USFDA has sought feedback on Distributed and Point-of-Care Drug Manufacturing. It makes the following statement for Distributed and POC Manufacturing (1). Focus of DM and POC is US based. Perspective and comments presented are my own and not influenced by any profit and non-profit making organization.
“Pharmaceutical manufacturers have generally produced drugs at large fixed-location facilities, but some are now developing smaller, mobile drug manufacturing processes that can be deployed to multiple locations, including at the point of care, such as at a hospital or clinic. These novel distributed manufacturing (DM) and point-of-care (POC) manufacturing technologies have the potential to improve the reliability and robustness of the drug supply chain. The U.S. Food and Drug Administration is keenly interested in these technologies because they could potentially provide flexibility for drug manufacturers to enable rapid and localized response to changing demand and increase timely access to quality drugs for U.S. patients.”
Underlying question is that using FDA’s current review and approval scenario how much time it would take to set up and fill the “rapid and localized response”. What would be considered reasonable and who is going to be held accountable? There are questions and comments that need to be addressed/considered.
1. Has USFDA considered and reviewed the patient volume need for such manufacturing and distribution in USA from company’s business perspective? It is critical that it be done.
2. Who would prioritize the drugs and their quantities? Who would manufacture the prioritized drugs? What would it take? What if due to lack of profitability no company wants to produce the drugs. What has FDA done or do to expedite availability (2,3) of the needed products?
3. What has USFDA done for the companies to facilitate avail such business opportunities i.e. has it simplified its approval processes from multiple years to few months (2,3)?
4. DM and POC opportunities have existed for a long time. What has stopped companies from capitalizing on such profit making opportunities? Is it the regulations or the investment each company has to make for each specific drug (limited volume) for them to have sufficient return?
5. Since there are not very many generic API production facilities in US, DM and POC business opportunities will be limited. Has USFDA considered this limitation? Approval times and regulations will have to be simplified (2,3).
6. For the brand drugs (API and their formulation) being produced in US, why would the companies not use their existing facilities to serve the DM and POC needs. No additional manufacturing plant would be needed. No one wants to have additional “white elephants” that will be used sparingly (4). This holds true for the generic drug producers also.
7. Cost of drugs produced at USA located DM and POC will be higher than the current prices. This will be due to higher overall costs compared to China and India and PBMs (pharmacy benefit managers) and associates wanting to retain their profit margins. Only direct distribution to patients would lower prices (5). PBM et.al. will strongly oppose such move. Alternate business models and proposals discussed (6) can be searched (key word: alternate business) and need to be considered.
8. Based on review of the discussion paper for DM and POC post (7) it seems that the filing and approval requirements for even for limited quantity DM and POC business would be the same as they are for the current NDAs and ANDAs. This will be an obstacle as the drugs will not be available when needed, even in emergencies. Drugs could be available by bringing DM and POC manufacturing home. This could be done by significantly reducing NDA (new drug application) and ANDA (abbreviated new drug application) approval times. Pathways are available (2,3). It is recognized that drug safety and efficacy cannot be compromised but to bring pharma manufacturing home approval time reduction is critical. Companies need to be held responsible and if do not comply there could be business consequences.
9. Pharmaceutical companies who want to establish manufacturing facilities in USA and participate in DM and POC or any similar opportunity, based on the current landscape, will have to internally prove their innovative methods (e.g. continuous or modular or mobile (8, 9) ) to assure the product quality will be as designed. They will be challenged for time to commercialize as each process will have to be proven internally and then to USFDA. This would pose an enormous burden on acquiring experienced chemists and chemical engineers and time. Brand companies due to patent expiry time limitations do not have the time for such process developments unless they start such effort from the onset (9). Batch processes will stay as the routine method. To use continuous or mobile processes business model change would be needed (9) and need to be considered Generics will have to review their short and long term business model for each product but will be similarly challenged. Another serious question of confidentiality will be there and it is why FDA personnel should be taught the details of confidential chemistries and methods as long as the company guarantees quality product.
10. Introduction of every new processing method at companies and USFDA, based on recent six years needed for Continuous Direct Compression (10) from FDA, suggests that innovation incorporation at companies will be a tough sell internally and no company will innovate. Every process could include different unit operations and that means it will delay approval. Companies do not have such time luxuries. Question is why the companies have to go through such processes if they guarantee product quality and consistency and have fast approvals of NDA and ANDA. Companies innovate but teaching USFDA the technologies they use should not be needed. Product quality , efficacy and consistency should the underlying requirement.
If USFDA can address, simplify and shorten its processes (2,3) not only it will make Distributed and Point of Care manufacturing possible but also would set an environment to bring pharmaceutical manufacturing home, comply with the Executive orders (11,12, 13) and alleviate shortages. This along with direct selling to patients will lower drug prices. All this will require an alternate business model that could lead to “net zero emissions” in pharma (15). However, to these to happen two entities (USFDA and PBMs) will put significant resistance (5,14).
Girish Malhotra, PE
EPCOT International
References
1. FDA Seeks Feedback on Distributed and Point-of-Care Drug Manufacturing https://www.fda.gov/news-events/fda-voices/fda-seeks-feedback-distributed-and-point-care-drug-manufacturing October 14, 2022 Accessed November 15, 2022
2. Malhotra, Girish: Can the Review and Approval Process for ANDA at USFDA be Reduced from Ten Months to Three Months? Profitability through Simplicity, March 25, 2017 Accessed November 10, 2022
3. Malhotra, Girish: What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days? Profitability through Simplicity, October 24, 2018
4. Benchmarking Shows Need to Improve Uptime, Capacity Utilization, Pharmaceutical Manufacturing, September 7, 2007 Accessed November 12, 2022
5. Malhotra, Girish: Improving Drug Affordability for the United States Populous through Alternate Business Models, Profitability through Simplicity, May 4, 2018, Accessed November 10, 2022
6. Malhotra, Girish: Profitability through Simplicity Accessed November 14, 2022
7. Distributed Manufacturing and Point-of-Care Manufacturing of Drugs, Discussion Paper, October 18, 2022 Accessed November 4, 2022
8. Continuous production Cambridge Dictionary, Accessed November 19, 2022
9. Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter.com Accessed June 10, 2022
10. ETP Graduates its First Technology February 22, 2022 Accessed November 16, 2022
11. Executive Order 13588 Reducing Prescription Drug Shortages, October 31, 2011, Accessed August 31, 2020
12. Executive Order 13944 https://www.govinfo.gov/content/pkg/FR-2020-08-14/pdf/2020-18012.pdf Accessed April 26, 2022
13. Executive Order on America’s Supply Chains https://www.whitehouse.gov/briefing-room/presidential-actions/2021/02/24/executive-order-on-americas-supply-chains/ Feb. 21, 2021 Accessed May 30, 2022
14. Malhotra, Girish: Innovation in Pharmaceuticals Manufacturing Technologies, Distribution & Regulations: Are they Easy or a Challenge? Profitability through Simplicity, September 26, 2022 Accessed November 10, 2022
15. Malhotra, Girish: Climate Change and Greening of Pharmaceutical Manufacturing Profitability through Simplicity January 24, 2022 Accessed November 15, 2022