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 128 drugs facing a shortage, the House Committee on Oversight and Accountability requested a staff-level briefing on how to better understand the FDA's response and mitigation strategies to improve and sustain the supply of high quality, life-supporting medications available to Americans.5
In general, pharma industry has a general tendency to lag in advanced manufacturing technologies. Drivers of this include a strong bias toward processes with longer industry track records and low-cost manufacturing solutions. Considerable reliance on foreign pharmaceutical manufacturing that depends predominately on decades-old batch processing technology, which is cheaper but less automated and more difficult to scale production, which quickly raises serious concerns regarding the uninterrupted delivery of high-quality pharmaceutical products in the future. Other factors at play in determining whether to manufacture pharmaceutical products in the US or abroad include corporate taxes, differential labor and manufacturing costs, regulatory and environmental costs, and foreign exchange hedging expense. Differential costs of production have been widely referenced as a primary reason for the loss of US manufacturing over the last several decades. The ascendancy of China as a major manufacturing hub over the years was accomplished in large measure by much lower labor, land, and capital costs as well as more relaxed environmental regulations. Wage and cost pressures over time, however, have reduced the China cost advantage in recent years to a slim 4% lower cost of manufacturing compared to the US.6 This shift in overall manufacturing competitiveness along with the potential of more automated technologies such as CM that require smaller plant footprints could encourage more pharmaceutical manufacturing in the US.
A study6 examining the risks and economics associated with investing in CM versus conventional batch manufacturing for production of Oral Solid Dosage pharmaceutical (OSD) products in the USA and abroad was performed. The stochastic Net Present Value (NPV) simulation of brand and generic manufacturing for new facilities was conducted comparing batch and continuous manufacturing processes leveraging actual industry financial revenue and cost information and detailed engineering cost information of batch and CM manufacturing processes from a seminal manufacturing cost analysis of these two technologies. The results clearly suggest that the lower costs associated with CM technology should lead to both brand and generic companies investing in the more CM manufacturing technology. The simulation analysis demonstrated that under current U.S. tax rates, investing in batch technology at US sites would be economically more attractive than investing in batch technology in China or India. Investing in CM technology in the US under current tax rates results in positive expected net NPV's over batch technology investments in China or India for both brand and generic companies. The US tax policy has a material impact on whether pharmaceutical companies would decide to invest on the USA or not for their manufacturing.
Trout and colleagues from the International Symposium on Continuous Manufacturing of Pharmaceuticals published a paper7 in the Journal of Pharmaceutical Sciences outlining benefits of continuous drug production, including enhanced domestic supply to improve national security. The authors advocate for tax incentives for investing in continuous manufacturing and an expedited approval process for drugs made with continuous processes.
However, we need to be realistic that one cannot expect the US to suddenly become self-sufficient.8 Nor is it realistic to think that drug supply stretching back to basic raw materials can be quickly repatriated. It would take a decade or more, if at all. The call for increased US supply chain security as advancing an ongoing effort rather than a fundamental change. Also, what we could see more realistically, is not a replacement of the supply chain but an augmentation. For API manufacturing, not all chemistries lend themselves to CM. The most successful organizations have taken a hybrid approach and used CM where it makes sense. Flow chemistry-based CM, would be a key component to making US production cost competitive.
1. Sana Ahmad, With ICH Q13, will continuous manufacturing break through? qbdvision.com, 9th March 2023
2. Gabriella Dahlgren et al. ICH Q13 and What Is Next for Continuous Manufacturing | Pharmaceutical Engineering (ispe.org), July / August 2023.
3. Hahn SM. US Food and Drug Administration, FDA publishes list of essential medicines, medical countermeasures, critical inputs required by Executive Order, FDA Statement. 2020.
4. US Government Accountability Office. Testimony before the Subcommittee on agriculture, rural development, food and drug administration, and related agencies, committee on appropriations, house of representatives, statement of Mary Denigan-Macauley, director, health care, drug safety FDA's future inspection plans need to address issues presented by COVID-19 Backlog. 2020.
5. Comer J. McClain L. Letter (PDF) to FDA Commissioner Robert Califf. November 2, 2023.
6. Clifford V. Rossi, A Comparative Investment Analysis of Batch Versus Continuous Pharmaceutical Manufacturing Technologies, Journal of Pharmaceutical Innovation, 17:1373-1391, 2022.
7. Why we need continuous manufacturing and how to make it happen. Journal of Pharmaceutical Sciences, Vol 108, Issue 11, p: 3521-3523, Nov 2019.
8. Chemical & Engineering News, Bringing drug production back to the US, Volume 98, Issue 25, June 2020.
ABOUT THE AUTHOR
Deepak Hegde, Ph.D., M.F.M, is an industrial pharmacist by training. He has a been involved in development and commercialization of both innovative and generic drugs from a very early phase of development to technical transfers for commercial manufacturing sites, for the past 25 years. During his career, he has worked at Rhone Poulenc, Novartis (Sandoz), USV Ltd., WuXi AppTec, GSK & EOC Pharma. He is currently working with Shenzhen Pharmacin Co. Ltd. as Senior Vice President-Technology & Manufacturing.
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