ABSTRACT: This article, which is Part 2 of the series on continuous manufacturing focuses on the challenges still open to CM after the publication of ICH Q13 Guidance document and how CM could contribute to in-shoring back to US.
Challenges still open to CM
Guidance like ICH Q13 will no doubt be helpful to the industry in terms of implementation of CM, but the industry still faces a critical adoption challenge. Q13 is focused on the "what" not the "how," which is what manufacturers want to see to allow for product-, modality-, and company-specific approaches to be taken. In the Q13 document, there is less prescriptive information on "exactly how to do", or "why not to do", hence this format can delay implementation within some companies. The guidance is also focused on topics which are unique to CM, but not necessarily complementary or enabling technologies unless they are unique to CM.
Some items like process analytical technology (PAT), modeling, and in-depth discussion around continuous process verification are not in the scope of this document. However regulatory harmonization in some of these areas is crucial for full implementation of CM. However, for a lot of companies, it will take a lot of time, effort, and focus to develop the personnel and systems necessary to reach the level of process understanding and control required for successful implementation of CM.
In terms of control strategy, CM processes ask for a continuous control of attributes and parameters throughout the lifecycle, through an in-depth understanding of process dynamics, detailed material characterization, advanced process modeling, monitoring, controls, and much more. Control strategies optimized for stepwise batch processes will be very difficult to translate directly to CM methods. They would need to develop the strategy and data structures needed to control such advanced manufacturing methods through a multi-disciplinary approach involving people, processes, systems, and facilities. 1
Within Q13 there is very little guidance on process transfer and equivalency for CM processes.2 The guideline does address scale-up, but primarily from the standpoint of utilization within the same process train, or a "like-for-like." It doesn't really address process or equipment changes. When considering the same situation for traditional batch manufacturing, there are guidelines like scale-up and post-approval changes (SUPAC) guidance that aid in identifying levels of change and associated chemistry, manufacturing, and controls (CMC) changes. Given the similarity in design and operating principles of continuous direct compression manufacturing trains and processes, it would benefit the adoption if the requirements for changing equipment or manufacturing site were outlined. Regarding network strategy, many early adopters have sought to minimize differences and to invoke a "like-for-like" strategy as outlined within the scale-up portion of ICH Q13. this type of strategy limits the opportunities to make changes based on lessons learned or improvements available in the market. Although there has been a push for modularity within CM systems in recent years that has been mostly embraced by equipment manufacturers, which would make it easier to modify systems to be more similar, additional guidance on equivalency would help provide clarity and ease the perception of the need for like-for-like systems. The like for like approach makes life more complicated for CRO/CDMO's as there is no way they can have a like for like or very similar systems for multiple customers.
CM - An opportunity for In-shoring?
Provision of a continuous supply of affordable, safe, and effective pharmaceutical products, particularly those defined as "essential medicines" by the Food and Drug Administration (FDA) is a national imperative as evidenced by one of the first executive orders of the Biden administration to strengthen domestic supply chains.3 74% of all active pharmaceutical ingredients (APIs) and 54% of all finished dosage form (FDF) human drug products were manufactured at facilities outside the USA.4 In Nov 2023, with 1...
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