Continuous Progress in Continuous Manufacturing
by David Koziel
As biopharmaceutical professionals, we are witnesses to an exciting time in drug and process development. With biosimilars on the rise, upstream process titers steadily increasing (10- to 100-fold since the 1980s) and downstream processing causing up to 80% of total process costs, a multitude of advanced manufacturing technologies recently emerged (see Figure 1) [1-3]. One particularly revolutionary advanced approach spanning all topics in Figure 1 is continuous manufacturing (CM) of biopharmaceuticals as an alternative to traditional batch manufacturing.
The common batch manufacturing approach for a recombinant protein features multiple discrete steps usually followed by a hold time for storage or offline testing before the following unit operation commences. CM eliminates these hold steps by continuously feeding material into an assembly of fully connected (“integrated”) unit operations, promising reduced overall processing time, facility footprints, probability of human error and increased flexibility in responding to changing market demands.
However, the pharmaceutical industry is slow in embracing CM and other emerging technologies. For one, this is due to uncertainties regarding process economics [7, 8]. Another issue being called out by manufacturers is the absence of proper regulatory guidance and incentive as well as a lack of standard approaches and harmonization among regulatory agencies [9, 10]. To encourage the adaption of innovative technologies FDA, EMA, and PMDA each declared their backing of innovative manufacturing and established expert teams serving as primary points of contact for manufacturers:
• FDA Emerging Technology Team
• EMA Process Analytical Technology (PAT) Team
• PMDA Innovative Manufacturing Technology Working Group
Regulators worldwide therefore show considerable initiative on boosting the advance of CM, as is also evident in the approval of five products manufactured via continuous processes since 2015 – all products so far being small molecules, however . To support biotech manufacturers, EMA issued a guideline covering enhanced approaches of process validation and required regulatory data for biotechnology-derived products in 2016 . The agencies further agreed to work on new ICH Q13 “Continuous Manufacturing for Drug Substances and Drug Products” and ICH Q14 “Analytical Procedure Development and Revision of Q2(R1) Analytical Validation” Guidelines – both due in 2021 – to lay the path for advanced technologies with guidance on definitions, on control, validation and regulatory requirements and on the use of modern analytical technologies like Near Infrared (NIR) and Raman spectroscopy as well as concepts like Real Time Release Testing (RTRT) and Quality by Design (QbD) [13, 14].
Even more, on February 26th, 2019 the FDA issued a draft guidance entitled “Quality Considerations for Continuous Manufacturing” covering several central topics concerning CM, e.g. by addressing important definitions of process dynamics and batches, control strategies and process validation. However, in line with the products approved so far, the FDA’s guidance has a strong focus on small molecules. Therefore, while the way is being paved for CM in general, we very well might have to wait until 2021 for definitive ICH guidance regarding biopharmaceuticals.
It remains to be seen if the first continuously manufactured therapeutic recombinant protein will be approved before or after the availability specific biologics guidance. Either way this will mark the next revolutionary milestone for biopharmaceuticals, and we await it excitedly.
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