USFDA at least since 2013 (1) has been promoting use of advanced manufacturing technologies (AMT) and that includes “continuous manufacturing (CM) (2) for the manufacture and reduce shortages of drugs (3,4,5). It has held various conversations and even involved National Institute of Sciences (NAS). This report “Building Resilience into the Nation's Medical Product Supply Chains (6) is a disturbing as it suggests increasing reliance through foreign relationships.
FDA (7) has continued to convince the pharmaceutical industry to use advanced manufacturing technologies (AMT) but seems like no one is buying what it has been selling.
What are these technologies is not clear. Do AMT include manufacture of API along with their formulations or anything else? A clarification from FDA was asked from its CDER/OPPQ/Office of Policy for Pharmaceutical Quality. A very terse response was received “they will respond in several weeks”. This is especially enlightening and interesting when FDA has been touting to the world to adopt such technologies. If FDA is trying to promote adoption of better manufacturing technologies, it would be beneficial if they were more forthcoming in addressing asked questions.
Even after all the conversations and congressional hearings and claims that these will reduce shortages FDA’s effort that has not resulted in any progress in commercializing AMTs at the pharmaceutical companies. This basically suggests that this effort is not going anywhere. If after effort of more than five years and millions of tax payer dollars that have been doled out to universities and other institutions nothing meaningful has happened. It basically suggests that companies are not buying what USFDA is selling.
It is ironic that FDA wants companies to incorporate “continuous manufacturing (CM) (2)” but has not shared what is its understanding and definition. In the manufacturing world there is an established definition (2). It would be interesting how FDA’s definition compares with the established definition. It also needs to very clearly explain what does it call “drug manufacturing”. Is it just formulation of active pharmaceutical ingredients (API) or combination of manufacture of APIs and their formulations? We have to remember that without API there is not drug. It is just a placebo.
FDA has called formulation of certain cancer cure drugs (limited global population which means limited demand) as continuous processes (CM) (8). Involved companies formulate batch produced API to finished products. Since these products are formulated on stop and go basis i.e. batch production (9), the underlying question is why FDA distorting facts and calling these processes CM. Is it trying to convince the pharma industry that it needs to change its manufacturing practices? Justification and rationale are needed. Even press has been talking about CM (2) when they have no idea what it means.
Based on formulation and compaction technologies that have been commercial and are used to produce many products, question that needs to be addressed is “why the pharmaceutical industry has not adopted established (more than fifty years) technology “en masse”. Is it lack of experience, business model or regulatory interference or being comfortable and profitable with quality by “analysis paralysis” processes?
It is a well-known fact that industry invents drug products. New and/or existing technologies and methods are used produce quality products. However, FDA’s telling the industry that new technologies need to be approved (10) before they can be implemented is a deterrent for brand and generic drug industry. No one knows what these technologies are. businesses. With FDA’s staff having minimal to no or minimal experience in product and process development, design and commercializing any drug molecule and their manufacturing processes, it would amount to further delays from the current times in brand and generic products. This is an un-necessary interference and oversight of a company. Question is how FDA will help.
Industry should be meeting the necessary drug performance criterion using the methods and processes it has developed, tested inhouse and would want to commercialize ASAP. Every product goes through three steps a) lab, b) pilot plant and c) commercial scale. This will be true for every product if it will be produced using a continuous process (2). Due to FDA staff’s limited experience suggested pre-approval review etc.(7) will result is further commercialization delays as they have no hands on experience of process development. This will result in further commercialization delays. If the industry does not see value in this effort they will not change their existing practices and/or consider any new technologies.
USFDA has to be very clear of the pathway it wants industry to follow to implement new technologies. FDA has to layout parameters/questions regarding the technology it wants to the industry to address along with a timetable. Goal has to be commercialization of drug in minimal time after its efficacy has been recognized by the pharma company and proven. Pathway for brand and generic drug will be different. There is big gap between FDA and industry as no headway has been made to improve manufacturing technologies. Industry has to recognize financial value and they do not see it as they are profitable.
Pharmaceutical industry would be enthusiastic and welcoming if products produced using better manufacturing technologies could be commercialized much sooner than the current times for NDA (new drug applications) and ANDA (abbreviated new drug applications). For that to happen the triumvirate (FDA, Pharma companies, and Pharmacy Benefit Managers (PBM)) have to change the current methods. My thoughts are a stretch and will face resistance from each. Most will come from FDA and PBMs. Pharma companies most likely would like them as they will lead to shorter time needed for commercialization i.e. higher revenues and profits.
FDA:
FDA when it comes to NDA and ANDA approval needs to eliminate every pre-approval meetings and that includes any new manufacturing technology introduction and use templates to get information it would consider necessary for their review and approval (11,12). These meetings are suggestive that the applicant companies do not know and/or understand what all is necessary for approval and they have to teach FDA what is the rationale and value of their innovations. Once FDA has the knowledge, it is possible that approval times could be reduced from current times (13, 14, 15).
Is FDA personnel due to lack of their experience in process development, scaleup and commercialization especially in “continuous” API and formulations using these meetings to further delay approvals. Basically this could be considered that FDA is learning on the fly what all is necessary for approval. FDA needs to create its expectation guidelines for every new (NDA) and existing (ANDA) drug each applicant company has to follow. These guidelines would be routinely updated so going forward companies. Assimilation of this suggestion will be difficult for FDA.
Pharma companies:
Pharma companies have to have every “t” crossed and “i” dotted when it is submitting information required by FDA for their NDA and ANDA as if they will consume first tablet that comes of the production line and their life depended on it. For continuous API manufacturing and their formulations it is very likely that pharma’s current manufacturing landscape would have to be changed (16, 17, 18). Companies would be challenged by FDA as they might have to familiarize FDA personnel with nuances of continuous manufacturing. Not having any process development, scale up and commercialization experience this can be a challenge. Chemists and chemical engineers will need company support, a challenge.
PBMs:
For Pharma companies to get excited about consideration and incorporation of newer and better manufacturing technologies, in addition to faster approval than current times, they should be allowed to direct market their FDA approved products by bypassing the formulary lists. Patient and physician should be deciding which approved drug they want to use. PBMs should not be interfering in patient’s life. Having a choice of drug would bring highest quality product at the best price competition to market. Competition is healthy and good for encouraged. PBMs are not required to meet quality standards. They should be held accountable (14).
Yes in the final analysis suggestions made here could be considered radical and not to the linking of parties involved. FDA has been going around with all sorts of permutations and combinations but nothing meaningful has materialized. It has not created an environment to innovate. Pharma industry has ignored FDA’s suggestions. PBMs have no interest in reducing shortages. Unless the accountability is shared by each party involved, US drug system (manufacturing, approval and distribution) have and will limp along and patient will continue to suffer.
Path forward:
With FDA’s effort of more than eight years, no progress has been made to incorporate proven better manufacturing technologies used elsewhere in API manufacture and their formulations. Pharma manufacturers are comfortable with the current methods that have been in use from 1940-‘50s as they are profitable (18). PBMs have no interest in what manufacturing methods/technologies are used as they just sell/distribute drugs to patients at their partial monopoly prices. Shortages have become way of life. An outlier approach is needed if we want to reduce shortages and include better manufacturing technologies.
FDA could promote the modified filing process with a stipulation that companies will have faster approvals than the current times i.e. higher profits. As part of the buy in for shorter approval time, FDA could use its legislative clout and bypass the current marketing channels i.e. formulary constraints. Manufacturers would offer the drugs to patients through alternate channels. PBMs will resist these suggestions as their stranglehold on generic markets would be influenced.
Suggested pathway should encourage generic manufacturers to invest in better manufacturing technologies i.e. continuous API manufacturing and their formulations. If FDA’s test with generics is a success, it could be extended to brand drugs. Yes brand drug product and process information requirements for approval will be different but the current logjam of slow action will be broken.
FDA would need to start the approval simplification process by creating templets that detail information needed for approval. Creation of information asking templets (14) could be test of FDA’s internal knowledge and competence. There could be significant internal resistance as the review and approval methods would change. FDA’s pre-meetings etc. would have to be curtailed. This would place the onus of convincing FDA to grant the approval. Companies have more to lose if they do not receive timely approval. Such a change is needed if we collectively want to simplify the age old process. To implement the suggested change FDA may have to avail congressional help, if necessary.
Companies may include additional information, some of it could be redundant. Excess of submitted information may help the approval process. In the proposed process FDA personnel will still have an opportunity to ask for additional information (14)to complete the review resulting in grant and/or denial. Review and grant process will have defined time window. Once ANDA is approved certain restrictions could be placed on the filing company i.e. it cannot transfer the approved ANDA to any other profit making company in the next twelve months and it has to produce the product for sale in USA within 1-4 months of the approval. Success with generics could be applied for brand drugs.
Since companies will have FDA decision in a finite time rather than unknown time, they should be enthusiastic about the suggested process. They would be able to commercialize their manufacturing process innovations and get a better return on their investment. Yes in the final analysis suggestions made here are radical and may not to the liking of some involved.
FDA and US Congress have been talking and making noise but no solution has been proposed. As suggested earlier chemical engineers are not practicing unit processes (19) and unit operations (20) they have been taught to the fullest extent. The process outlined (16, 17,18) will allow them to incorporate them and create excellent processes to produce quality products. It is time pharma manufacturing comes of age.
Product and manufacturing process technology innovation comes from pharma companies. They do their first part but as said earlier dur to profitability they have lagged on the second part. Unless responsibility to reduce shortages is shared by each party involved, US drug system (manufacturing, approval and distribution) will continue to limp along and patient will suffer. It is time to consider better alternate processes to reduce shortages that include better manufacturing technologies and alternate drug distribution model. We have the minds and chutzpah to excel. Time is now.
Girish Malhotra, PE
EPCOT International
References:
1. Strategic Plan for Preventing and Mitigating Drug Shortages Accessed March 31, 2024
3. TESTIMONY OF JANET WOODCOCK, MD December 10, 2019
4. Agency Drug Shortages Task Force October 30, 2019 https://www.fda.gov/drugs/drug-shortages/agency-drug-shortages-task-force
5. Malhotra, Girish: Identifying the Root Causes of Drug Shortages and Finding An Enduring Solution, Profitability through Simplicity, December 7, 2018
6. Building resilience into the Nation’s Medical Product’s Supply, National Academy of Scienceshttps://nap.nationalacademies.org/read/26420 Accessed April 22, 2022
7. Advanced Manufacturing Technologies Designation Program, Guidance for Industry, December 2023 https://www.fda.gov/media/174651/download
8. Malhotra, Girish: Batch, Continuous or "Fake/False" Continuous Processes in Pharmaceutical Manufacturing,Profitability through Simplicity, July 20, 2017
9. Batch Production https://en.wikipedia.org/wiki/Batch_production
10. Lifecycle of an Emerging Technology Program (ETP) https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/lifecycle-emerging-technology-program-etp
11. 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
12. Malhotra, Girish: What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days? Profitability through Simplicity October 24, 2018
13. Malhotra, Girish: Strategies to Increase Generic Drug Competition and Bring Manufacturing to The United States of America, Profitability through Simplicity, March 16, 2020
14. Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability, Profitability through Simplicity December 6, 2019
15. Malhotra, Girish: Roadmap to Reduce Drug Shortages Profitability through Simplicity October 30, 2023
16. Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability John Wiley & Sons, February 2011
17. Malhotra, Girish: Chapter 4 “Simplified Process Development and Commercialization” in “ Quality by Design-Putting Theory into Practice” co-published by Parenteral Drug Association and DHI Publishing© February 2011
18. Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation DeGruyter April 2022
19. Shreve, R. Norris: Unit Process In Chemical Processing, Ind. Eng. Chem., 1954, 46 (4), pp. 672–672
20. Unit Operation, https://en.wikipedia.org/wiki/Unit_operation , Accessed July 11, 2017
