Improving Manufacturing Efficiency Requires Regulatory Reform

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CPhI expert, Girish Malhotra, warns that without urgent regulatory reform, the industry would remain reluctant to make process changes that will improve manufacturing efficiency due to the financial and time constraints of re-approval.

CPhI Worldwide, organized by UBM EMEA, has launched the first part of its annual report, in which CPhI expert and president of Epcot International, Girish Malhotra calls for a radical solution to improve pharmaceutical manufacturing processes. The current framework, despite its emphasis on quality by design (QbD), does not breed a culture of continuous improvement because of the regulatory hurdles imposed.

According to Malhotra, the industry should be allowed to commercialize process improvements (whether it’s yield, process/operating conditions, operating parameters, or cycle time) in the manufacture of approved APIs and their formulations without regulatory re-approval. It is the responsibility of the manufacturer to provide guarantee that the changes will not affect product efficacy and performance.

If these quality standards are not met, Malhotra suggested a stipulation that the company proposing improvements will be barred from making the product using the alternate process for the next two or three years. And if the same company decides to use the alternative process in future, it will have to go through the full re-approval process. He added that minor changes that do not change the current filed processing methods will be excluded, and this condition will apply to OTC, branded, and generic drug products.

The Code of Federal Regulations Title 21 (21CFR314.7) was established by FDA to provide assurance that there is no deviation, by the manufacturer’s choice, from the manufacturing methods and practices that have been filed for the components involved in the production of any drug on the market. The regulator requires every change to be reported and as a result, companies are reluctant to make process changes even when the benefits for finished drug and patient are clear. This is because of the financial and time constraints involved in implementing any process changes.  


Malhotra commented in the CPhI annual report, “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 becomes a natural part of the process development before a process is commercialized. But after the fact, process change is extremely difficult.”

He stressed that a new regulatory regime is needed to encourage process improvements. According to him, this will be a huge step forward for the industry but he is confident that the risks will be outweighed by the benefits achieved from improving manufacturing efficiencies-such as cost reduction, improved profits, and a larger customer base. He admitted that his proposal may come across as audacious but said, unless such bold steps are considered, change in unlikely to happen in pharma’s manufacturing methodologies.

The full article can be viewed online and will be featured within the CPhI annual report, which is to be released at CPhI Worldwide 2015 in Madrid, October 13–15.