All opinions are my own.

Friday, August 7, 2015

Impact of 21CFR 314.70 on The Life of a Pharmaceutical Manufacturing Process

Regulations are necessary for quality assurance of drugs. FDA established 21CFR314.70. It is a very important rule. It assures that there is no “by manufacturer’s choice” deviation from the manufacturing methods and practices that have been filed for the active pharmaceutical ingredient (API) and their formulations, labeling and packing etc.  

My interpretation of 21CFR314.70:

21CFR 314.70 calls for reporting any changes that have been made in anything to do with production of a saleable pharmaceutical product and that includes API. Changes include process method or operating conditions, operating parameters, equipment or test methods etc. Their impact on the drug efficacy and performance has to be assessed by the drug producer. Basically the idea is the producer has to assure that the efficacy and performance of the drug does not change from the approved product.  

I call this regulation an opportunity if the pharma companies want to have the best of the technologies to maximize their profits and increase their patient base. To achieve an effort or lets call a different thinking would be needed. Since it would be different from the current thinking, many would say, “Can’t be done.” That would be considered normal.

21 CFR314.70 encourages “continuous improvements” in the processes that will create the best product for clinical trials and that’s the way it should be. QbD (quality by design) becomes natural part of the process development before a process is commercialized. However, in my estimation all this has to be done prior to going to clinical trials. Benefits will be infectious.  

The Simplest and the Difficult Part:

Reporting part of the regulation is the simplest of the change exercise. However, section 314.70 (2) specifically asks “holder of an approved application…. must assess the effects of the change before distributing a drug” and it is the difficult part. 

This CFR asks for assurance that the process changes have not altered the performance and efficacy of the drug that has been approved by the regulatory bodies. In order to prove this aspect, company may have to re-do all of the necessary tests that were done including clinical trials to get the necessary approval. This would be like starting from scratch and can be an expensive and time consuming process.

Since changes can have a significant financial impact, unless there are compelling reasons and cost justification, no company would go through the change process and that includes continuous improvements. This is especially true for a brand drug due to its limited patent life after the drug has been approved. Generics could incorporate the best of the technologies and methods but due to competitive pressures to be the first to market, not sufficient time is spent to perfect what all is involved.

Thus, any process change after the drug has been approved is rather difficult. This inability has significant ramifications. The biggest is no process improvements can be made on majority of the existing approved drugs for the fear of different performance, impurities and altered efficacy. Costs related to process inefficiencies are passed on to the patients, a sad and sorry consequence of the good intentioned regulation. Additional unfortunate part is that many of the drugs become out of reach of needy.

Other Side of the Coin:

Is there a solution to include the best methods? Yes there is and it is simple. As stated earlier normal reaction would be “can’t be done”.

Companies manufacturing APIs and their formulations will have to think and act differently. They have to give away their deep-rooted and imbedded traditions. Process development chemists and chemical engineers who would scale-up and eventually commercialize the products would have to get involved in the development process at an early stage. Every one involved would have to consider and imagine how the commercial processes would operate. In these initial stages the developers would need to review safety and environmental aspects keeping in mind how cGMP requirements etc. will impact asset utilization. There will be lot of learning and the knowledge gained would facilitate efficient process development.

It is normal in the laboratory to isolate intermediates and that is fine for a lab process. However, for a commercial process it would be necessary create a path where isolation is to be avoided. This is not normal in pharma manufacturing. Different thinking would be needed.

Manufacturing recipes exploiting sociochemicology of chemicals will have to be included to create the best processes. Chemical industry, pharma’s older cousin, has practiced these methods and they can be easily translated to produce API and their formulations.

FDA and EMA are issuing various guidances to cajole the industry to improve their manufacturing practices and technologies. Till the industry takes the steps to modernize their methods, not much will change. By the way using better analytical equipment is not process technology improvement, at least not in my book. To me it is like replacing a dull knife with a sharper knife.


Finally 21CFR314.70 latently suggests creating and having the best processes before clinical trials are the best option. Pharmaceuticals can vigorously incorporate process of “continuous improvements” in their API manufacturing and formulation processes before they go to clinical trials. They can very easily exploit “what if” scenarios to serve different levels of population. Such an analysis would allow them to best consider and incorporate batch vs. continuous (1, 2, 3) processes for API manufacture and/or formulations, an unprecedented opportunity.

In my analysis pre-21CFR314.70 thoughtful process development can be a tremendous win. Changes made after drug approval will increase workload for the companies and regulatory bodies and this makes changes difficult to incorporate at best. 

Girish Malhotra, PE
EPCOT International

  1. Malhotra, Girish: Why Fitting a Square Plug in a Round hole is Profitable for Pharma and Most Likely Will Stay? Profitability through Simplicity, http://pharmachemicalscoatings.blogspot.com/2014/08/why-fitting-square-plug-in-round-hole.html
2.     Malhotra, Girish: A Blueprint for Improved Pharma Competitiveness, Contract Pharma, Vol. 16, 7, Pg. 46-49, September 2014, http://www.contractpharma.com/issues/2014-09-01/view_features/a-blueprint-for-improved-pharma-competitiveness/   

  1. Malhotra, Girish: Continuous Process in Pharmaceutical Manufacturing: Considerations, Nuances and Challenges, Contact Pharma, June 2, 2015, http://www.contractpharma.com/issues/2015-06-01/view_features/continuous-process-in-pharmaceutical-manufacturing-considerations-nuances-and-challenges

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