My perspective for Pharmaceutical Manufacturing Technologies/Processes and Continuous Improvements
Introduction
Regulations are necessary for quality
assurance of drugs. FDA established 21CFR314.70 (1,2) and 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 components involved in the manufacture of any salable drug – the active pharmaceutical
ingredient (API) and their formulation – and labeling, packaging etc. Every
change has to be reported. Drastic process changes are discouraged.
When there is a discussion about
pharmaceutical manufacturing generally only formulations are considered. API
manufacturing is ignored and it should not be. Without API there is no drug. 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. However,
in my estimation under the current rules all of this has to be done prior to
going to clinical trials. QbD (quality by design) becomes a natural part of the
process development before a process is commercialized. After the fact process
change is difficult.
Batch processes
Generally, most APIs and their
formulations are produced using batch processes. Existing approved products
require annual reporting of improvements/changes. Most of the changes are
minor. However, if the processes are to be revamped for process yield,
operating parameters and manufacturing
methods, they are going to be the biggest challenge as the efficacy of the API
and its formulations, especially prescription drugs could change. In my estimation
re-approval would be needed. This can be a monumental task, even for over the
counter drugs (OTC) not requiring prescriptions, because new monographs may
have to be established. Money and time investment would be necessary. Such
changes are major “continuous improvements” and deterrent for prescription
drugs.
Continuous Manufacturing
Continuous manufacturing for API and
their formulations is pharma’s new and least understood buzzword. In the annals
of chemical engineering and for that matter in any industry “continuous
manufacturing” means 24x7x50 hours of operation per year with pre-established
down time. There are few selected APIs (OTC or prescription) that can be
converted to continuous processes (3, 4, 5).
Totally different operational thinking/models
would be required. The use of existing manufacturing equipment and technologies
is very feasible.
Continuous processes for formulations
should have been commercialized over sixty years ago.
Manufacturing technologies and
equipment along with knowledge base for such processes have existed since, but
not incorporated. This is due to traditions of business and lack of application
of chemical engineering knowledge base to commercialize such processes.
Benefits and Challenges of Continuous
Improvement
Benefits of cost reduction, improved
profits and larger customer base due to improved manufacturing technologies are
huge and well documented. Best of the process technologies have to be created
before clinical trials. As we know “after the fact” improvements, under the
current regulatory environment, would not happen due to the financial and time
elements discussed above.
Only a “maverick company or creative
destructionist” can take on the task. Success would completely change the
pharma landscape. I am not sure if pharma related components and that includes
companies, legislature, vested interest groups, are ready for such an
evolution.
There will be microscopic examination
and doubts raised, forcing many delays even if the companies do the “right” things
based on excellent science and engineering.
Alternate Proposal
I would propose the following. I am
sure there will be plenty of scrutiny and naysayers – unless we take bold steps
not much changes. If there are alternate better ideas, let us discuss those
also. I propose that the pharmaceutical industry be allowed to commercialize
process improvements (yield, process/operating conditions, operating
parameters, cycle time) in the manufacture of approved APIs and their
formulations.
The manufacturing company will
guarantee that the product efficacy and performance, along with impurities, will
be better than the approved product produced by the company. There would be an
added stipulation that if for any reason product performance, efficacy,
labeling and impurities do not meet or are worse off from the approved product,
company proposing improvements will be barred from making the product using
alternate process for the next e.g. two or three years. If they do decide to
use the alternate process, they will have to go through the re-approval
process. Minor changes that do not change the current filed processing methods
etc. would be excluded. This would apply to OTC, brand and generic products
also.
I propose that the pharmaceutical industry
be allowed to commercialize process improvements in the manufacture of approved
APIs and their formulations – without re-approval
Unless bold steps are considered, very little will change in the current pharma’s manufacturing methodologies or anywhere, for that matter
Conclusion
I admit that my proposal is a bit bold
but unless such bold steps are considered, very little will change in the
current pharma’s manufacturing methodologies or anywhere, for that matter. If
incorporated in pharmaceutical manufacturing landscape, continuous improvements
and innovation could become a routine and it could be extended to the whole healthcare
industry. Wright Brothers did and so was the adventure of sending humans to
moon and bringing them back. A successful trek to Pluto would also fit the
category. It is time for the pharma industry to be bold. It has an opportunity to
add as much as 20% of the global population (~1.4 billion) to its customer
base, an unprecedented opportunity for any industry on the planet. Profits will
improve and healthcare costs can come done. It would be a win-win.
Girish Malhotra
EPCOT International
This was presented at CPhI Madrid October 2015.
References
1. CFR - Code of Federal Regulations
Title 21
2. Malhotra, Girish: Impact of 21CFR
314.70 on The Life of a
Pharmaceutical Manufacturing Process,
Profitability through Simplicity, http://pharmachemicalscoatings.blogspot.com/2015/08/impact-of-21cfr-314670-on-life-of.html
3. 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
4. Malhotra, Girish: A Blueprint for Improved
Pharma Competitiveness, Contract Pharma, Vol. 16, 7, Pg. 46-49, September 2014,
5. Malhotra, Girish: Continuous Process
in Pharmaceutical Manufacturing: Considerations, Nuances and Challenges, Contact
Pharma, June 2, 2015,
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