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.
Recap:
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
President
EPCOT International
- 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/
- 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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