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Wednesday, October 16, 2019

Are US FDA 483 Citations a "Medal of Honor" or “Rite of Passage” to Disgrace for the Pharma companies?

Lately frequency of FDA 483 (1) citations for companies from China and India have increased. Should they be considered a badge of honor for making the elite club or sign of poor management? Conclusion depends on reader’s perspective. Perspective presented here is mine and there is no financial or any other obligation with any educational/commercial or regulatory body.

To each engineering purist and practitioner every process’s design and practice are execution of precise science. Defined practice results in repeatable quality product. Any deviations will result in off-specification results. Corrections to produce quality are expensive and negatively impact financial results of every operating company. This is a known fact and does not need to be repeated over and over again.

Getting a 483 citation is telling of mindset and culture of every manufacturing company. It is an indication that they have difficulty living up to their commitment they have made to the regulators and their shareholders. They also tell everyone that their manufacturing and product quality has issues and every element of the manufacturing process needs attention. Without crossing every “t” and dotting every “i” they will suffer on an ongoing basis. Corrective actions are needed for their mind set, thought process and execution of their strategies. All this might seem demanding and difficult but would be needed for their longevity. Corrective effort is needed. 

As they say it takes two to tango. My conjecture is that manufacturing companies and the regulators are equally responsible for 483 citations. For product quality each has a role to play. Best is to start with the regulatory approval process as it defines expectations for the product quality and manufacturing behavior. 

Current ANDA Filing Process:

FDA’s current ANDA approval process is cumbersome and iterative at best. FDA might believe that it has a simple and precise filing and approval process but unfortunately the overall process is long and expensive. Since it takes few multiples of 90 days to get an approval, everyone calls the process burdensome and festered with “continuous back and forth busy work”. Simply, I call the current process a “Quality by Analysis (aggravation)” exercise. USFDA needs to simplify the process, define a clear road map and directions to facilitate the process (2,3,4,5). FDA has been preaching companies to practice QbD (quality by design) but it cannot follow it. They have to practice if they want companies to follow (6). Once such practice is put in place, my hope is we will see increased competition and significant drug cost reductions. 

Manufacturing Company Obligation:

Generally ANDA approval process demands manufacturing company using FDA instructions detail what and how it intends to manage and control every nuance of their manufacturing process, product quality as well as the needed paperwork. It is company’s moral as well legal obligation to abide by all of its commitments that are spelled out in their ANDA application. 

If any company for any reason does not and cannot follow its commitment outlined in its ANDA, regulatory body should not be suggesting repeated “voluntary corrective actions (7)” but issuing “official action (8)” to stop manufacture and shipments. Prolonged voluntary actions and ensuing corrective action delays suggest that the company is playing with the regulators. In addition, I believe regulators are also hesitant to make hard decisions. 

My conjecture is that 483 citations should not happen at all if company clearly knows and understands its manufacturing process, all of its nuances and files all of the necessary information from the get go for regulatory approval. Process centricity at companies is the key for a robust process (9)

It is very possible that FDA personnel due to lack of manufacturing experience might not understand technology innovations. Companies might have to prove their value to FDA. Companies know more about their process than the regulators. I believe repeat product quality from such processes should be proof enough. 

Since the ANDA filing and approval process is long, a blatant question needs to be answered. Does FDA have people who have hands on chemists and engineers who understand nuances of manufacturing. Can they lay out necessary and simple road maps for ANDA filings? If not, the ANDA approval process will remain flawed and prolonged like we have.                

Can 483s be Minimized/Avoided?

Answer is unequivocal YES. If I was running a pharma company and received a 483 citation, it would be the most humiliating thing happened. This would be totally unacceptable as we failed to live to the commitment made. To avoid 483s from happening again, situations that led to citation have to be corrected. This would include a complete review of products, their process design, manufacturing practice, equipment design and production scheduling. Their batch process instructions have to be reviewed and everything has to be electronically recorded and monitored. Process might sound stringent but is necessary for continued success. 

I can see why these citations are happening. They could be combination of too many products being produced in the same equipment, scheduling, raw material, cGMP and personnel issues. Training might be an issue also. Equipment upgrades might be necessary and that could be a financial strain. Operating strategies and methods have to be reviewed. 

Based on my experience if a company does not have control of its manufacturing process and related actions, the process will deviate from its established norms. These deviations will show up in its paperwork no matter how much effort is made to conceal them. This is normal. 

Companies have to be on top of their game 24x7x50 hours per year. They have to be held responsible and accountable for every processing step. Product quality is serious business especially in healthcare. “C” and “E” levels at every company understand the ramifications of less than quality. 

Companies have to bear financial consequences of repeat 483s and their shareholders should question company’s management on a corrective action schedule. If I were a regulator, after the first 483, I would recommend Official Action be taken against the site. Only then companies will understand that product quality is critical for their own ongoing existence. 

Unless regulators take a tough stand, I just don’t see much changing. To companies repeat (1) 483s are just a game of “cat and mouse” as they can get away with minimum compliance. 483’s now are Medal of Honor. 

Girish Malhotra, PE
EPCOT International

1.     Frequently requested or proactively posted compliance records, FDA.gov, October 14, 2019 
2.     Malhotra, Girish: What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days? Profitability through Simplicity, October 24, 2018
3.     Malhotra, Girish: ANDA (Abbreviated New Drug Application) / NDA (New Drug Applications) Filing Simplification: Road Maps are a Must, Profitability through Simplicity, Amy 11, 2017
4.     Malhotra, Girish: Simplified Roadmap for ANDA/NDA Submission and Approval will change Pharma Landscape, Profitability through Simplicity, November 25, 2018
5.     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
6.     Malhotra, Girish: Impact of Regulations, Drug Manufacturing and Pharma Supply Chain (PBMs and allies) in Drug Shortages and Affordability Part 1, Profitability through Simplicity, March 9, 2019
7.     Volunteer Action Indicated, FDA.gov Accessed October 14, 2019
8.     Official Action Indicated, FDA.gov Accessed October 14,  2019
9.     Malhotra, Girish: Process Centricity is the Key to Quality by Design, Profitability through Simplicity, April 6, 2010

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