history, many drug companies are finding that niche therapies, particularly those that may treat numerous indications, not only provide patients with life-saving medications, but also realize attractive financials if developed in a streamlined and cost-efficient manner. There are over 7,000 different types of rare diseases and disorders, yet only a couple of hundred approved therapies designated as orphan drugs. According to EvaluatePharma, although the average Phase III development time for orphan drugs is not shorter than that for non-orphan drugs, the Phase III drug development costs for the former are half those of the latter, and the anticipated return on investment for a Phase III/filed orphan drug is nearly twice that for a non-orphan drug.

As a result, EvaluatePharma estimates that the orphan drug market is growing at an annual rate of 11%, more than double that of the overall prescription drug market (5%), and by 2020 will reach $176 billion in annual sales and account for 19% of the total non-generic prescription market. In 2013 alone, 260 orphan drug designations were granted. In 2014, the FDA approved 15 NDAs and seven BLAs with the orphan drug designation, along with 24 supplemental approvals.

Many companies are also pursuing the new breakthrough designation established in 2012 by FDASIA, the Food and Drug Administration Safety and Innovation Act. A candidate qualifies for breakthrough therapy designation if preliminary clinical evidence suggests that the drug may have substantial improvement over available therapies on at least one clinically significant endpoint. The development and approval times for breakthrough therapies are typically half that of the seven years for conventional drugs, and both the sponsor and CDMO benefit from greater FDA guidance and communication with the agency. FDA’s CDER approved 14 breakthrough therapies in 2014 and nine in 2015 as of August 21. 

Of the firms pursuing the development of orphan drugs and breakthrough therapies, many are small or emerging pharmaceutical or biopharmaceutical companies focused on niche, small molecule therapies. These companies often have limited resources in terms of laboratory, analytical, and manufacturing equipment (indeed, some are virtual companies in that respect) and depend heavily on service providers to perform crucial process and formulation development, validation, regulatory compliance, and manufacturing activities. The choice of CDMO can therefore have a direct impact on the success or failure of the new drug.

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Continuous Tableting (CT) is defined as continuous manufacturing of oral dose drugs, specifically tablets. As per ICH's Q13 definition1, a continuous manufacturing process in the pharmaceutical industry comprises at least two unit operations integrated from a mechanical and software perspective. There is a wide combination of possible CT process configurations that are dependent on the needs of the intended product formulation and each of the individual unit operations that constitute the process train can be continuous, semi-continuous, or batch processes. The typical manufacturing processes for tablet formulation are direct compression (DC), dry granulation (DG) and wet granulation (WG)2 - details on these manufacturing processes are beyond the scope of this article, so the interested reader is directed to relevant literature. The actual implementation of CT technology in a facility can broadly vary depending on the level of desired integration and automation. Process trains can be designed to be flexible and converted between multiple configurations (e.g. continuous DC, DG and WG), controlled by the end user from one single software and within a single clean room. The other possibility would be for subsections of the CT process to be divided into multiple clean rooms where inprocess materials are transferred between suites via a bin-to-bin approach (e.g. a granulation suite to prepare granules from raw materials followed by continuous DC (CDC) to blend the granules and produce tablets). The level of automation and instrumentation designed into the CT process (typically involving Process Analytical Technologies, PAT) can open the possibility to implement sophisticated control strategies. Key components of a control strategy that need to be considered for CT are material tracking and genealogy, knowledge of the residence time distribution (RTD), and in-process controls (spectroscopic and/or soft sensors based on process parameters). Holistically, these control strategy elements enable the implementation of a material diversion strategy to automatically divert out of specification material from the process. In their most advanced form, control strategies may also enable real time release testing (RTRt) of the final tablet drug product and reduce the off-line analytical burden and the number of operators needed to manage the process.   Read the full article at gmp-journal.com  

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